AIDS/HIV Treatment Directory Vol. 8, no. 3

Page  [unnumbered] - Compiled and Published by: 10M - D '010 --- N- CD9

Page  [unnumbered] This Edition of The AIDS/HIV Treatment Directory Made Possible in Part by: John M. LloydN. Foundation Los Angeles, California CLIMAX a Boulevard Boy Production Pride Weekend, NYC June 30, 1996 SPIRIT Aria Productions, Tracks 2000, and Brother Help Thyself Quilt Weekend - Washington, DC October 12, 1996 TRIBAL CONTEST AND DANCE Produced by the Organizing Committee of LEATHERMASTER NYC November 16, 1996 -PROPHECYProduced by Phoenix Rising White Party Weekend - Miami Beach, FL December 1, 1996 Special Thanks: HX MAGAZINE, NYC; INTERNATIONAL GEMMOLOGICAL INFORMATION, NYC and 12 GODS BENEFIT, Mykonos, Greece

Page  [unnumbered] When I tested HIV-positive in 1985, my doctor urged me to take control of my treatment. My doctor died of AIDS two years later, but thanks to AmFAR's Treatment Directory I'm still here and healthy. It's really comforting to know that the AmFAR Treatment Directory is there for you. You can use it to translate all the medical terms that you always forget by the time you get home from the doctor's office. And it's the best way to find out what the latest and most promising treatments are and how you can participate. I was one of the first people in the world to try the integrase inhibitor - which could be the next big AIDS drug - more than a year ago. AmFAR's Treatment Directory is the 'bible' for me and so many other people living with HIV/AIDS. Jim Sullivan Clinical Thial Participant, 1988, 1989, 1991, 1995, 1996 AmFAR Please accept the enclosed contribution of: l $15 D $25* 1 $50 l $100 l $250 Other $ *Your gift of this amount or more would be a tremendous help-- but for whatever you give, we thank you. NAME ADDRESS CITY/STATE/ZIP O Check O Amex O Visa Ei MC O Other ACCOUNT # EXP. DATE SIGNATURE P7T Please make your check payable to AmFAR and mail it in the enclosed envelope to American Foundation for AIDS Research, P.O. Box 96635, Washington, DC 20090-6635 Your gift to the American Foundation for AIDS Research is tax-deductible as a charitable contribution. FEDERAL EMPLOYEES: AmFAR qualifies for your payroll deduction plan, the Combined Federal Campaign. O Please send me information on being part of AmFAR's monthly giving program, "Friends of AmFAR." E Please send me information on planned giving and remembering AmFAR in my will. o E o c~oa) PI C3 a, ON CD) = O\ o CE 0j 0 LfH LI Cr = 0% =O 0 L.J 0 0) * Ir1. 0.

Page  [unnumbered] 0 I::i:-:::- 1 -::::::0;:: * E:: h b h hjO::_::~:--:: i~ll m_-:i o.E i~b*I 4i::i::-I:_ -i--:~i_-:Moisten gumed lap fod adsal

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Page  [unnumbered] SAMFAR SPONSORED I' PUBLICATIONS AIDS CLINICAL CARE Published monthly, AIDS Clinical Care provides the latest and most essential information on the clinical aspects of treating HIV-infected patients. The easy-to-scan newsletter format presents feature articles by leading AIDS clinicians, concise summaries from AIDS medical literature, and updated treatment tables for practical reference. U.S. rate (1st class delivery): $89.00, International (air delivery): $117. Please make payments to: AIDS Clinical Care, c/o Massachusetts Medical Society, P.O. Box 9085, Waltham, MA 02254-9085; or call toll-free: 1-800-843-6356. Please allow 4-6 weeks for delivery. AIDS/HIV TREATMENT DIRECTORY The most comprehensive source of information on approved and experimental treatments for HIV infection, opportunistic infections and other HIV-related disorders. Published twice a year, this unique resource includes up-to-date information on clinical trial results, open protocols and enrollment information, expanded access / Treatment IND programs, financial assistance programs and additional resources for HIV/AIDS treatment information. A subscription (payable by check, money order or credit card) in the U.S. or Canada is $55 for an individual and $125 for a physician or institution. For anywhere outside the U.S./Canada, an individual subscription is $77 (credit card) or $100 (check or money order) and for a physician /institution it is $150 (credit card) or $200 (check/money order). For credit card orders you may call 1-800-38-AmFAR. E YES, I want to subscribe to AIDS CLINICAL CARE. SU.S. Name j (1st class delivery) 2 U.S. $89.00 Sp 0Q Specialty Sc [- International SU " (air delivery) Address, vU.S. $117 City, Payment enclosed State Zip SBill me Country Credit Card Orders call toll-free: 1-800-843-6356 Please allow 4-6 weeks for delivery of your first issue. IXM01 Please check appropriate box. US/Canada (USD) S O $55 for Individuals: $125 for Physician/Institution International (Credit Cards Only - USD) O $77 for Individuals S O $150 for Physician/Institution S International (Check or Money Order - USD) O $100 for Individuals O $200 for Physician/Institution O E Payment enclosed Charge to my: O Visa 1 Mastercard O AMEX Exp. Date Card No. Signature Name Specialty Address City State Zip Country Please allow 4 - 6 weeks for your first issue.. WfMM I W0aWMW==Ma '-----w MmaaMW-------------WWWa----

Page  i AIDS/HIV TREATMENT DIRECTORY Compiled and Published By: AMERICAN FOUNDATION fOR AIDS RESEARCH (AMFAR) 733 Third Avenue, 12th Floor, New York, NY 10017 MEDICAL EDITORS Donald Abrams, M.D. Deborah Cotton, M.D., M.P.H. Martin Markowitz, M.D. Kenneth Mayer, M.D. ASSOCIATE MEDICAL EDITORS Constance Benson, M.D. Mark Jacobson, M.D. Jonathan Kagan, Ph.D. Donald Kotler, M.D. Joseph Kovacs, M.D. Susan Krown, M.D. Michael Lederman, M.D. Henry Masur, M.D. Justin McArthur, M.D. Joseph Wheat, M.D. VOLUME 8 NUMBER 3 January 1997

Page  ii This information is intended to be utilized as reference and resource material only. The American Foundation for AIDS Research (AmFAR) makes no representation, warranty or endorsement, express or implied, as to any of the information within this directory. Readers who wish to utilize any information in this directory should first consult a physician or other health-care provider. Readers are further cautioned that certain studies referred to in this directory which have been conducted without FDA approval and oversight may not have involved the same standards, criteria, monitoring procedures or protections that are required in FDA-approved studies. Any views and opinions expressed within any publication or other information source appearing in this directory are solely those of the individual author, authors, or other information source and do not necessarily represent the opinion of or any endorsement by the American Foundation for AIDS Research (AmFAR). The AIDS/HIV Treatment Directory is published by AmFAR's department of Clinical Research and Information (DCRI) EDITORIAL STAFF EDITOR-IN-CHIEF: ASSOCIATE EDITOR: PROJECTS COORDINATOR: COMPUTER SYSTEM / PRODUCTION: COMMUNITY LIAISON: DCRI ADMINISTRATIVE ASST. VOLUNTEER STAFF ADMINISTRATIVE: RESEARCH: PRINTING & FULFILLMENT: ELLEN C. COOPER, MD, MPH TIM HORN JOE GUIMENTO, MPA DON MOSCHBERGER CANDIDA SCOTT-PIEL PAUL DONAHUE DAN KRAUSS KEITH PHILLIPS, KRISTIN KLEIN BILL BYER, SKILLCRAFT GROUP SPECIAL THANKS TO AMFAR STAFF To Don, your simply the very best! Sue Doster for technical assistance; Raul Norman-Tenazas for the cover design; Jay Blotcher, Diane Boehm, and Teresa Coffey for copy editing assistance and William Figueroa for translation. Please direct all correspondences and address changes to: American Foundation for AIDS Research (AmFAR) 733 Third Avenue, 12th Floor New York, NY 10017-3204 Phone: 212/682-7440; Fax: 212/682-9812; E-mail: txdir@amfar.org POSTMASTER: Send address change (form 3599) to American Foundation for AIDS Research, 733 Third Avenue, 12th Floor, New York, NY 10017-3204 Copyright 1997 by the American Foundation for AIDS Research (AmFAR). All rights reserved. No part of this publication may be produced in any form or language without written permission from the Publisher. Volume VIII, Number 3, Published January 1997 Library of Congress ISSN 0898-5030 Printed in the United States of America

Page  iii The American Foundation for AIDS Research (AmFAR) is the nation's leading nonprofit organization dedicated to the support of AIDS research (both basic-biomedical and clinical research), AIDS prevention, and the advocacy of sound AIDS-related public policy. Since 1985, AmFAR has invested nearly $83 million in grants to 1,700 research projects. AmFAR mobilizes the good will, energy, and generosity of caring people everywhere to end the AIDS epidemic. With this issue, the staff of the AIDS/HIV Treatment Directory gratefully acknowledges the hard work and dedication of the many individuals who contributed whole-heartedly to its publication over the past ten years. To the study coordinators, nurses, doctors and adminstrative staff at the HIVIAIDS clinical trial sites nationwide, Thank you for taking the time to return our phone calls, answer our questions and respond to our clinical trial surveys. Thanks also to: AIDS Clinical Trial Information Service (1-800-TRIALS-A) and the AIDS Treatment Information Services; AIDSWATCH special giving campaign; Donald Abrams, M.D.; Moises Agosto; Keith Alcorn; Katheryn Anastos, M.D.; Bruce Anderson; Matthew Anderson; Will Anderson; Expodito Aponte; Kevin Armington; Duncan Arp; Alberto Avendano, M.D.; Abdel Babiker, Ph.D.; Cornelius Baker; John Baker; Ronald Baker, PhD; Walter "Chip" Baker; Matthew Bank; David Barr; Mike Barr; Ruthann Bates; Justine Beachley; Constance Benson, M.D.; Marc Berkley; Seymour Bernstein, Ph.D.; Gail Bolan, M.D.; June Bray, RN, MPH; Harry Brown; Bob Brown; Leonore Burts; Bill Byer; Canadian HIV Trails Network; Marissa Cardinale; CAREMARK, Inc.; Charles C.J. Carpenter, M.D.; Marcia Carlyn, Ph.D.; Mary Beth Caschetta; Center for Disease Control, Richard Chaisson, M.D.; Ardith Chang, Ph.D.; Lisa Chiu; Fred Clark; Jeanne Cloppse: Alan Clore; Meg & Pat Codd; Kenneth Cole; Pablo Colon, M.D.; Chris Costas; Corley Printing; David Corkery, Paul Corser; Deborah Cotton, MD, MPH; Sally Cooper; Ed Cowen; Michael Cowling; Spencer Cox; Lori Crank; Stephen Curley; Susan D'Alessandro;; Dad; Greg Dawson; Erik De Clercq, M.D, Ph.D; Victor de Gruttola, Ph.D.; Risa Denenberg, FNP; Rebecca Dennison; Luis Lopez-Detres; Douglas Dieterich, M.D.; DIFFA; Jesse Dobson; Tina Duchane; Novella Dudley; Floyd Dunn; Gale Dutcher; Martha Eibel, M.D.,Ira Elliot; Jon Engbretson; Liz Fallon; Gacy Felps; Kevin Fitzpatrick; Timothy Flanigan, M.D.; John Francis; Matt Foreman; Marcel Fortin; Heath Fowlie Garance FrankeRuta; Cassandra Freedom-Jones, NRL; Mark S. Frey; Mark B. Feinberg, M.D., Ph.D.; Ken Fornataro; Charlie Franchino; Eric Fretz; Dorothy Friedberg, M.D., PhD.; Chuck Frutchey; Robert Fullilove; Mindy Fullilove; Murray B. Gardner, M.D.; Brian Gazzard, M.D., F.R.C.P.; Peter George; Patty Glynn; David Gold; Gregg Gonsalves; Michael Gottlieb, M.D.; E.J. Grassman Trust; Michael Grieco, M.D.; Howard Grossman, M.D., P.C.; Samuel Grubman, M.D.; Greg Haas; Harley Hackett; Leslie Hanna; Mark Harrington, William A. Haseltine, Ph.D.; John Hatchett; Sue Herbert; Lisa Hernandez; Derek Hodel; Bob Huff; Barbara Hughes; Bob Hultz; Kathy Hyett; HX Magazine; Mark Jacobson, M.D.; Alex Juhasz; John James; Pat Jankowski; Anthony Japour, M.D.; Richard Jeffries; Jonathan Kagan, Ph.D.; Mitchell Kaplan, PhD; Lou Katoff; Deborah Katz; Wayen Kawadler; Bruce Kent; Linda Keyes; Mary Ann Kiernan, M.P.A.; Edward King; David Kirby; Kiyoshi Kuromiya; Stephan Korcia; Donald Kotler, M.D.; Joseph Kovacs, M.D.; Arthur Krim; Mathilde Krim, Ph.D.; Susan Krown, M.D.; Mark Krueger; Ellen LaPointe; the Leathermaster NYC/Mr. Leather New York Organizing Committee; Michael Lederman, M.D.; Lederle Laboratories' Library & Literature Services staff; Jeff Levi; Mary Ann Liebert, Inc.; Ronnie Lieberman, M.D.; LIFEBEAT; Marilyn Lockyear; J. Barton Loeser; Rick Loftus; Michelle Lopez; Benjamin Luft, M.D.; the Robert Mapplethorpe Foundation; Martin Markowitz, M.D.; Bill Martin; Henry Masur, M.D.; Frederick Mayer, RPh, MPH; Kenneth Mayer, M.D.; Justin McArthur, M.D.; James Magner; Robert Magner; Sheila Magner; John Manzon; Michael Marco; Chuck Mayer; Russ MCDonald; Mary MCMechan; Alexander McMeeking, M.D.; Paul Meier, Ph.D., Craig Metroka, M.D., Ph.D.; Nancy Mertzel; Mark Milano; Donna Mildvan; Mom; Susan Morabito; Mary Nalaschi; National AIDS Clearinghouse; National Hemophilia Foundation; National Institute of Allergies and Infectious Diseases; National Library of Medicine; Alison Needham; Charles Nelson; Kenneth Noller, M.D.; Michael O'Shaughnessy, M.D; Dean Ouellette; William Owen, M.D.; John Owens; Sondra Palleja, M.D.; Virginia Parks; F. Darrin Perry; Ronald Porter; Richard Price, MD; Rebecca Pringle-Smith; Jim Pruitt; Pharmaceutical Research and Manufacturers of America (PhRMA) and its member companies; William G. Powderly, M.D.; Richard Price, M.D.; PWA Health Group; PWA-RAG, Inc.; Judith Rabkin, Ph.D.; Richard Rabkin, M.D., Ph.D.; Matt Rader; Margaret Ragni, M.D.; Patricia Randall; Red, Hot Organization, Rev. Maggie Reinfeld; Jossie Rigal; Michael Saag, M.D.; Scott Sanders; Trudi Sandmeier; Sharon Safrin, M.D.; Gisela Schecter, M.D.; Neil Schram, M.D.; Peter Scott; Judy Shuler; Jane Silver; Merv Silverman, M.D, MPH; Joe Skrzypczak; Theo Smart; Michael Smith; Rosemary Soave, M.D.; Joseph Sonnabend,MBBCh, MRCP; Stephanie Spina; John Starr; Mitchell Speer; Gregory Sullivan; Jim Sullivan; Robyn Sussel; Syracuse University, 1996 Graduate Students, S.I. Newhouse School of Public Communications; TAG; Tina; Melanie Thompson,M.D.; Bill Thorne; Don Tobias; Gabriel Torres, M.D.; Melissa Turner; Trish Holleran-Tweedly; Keith Wells; Tim Westmoreland; Joseph Wheat, M.D.; Rita White; Phill Wilson; Doug Wingo; Ed Yerks; Michael Youle, MB ChB; Lowell S. Young, M.D; Van Pelt Foundation; Judith Van Pelt; Robert Vasquez; Cheryl Zoeller; Phil Zwickler and to anyone whose name was inadvertently left off this list, thank you! The AIDS/HIV Treatment Directory is dedicated to the memory of Terry Beirn.

Page  iv ABOUT THIS DIRECTORY This edition of the AIDS/HIV Treatment Directory marks the publication's tenth anniversary. Although this is not a milestone to be celebrated, it is a most appropriate time to extend our heartfelt thanks and appreciation to all who have contributed time, talents, and information to making the Directory the most comprehensive, timely, and objective resource available for information on treatments, both approved and experimental, for HIV/AIDS. Ten years ago, there was literally no reliable source of information on the various approaches being tested as treatments for HIV infection. Pharmaceutical companies considered all available data on drugs in development as proprietary information. Throughout the research community, the sites where new compounds were being studied in clinical trials were not to be talked about outside "proper" scientific forums. To people living with HIV/AIDS and their doctors, such attitudes and restrictive "proper" forums for disseminating information stood as formidable barriers to treatment decision-making. In 1985, these barriers began to crumble. The AIDS Medical Foundation (AMF), a precursor of the American Foundation for AIDS Research (AmFAR), sponsored a media briefing to tell medical reporters about the emerging scientific understanding of AIDS. At the last minute, Dr. Jean Claude Chermann of the Pasteur Institute in Paris, was added to the program; his brief, unscheduled appearance created both news and controversy. The news was Dr. Chermann's report - the first - on HPA-233, an experimental drug being clinically tested in people with AIDS. The controversy arose because he chose to present his findings in a public forum, not an "established and proper" scientific forum, i.e., a medical conference or peer-reviewed journal. The new treatment - the newslater proved to be ineffective; the controversy, however, became the catalyst for public access to information about other experimental treatments being tested. However, access to treatment information did not come easily. It took endless hours of work by "treatment advocates" to discover which companies were developing compounds and where they were conducting their clinical studies. It also took education- self-education by these advocates- to understand the science of drug development and clincial research. Such knowledge was essential if they were to communicate with the research community and to gain its respect. Ultimately, they did both and, joining forces with the research community, have since revolutionized the drug development and approval processes. As individuals living with HIV/AIDS, we are indebted to many people who were involved in that historic effort in detection. However, one man stands out above the rest; it was his tireless effort that secured the right of people with HIV/AIDS to the data necessary for informed treatment decision-making. That man was Terry Beirn, AMF's (and later, AmFAR's) Program Officer and a staff member of the U.S. Senate Committee on Labor and Human Resources. Terry's tenacious - even, some would say, maniacal - investigative work laid the foundation for the first directory of its kind, the AmFAR Directory of Experimental Treatments for AIDS & ARC. This publication later was renamed the AIDS/HIV Experimental Treatment Directory; today it is the AIDS/HIV Treatment Directory, or, simply, "the pink book." The name changed as the contents changed, always in response to the growing and diverse treatment-information needs of people with HIV/AIDS and their doctors. As Terry once wrote on this page, "We await fresh dispatches from the frontlines of AIDS drug development. As always, we will work to pass the information reaching our hands as quickly and objectively as we know how." Joe Guimento Projects Coordinator, Treatment Information Services iv

Page  1 TABLE OF CONTENTS ABOUT THIS DIRECTORY............................................................................................................................................................................iv TA BLE O F CO N TEN TS.......................................................................................................................................................................... 1 TABLE OF ANTIRETROVIRAL AND IMMUNE-BASED THERAPIES...........................................................................................2 TABLE OF OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS.............................................................................4 PROGRESS NOTES: VIRAL LOAD IN VANCOUVER......................................................................................................................6 TREATMENTS FOR HIV INFECTION ANTIRETROVIRAL THERAPY.......................................................... 15................... TREATMENTS FOR HIV INFECTION IMMUNE-BASED THERAPIES.............................................................................51 DESCRIPTIONS OF TREATMENTS FOR OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS.................................. 67 OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS TREATMENT RESULTS................................................................ 80 USPHS / IDSA GUIDELINES: PROPHYLAXIS OF OPPORTUNISTIC INFECTIONS................................................................... 141 TRIALS FOR HIV INFECTION: ANTIRETROVIRAL THERAPY.................................................................................................... 142 TRIALS FOR HIV INFECTION: IMMUNE-BASED THERAPIES.....................................................................................4 TRIALS FOR OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS............................................... 73.................. COMPASSIONATE USE I TREATMENT IND / EXPANDED ACCESS PROTOCOLS...............................................................207 STATE DRUG ASSISTANCE PROGRAMS........................................................................................................................................ 209 DRUG ASSISTANCE PROGRAMS OF PHARMACEUTICAL COMPANIES.................................................................................................. 210 NEWSLETTERS AND OTHER INFORMATION RESOURCES.....................................................................................217 GLOSSA RY........................................................................................................................................................................................................ 224 IN D E X.........................37................................................................................................................................................................... 237 KEY TO ABBREVIATIONS AND SYMBOLS...............M........................................ INSIDE BACK COVER

Page  2 Table of Antiretroviral and Immune-Based Therapies TABLE OF ANTIRETROVIRAL AND IMMUNE-BASED THERAPIES Numbers in Bold refer to a specific class of drugs. Descriptions and trial results of each individual compound, whether alone or in combination with other compounds, are listed accordingly under each drug class. For specific clinical trial listings, please see index on page 237. ANTIRETROVIRAL THERAPY REVERSE TRANSCRIPTASE INHIBITORS Nucleoside Analogues............ 15 AZT (zidovudine).................................. 15 ddC (zalcitabine).................................18 ddl (didanosine).................................. 19 d4T (stavudine).................................. 22 3TC (lam ivudine).................................. 23 1592U 89................................................ 23 PMEA/BisPom PMEA............................... 24 Nucleoside Analogues Combinations..................... 25 ddC & AZT...................... 25 ddl & AZT...................................... 25 d4T & AZT..................................... 27 d4T & ddl....................................... 27 3TC & AZT............................... 27 Comparing Combinations of Nucleoside Analogues.......... 29 ACTG 175 AZT + ddl vs AZT + ddC vs AZT vs ddl.........29 Delta Trial AZT + ddl vs AZT + ddC vs AZT........29 CPCRA 007 AZT + ddl vs AZT + ddC cs AZT........ 30 NON-NUCLEOSIDE REVERSE (NNRTI) TRANSCRIPTASE INHIBITORS... 30 Delavirdine (U90).........................................31 DM P-266.....................................................32 Loviride................................................. 32 Nevirapine (BI-RG-587)........................ 33 NNRTI & Nucleoside Analogues Combinations..... 34 Delavirdine & AZT................................ 34 Delavirdine & ddl.................................. 34 Nevirapine & AZT..................................35 Nevirapine & AZT & ddl............................... 35 PROTEASE INHIBITORS......... 36 Indinavir (Crixivan, MK-639, L-735, 524).....37 Nelfinavir (Viracept, AG-1343).................... 38 Ritonavir (Norvir, ABT-538)..................39 Saquinavir (Ro 39-8959).....................40 141W94 (VX-478).......................................41 Protease Inhibitor & Nucleoside Analogue Combinations........... 42 Indinavir & AZT....................................... 42 Indinavir & AZT & ddl...........................42 Indinavir & AZT & 3TC.......................... 42 Nelfinavir & AZT & 3TC...............................43 Nelfinavir & d4T.....................................43 Ritonavir & AZT.....................................43 Ritonavir & AZT & ddC.......................... 44 Ritonavir & AZT & 3TC.............................44 Saquinavir & AZT & ddC...................... 45 Saquinavir & AZT & 3TC.....................45 Saquinavir & ddC.......................................44 Protease Inhibitor Combinations.......................... 45 Ritonavir & Saquinavir.........................45 Protease Inhibitor Comparison Nelfinavir vs Ritonavir (trial protocol)......... 157 INTERGRASE INHIBITORS.......... 46 AR-177 (Zintevir)......................................... 46 OTHER ANTIRETROVIRAL COMPOUNDS......................... 47 ALX40-4C............................................ 47 GEM 91 (Antisense Compound)............47 Hydroxyurea.................................... 49 MDL 38, 574A (Castanospermine analog, BuCAST)........... 50 ZINC FINGER INHIBITOR CI 1012 (trial protocol)....................... 159

Page  3 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 '7 IMMUNE-BASED THERAPY CYTOKINES............................. 51 Interleukin-12 (IL-12)................................. 51 Interleukin-2 (IL-2,PEG IL-2)........................ 52 GENE TRANSFER THERAPY...... 54 TUMOR NECROSIS (TNF) FACTOR INHIBITORS............. 55 OPC-8212 (Vesnarinone)........................... 55 Pentoxifylline................................... 56 Thalidomide.................................. 57 TNF Receptor Fc Fusion Protein (rhu TNFR:Fc)............................... 58 THERAPEUTIC VACCINES......... 58 gpl20 Vaccines.........................58 gpl60 Vaccines........................... 60 HIV-Immunogen......................... 61 OTHER IMMUNEBASED THERAPIES............... 62 Autologous CD8 Infusion............................ 62 F105 (gpl20 monoclonal antibody)........ 63 Human Growth Hormone (HGH) and Insulin-like Growth Factor........... 63 Passive Immunotherapy............................. 64 Thymic Humoral Factor (THF).............. 65 Thymopentin (TP-5)............................. 65

Page  4 Table of Opportunistic Infections TABLE OF OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS Numbers in Bold refer to text about opportunistic infections and treatment results. Other numbers refer to individual trials. For alphabetical description of drugs used for opportunistic infections, see page 67. A cross-reference index is included in the back of the directory, see page 237. BACTERIAL & MYCOBACTERIAL BACTERIAL INFECTIONS............ 80 TREATMENT TRIALS: Pneumococcal Vaccine.............. 173 MAC (MYCOBACTERIUM A VIUM COMPLEX)............................... 81 TREATMENT TRIALS: Clarithromycin + Ethambutol + Rifabutin vs Clarithromycin + Ethambutol vs Clarithromycin + Rifabutin.................... 173 Nelfinavir + MAC Treatment........... 174 Rifabutin Oral Suspension....................... 174 Rifapentine Alone or in Combination......... 174 Rifapentine + Isoniazid vs Rifampin + Isoniazid.................................... 174 PROPHYLAXIS TRIALS: Atovaqone & Azithromycin vs TMP/SMX... 175 Fluconazole, Clarithromycin, Rifabutin effects on TMP/SMX & Dapsome.......... 175 SALMONELLOSIS.......................... 86 SYPHILLISINEUROSHYPHILLIS... 87 TUBERCULOSIS......................... 88 TREATMENT TRIALS: Gamma IFN + Isoniazid + Rifampin + Ethambutol + Pyrazinamide + Vitamin B6....................... 175 Isoniazid + Rifampin + Ethambutol + Pyrazinamide...................... 176 PROPHLAXIS TRIALS: Isoniazid vs Rifabutin................................ 176 FUNGAL INFECTIONS ASPERGILLIOSIS...........................91 CANDIDIASIS...............................91 TREATMENT TRIALS: Amphotericin B Liquid Complex................ 177 Fluconazole............................................... 177 Fluconazole vs Amphotericin B................. 177 GM-CSF + Amphotericin B vs Amphotericin B................................ 177 GM-CSF + Fluconazole vs Fluconazole.... 178 Terbinafine (Lamisil)................ 178 PROPHYLAXIS TRIALS: Fluconazole (Women)......................... 178 COCCIDIOIDOMYCOSIS................91 PROPHYLAXIS TRIALS: Fluconazole....................................... 179 CRYPROCOCCAL MENINGITIS....95 TREATMENT TRIALS: AmBisome (lipsomal) vs Amphotericin B followed by Fluconazole..................................... 179 PROPHYLAXIS TRIALS: Fluconazole + Flucytosine...................... 180 HISTOPLASMOSIS.........................98 TREATMENT TRIALS: AmBisome (Liposomal) vs Ampho B......... 180 Intraconazole (IV) vs Ampho B with oral intraconazole maintenance............. 180 MALIGNANCIES KAPOSI'S SARCOMA.................... 99 TREATMENT TRIALS: AR-623 (Liposomal Tretinoin)...........181 Doxorubicin vs Daunorubicin................. 181 Etoposide (low-dose)....................... 181 HCG (Human Chorionic Gonadotropin). 182 Interleukin 12 (IL-12)........................182 Liarozole................................... 182 OPC 8212 (Vesnarinone, Arkin-Z)......... 182 Paclitaxel (Taxol).............................183 Platelet Factor 4 (PF4)......................183 Retinoic Acid (9-cis)........................183 Retinoic Acid, ALRT-1057 topical gel.... 184 ALRT-1057........................................... 184 LGD1069....................... 185 Retinoic Acid (all-trans) + Alph Interferon.......................... 185 Ritonavir + d4T + Alpha IFN................. 185 Soluable TNF Receptors........................ 185 Tecogalen (SP-PG, DS-4152)...............186 Thalidomide........................... 186 TNP-470............................... 186 Topotecan........................... 186 LYMPHOMA...............................1...103 TREATMENT TRIALS: 5-azacytdine.........................................187 Anti-B4 Blocked Ricin..................... 187 ARA-C + Adriamycin + Cisplatin + Decadron + Hydrea + ddl + IL-2..... 187 Chemotherapy................................ 188 Chemotherapy + ddl + G-CSF............... 188 Chemotherapy + Radiotherapy............. 188 Chemotherapy & Triple Combination Antiretrovirals............................ 189 Gallium Nitrate (NSC 15200)..................189 Hexamethylamine + Etoposide (VP-16). 189

Page  5 AIDS/HIV Treatment Directory Vol 8, No 3 January 199 7 IgG-RFB4-dGA (Ricin A-Chair Conjugated Anti-CD22)............ 189 IL-2 (ultra low-dose)......................... 190 OK-B7 with Iodine-131.................... 190 ProMACE - CytaBOM + TMP/SMX + G -C S F...................................... 190 Topotecan........................................ 190 PROTOZOAL INFECTIONS CRYPTOSPORIDIOSIS...........10..6....1 TREATMENT TRIALS: BACI (Bovine Anti-Cryptosporidiol Immunoglobulin)....................... 191 ISOSPORIASIS.......................... 1108 MICROSPORIDIOSIS.................. 108 Thalidomide..................... 191 PCP (PNEUMOCYSTIS CARINII PNEUMONIA)..............................110 TREATMENT TRIALS: Atovaquone (High vs Low Dose) vs Pentamidine....................... 191 Methadone + TMP/SMX......................... 192 TMP/SMX (Desensitization vs Direct Rechallenge)............................ 192 TOXOPLASMOSIS........................ 115 TREATMENT TRIALS: Atovaquone + Pyrimethamine vs Atovaquone + Sulfadiazine............. 193 VIRAL INFECTIONS CMV (CYTOMEGALOVIRUS)....... 119 TREATMENT TRIALS: 1263W94................................. 193 Foscarnet............................. 193 Foscarnet + Oral Hydration vs Foscarnet + IV Hydration................ 194 Ganciclovir.......................... 194 Ganciclovir (Intravitreal Pellet)............... 194 Ganciclovir (Oral vs IV)................... 194 HPMPC (Cidofovir)................. 195 ISIS 2922....................................... 195 ISIS 2922 + Ganciclovir vs Ganciclovir.. 196 Lobucavir (BMS 180, 194)..................... 196 Nelfinavir................................................ 196 MAINTENANCE TRIALS: Ganciclovir + G-CSF..................... 197 HEPATITIS................................. 1 25 TREATMENT TRIALS: Alpha Interferon....................... 197, 198 HERPES SIMPLEX....................... 127 TREATMENT TRIALS: Acyclovir.......................................... 198 Famciclovir...................................... 198 Valacyclovir...................................... 199 HERPES ZOSTER...................... 128 TREATMENT TRIALS: BV-ara-U (Sorivudine)..................... 199 HUMAN PAPPILOMA VIRUS....... 129 TREATMENT TRIALS: Alpha Interferon............................... 199 Isotretinoin vs Observation.................... 199 MOLLUSCUM CONTAGIOSUM... 130 ORAL HAIRY LEUKOPLAKIA...... 130 PM L............................................. 130 NEUROLOGICAL COMPLICATIONS DEMENTIA.............................. 131 TREATMENT TRIALS: 1592U89 + Antiretroviral.................. 200 Dextromethorphan...........................200 Thioctic Acid vs Thioctic Acid + Deprenyl................... 200 U90 (Delavirdine)............................ 200 PERIPHERAL NEUROPATHY...... 134 TREATMENT TRIALS: Acupuncture vs (Acupuncture + Amitriptyline)................................... 201 Lamotrigine........................... 201 Recombinant human nerve growth factor................. 201 OTHER COMPLICATIONS OF HIV APTHOUS ULCERS................... 135 DEPRESSION DEPRESSION TRIALS: Dexedrine..........................202 Testosterone vs Fluoxetine (Prozac)..... 202 DYSPLASIA see Human Papilloma Virus TREATMENT TRIALS: 5-FU (Women)............................... 202 DIARRHEA & MALABSORPTION................ 135 TREATMENT TRIALS: Diethylhomosperimine (DEHSPM)......... 202 Standard vs Oligosaccharide-based Oral Rehydration Solution........... 203 THROMBOCYTOPENIA............ 136 TREATMENT TRAILS: Anti-Rh Antibodies (Anti-D) + AZT + ddl.................................. 203 Lisofylline....................................... 203 WASTING SYNDROME................ 137 TREATMENT TRIALS: DEHSPM (Diethylhomospermine).........203 L-Carnitine...................................... 204 Megestrol Acetate (Oral Suspension).... 204 Megestrol Acetate + Testosterone enanthate.................. 204 Nandrolone Deconate..................... 204 Oxandrolone................................. 205 Testosterone................................... 205 Thalidomide.....................206

Page  6 Progress Notes: Viral Load in Vancouver PROGRESS NOTES VIRAL LOAD IN VANCOUVER Selected Highlights from an Article by Mark Harrington* POLICY DIRECTOR,TREATMENT ACTION GROUP (TAG) Virus load and CD4 counts have very diferent significance... Imagine the infected but asymptomatic patient as a train rushing along the tracks... unaware that just ahead is a canyon with a bridge destroyed by a recent flood When will they meet their inevitable fate? When will the patient progress to AIDS? There are two variables that need to be known: where the train is now, and how fast it is going. The CD4 count can be imagined as a measure of current distance from progression to AIDS and virus load as a measure of how fast the patient is getting there. John Coffin, HIV Viral Dynamics, 1996 INTRODUCTION The year 1996 has brought a sea change in AIDS research and treatment. Three major factors have contributed to this sea change: a new understanding of viral pathogenesis, new and powerful antiretroviral treatment regimens, and new, more powerful tools for measuring HIV levels in the blood and elsewhere in the body. Indeed, it was due to the sensitivity of these new viral load assays that researchers were able to determine the kinetics of HIV replication and immune system clearance within the infected human host, and devise new therapeutic approaches to reduce viral replication. The impact of the viral load assays on HIV pathogenesis and treatment research can be compared to the impact of the Hubble Space Telescope on cosmology: both allowed researchers to see their subject with unprecedented resolution. Previous methods of quantifying viral activity were cruder and much less sensitive than the new viral load assays, most of which measure HIV ribonucleic acid (RNA) in the blood. Originally, HIV infection was diagnosed indirectly, by detecting antibodies with ELISA or Western Blot tests. Later, several companies developed p24 antigen capture assays to measure blood levels of the viral capsid protein p24. Unfortunately, p24 levels correlated poorly with progression; many people progressed to AIDS and died without any detectable p24 in their blood. Whatever p24 they had was bound to anti-p24 antibodies and therefore undetectable. Subsequently, immune-complex dissociated (ICD) p24 assays were developed to address this problem, but p24 remained an insensitive marker for viral replication. After the XI International Conference on AIDS in Vancouver, British Columbia, on 8-11 July, 1996, it is clear that monitoring of plasma HIV RNA levels will become a standard tool for diagnosis, prognosis and treatment of HIV infection and for the medical monitoring of antiretroviral therapy. CD4+ T cell monitoring remains an important parameter, especially in more immune-compromised persons, but viral load will be a key determinant in initiating and changing treatment regimens. Unfortunately, while its usefulness is clear, how best to use viral load monitoring is still far from obvious, and there are several competing approaches to controlling viral load, which must be rigorously compared. Mark Harrington is Policy Director for the Treatment Action Group (TAG). He is a member of the NIH Office of AIDS Research Advisory Council (OARAC) and served most recently on the AID Research Program Evaluation Working Group (the Levine Committee) and on the Keystone National Dialogue on Developing a Framework to Conduct Studies to Optimize Medical Managemen HIV Disease. He was a founding member of the Community Constituency Group (CCG) of the AIDS Clinical Trials Group (ACTG), serving on the ACTG Opportunistic Infections Committee and Primary Infection Committee and is a founding member of TAG. Mr. Harrington has written and edited numerous reports published by TAG. He is currently finishing a book on the birth and gro of AIDS treatment activism. *This report was edited by Tim Horn, and represents selected highlights. For a complete copy of this report, please call the Treatment Action Group: 212/260-0030. PROGRESS NOTES is an open forum for views and thoughts on clinical management and clinical research in HIV/AIDS. )S it of its Ath

Page  7 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 197,7 THE ASSAYS Recently, several very powerful and sensitive tests for measuring the presence of HIV RNA in the blood have become available to researchers and to some clinicians and patients whose insurance covers their cost. The FDA has approved one viral load test, the Roche AmplicorTM reverse transcriptase polymerase chain reaction (RT PCR) test, for diagnostic and prognostic use. Two other tests, Chiron's QuantiplexTM branched-chain DNA (bDNA) test and Organon Teknika's nucleic acid sequence-based amplification assay (NASBA) are also available, though not yet FDA approved. The Roche test can detect down to about 200 RNA copies per cubic milliliter (mL); the Chiron and Organon tests detect to about 500 copies. New, more sensitive bDNA and PCR research assays can detect virus to a lower limit of around 25 copies/mL. Because different tests differ in their sensitivities, the same viral load test should be used in a given individual over time VIRAL LOAD & HIV PATHOGENESIS In 1995, David Ho and George Shaw revolutionized HIV research by showing that HIV replicates at an astonishing rate, with up to 10 billion HIV copies being made per day, and an equal number being removed by the immune system. Each milliliter of blood contained, on average, 60,000 HIV RNA copies, of which most were defective, replication-incompetent virus. Using Abbott's protease inhibitor ABT-538 (now NorvirTM brand ritonavir), Ho showed that the half-life for immune clearance of HIV was about 1.25 days, and the half-life of infected CD4+ T cells was similar (Ho 1995, Wei 1995, Perelson 1996). This discovery paved the way for new, more aggressive antiretroviral treatment strategies which are now bearing fruit. Early in HIV infection, virus production and immune system clearance lead to an apparent, but deceptive steady-state, when virus levels and CD4+ T cell levels appear to be in balance. Actually, the immune system is undertaking a heroic, but ultimately unsuccessful, effort to contain viral replication. At the time, drug therapy appeared capable of reducing the viral load by 50% or more, but unable to reduce viral levels below limits of detection. This would all change in 1996. In Vancouver, five studies using various combination anti-HIV regimens confirmed Dr. Ho's findings on the kinetics of viral and T cell replication, and demonstrated a two-phase viral decay slope, with a 90-99% reduction in the first two weeks of therapy, and a slower second-phase decline to undetectable viral levels over the next 12-24 weeks, reflecting clearance of chronically-infected T cells and macrophages (Ho Th.B.930). VIRAL LOAD & PROGNOSIS In Vancouver, multiple lines of evidence converged to demonstrate that viral load was clearly of great prognostic value in assessing a given HIV-infected individual's risk of progression and death over a two-, five- and ten-year period. The most compelling evidence was presented by John Mellors in a retrospective survey of 1,601 men from the Multicenter AIDS Cohort Study (MACS) using viral RNA levels in 1985 to predict clinical outcome in 1995 (Mellors Mo.B.533, We.B.410). Baseline HIV RNA was the most predictive factor for progression and survival in the MACS cohort. For 855 patients who died of AIDS the baseline RNA count was 24,200; for 993 who developed AIDS it was 19,145; for 749 who remain alive it was 4,426 and for those who did not develop AIDS it was 3,636. Those entering with viral load over 30,000/ml had a 13 -fold increased relative risk of AIDS and an 18-fold increased risk of death. Risk of progression and death grows steadily with increasing viral load. CD4 remained a useful predictor, especially for patients with lower CD4 cells. Mellors stated that viral load and CD4 should be used together in assessing prognosis, and cautioned that RNA levels in the MACS cohort were probably 30% lower than with contemporary testing because the MACS used heparinized blood samples. Six other papers confirmed the association between higher viral load and more rapid progression in adults and children (Graham We.B.411, Mofenson We.B.315, Rakusan We.B.3327, Shearer Th.B.910, Weverling Th.B.4330, Yerly We.B.413), though CD4 levels, particularly when low, remained valuable prognostically over shorter periods of time (Popescu Th.B.4298). Long-term non-progressors have lower viral load than rapid progressors, both in adult and in pediatric populations, and among long-term survivors with low CD4 counts, those with lower viral load remain healthier than those with higher viral load (LefrPre Mo.B.1380, O'Brien Mo.C.323). Of note, many children have viral load higher than adults, helping to explain why some children progress rapidly. (Shearer Th.B.910). Several studies tried to correlate HIV levels in plasma with HIV RNA and infectious cells in the semen and vaginal fluids (Caliendo LB.B.6024, Juriaans Th.A.4036). While higher plasma RNA levels correlated with higher levels of HIV in semen and vaginal fluids, lower levels did not guarantee that the genital fluids were non-infectious. Patients with low plasma RNA levels are still infectious. Other studies tried to correlate maternal RNA levels with the risk of transmitting HIV to offspring. Though higher plasma RNA increased the rate of transmission, there was no critical cut-off below which the risk of transmission was greatly reduced (Brown Tu.B.2374, Burns Tu.C.345). Regardless of viral load, mothers should be offered antiretroviral therapy to interrupt vertical transmission.

Page  8 Progress Notes: Viral Load in Vancouver VIRAL LOAD & TREATMENT John Coffin recently distinguished between three kinds of response to antiretroviral therapy: Until about a year ago, all antiviral therapy gave the response in viral load as little suppression in which the rapid decline in virus after treatment is followed by a rapid appearance of mutant virus and more or less complete return to the original set point. More recently, therapeutic regimens which give rise to partial suppression have been described... In this case, resistance mutations appear, but they are severely crippled for replication under the conditions of treatment, and they establish a much lower set point, probably with considerable, but not complete, clinical benefit... Finally, and most recently, apparent complete suppression has been observed with some combination treatments. In this case, the initial two-log decline in virus load is followed by a more gradual decline to below the limits of detection. (Coffin, HIV Viral Dynamics, 1996, in press). Below are examples of treatment regimens ftting Cofffin's three patterns. Antiretroviral Treatments and Their Response in Viral Load I a. LfliDAJAn I U.f.ff..m. I I-f,.m.Inab 1 1 combination therapy in AZT-experienced patients. In 1995 three studies (ACTG 175, CPCRA 007 and Delta) demonstrated partial suppression and demonstrated the efficacy of combination nucleoside therapy, which was more pronounced among AZT-naive patients. Reduction in Progression with Partial Suppression ACTG 175 Delta CPCRA 007 Death 45% 33% 13% One recent example will suffice. CPCRA 007 is a good example of a study demonstrating little suppression, in the case of the AZT-experienced majority of participants (in whom adding ddl or ddC was akin to sequential monotherapy with the added frisson of two-drug toxicity), and partial suppression in the minority of AZT-naive participants whose viral load data were presented in Vancouver by Douglas Mayers of Walter Reed. CPCRA 007 compared AZT monotherapy with AZT/ddl and AZT/ddC in 1,113 patients with fewer than 200 CD4+ cells/mm3 (Saravolatz LD, Mo.B.291). Overall, combination therapy was less well tolerated and no more effective than AZT monotherapy; however, among a subset of naive patients, combination therapy reduced the risk of disease progression and death. Using the Roche PCR assay, Dr. Mayers examined HIV RNA changes in the AZT-naive subset in 98 patients with blood samples available at baseline. The median baseline CD4+ count was 65 and median baseline log HIV RNA was 4.95. At six months, mean decreases in log HIV RNA levels were significantly greater on combination therapy (-0.7 on AZT /ddl. -0.5 on AZT/ddC, -0.0 on AZT). At twelve months the combination arms were still - 0.4 log below baseline and the AZT arm was at baseline. The six month difference was statistically significant, and the twelve-month difference was not. In this study, a one log difference in RNA at baseline was strongly correlated with increased risk of progression or death (RR 1.62, p=0.038). A one-log decrease in RNA at six months significantly lowered the risk of progression or death (RR=0.39, p=0.003) but not for mortality alone (RR=0.61, p=0.126). The authors concluded that AZT/ddl confers a greater decline in HIV RNA than AZT alone, and that baseline HIV RNA and a post-treatment decline in RNA of one log at six months were predictive of clinical response, independent of CD4+ counts. Apparently Complete Suppression of Plasma Viral RNA At an ICAAC late-breaker in fall 1995, Abbott's Don Norbeck presented a summary of results from a French study of AZT/ddC/ritonavir, in which 24% of patients had undetectable RNA and 30% undetectable infectious PBMCs at four months. At the time, this seemed implausible, and we deemed it an irresponsible, unsubstantiated claim (Harrington 1995), but it was the first of a gathering avalanche of reports that documented apparently complete suppression of plasma HIV RNA (Norbeck 1995). IIUV..L I O/ 1| Partial NFV AZT /ddl Supson RTV ddl / d4T Suppression 4 A7" I I.J %i.%-, SDLV = delavirdine; IDV = indinavir; NFV = nemnavr NVP = nevirapine; RTV = ritonavir; SQV = saquinavir. I Little Suppression & Partial Suppression There is no need here to go through the disappointing litany of trials demonstrating little suppression which have been generated in the nine years since AZT was licensed. Most studies published before 1995 demonstrated little suppression. Of these, most were of nucleoside monotherapy or nucleoside I

Page  9 _AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 In a late breaker session in Vancouver on July 11, several researchers provided data on new three-drug regimens which, over a 12-48 week period, appeared to reduce viral replication below the lower limit of detection in between 80-90% of participants. These results were seen with several regimens in several populations, including newly-infected acute seroconverters, treatment-naive patients with 50-600 CD4+ cells and treatment experienced patients with 50-400 CD4+ cells/mm3. Studies Reporting Undetectable Viral Load in Majority of Pariticpants PI N Population Regimen(s) Median follow- Percent Study Markowitz 11 Acute Infection AZT/3TC/NFV 12 100% Myers 152 ARV na ve AZT/ddl/NVP 28 70% vs. AZT/ddl 40% Cameon 65 ARV eRTV/SQV 6 50% IDV = indinavir NFV = nelinavir; NVP = nevirapine; RTV = ritonavir; SQV = sqaunavir. ARV=antiretroviral; Limits of detection ranged from <500/ml to <25/ml.] Over the course of these studies, the limits of detection changed as manufacturers introduced new, more sensitive assays. While initially some studies began with a lower limit of detection of 10,000 copies/ml; newer tests have reduced that level to 100 copies or even, in some cases, 25 copies (Ho). Concomitant with the reduction of viral load to such levels has been a delay in the emergence of virus strains resistant to any of the drugs involved in the regimen (Condra, Th.B.932). Acute Primary Infection Martin Markowitz reported on two studies carried out at the Aaron Diamond AIDS Research Center (ADARC) among newly-infected persons with acute primary HIV infection. These studies were designed to study the hypothesis that hitting the virus early, before significant seeding of lymphoid tissues or evolution of potentially drug-resistant mutants had taken place, would increase the likelihood of being able to potentially eradicate viral infection from the body. Each study used a three-drug regimen and reported that, among all patients who could tolerate and remain compliant with the three-drug regimen, viral load became undetectable (below 500 copies/ml as measured by the bDNA version 2.0 test) within twelve weeks, and remained so. In one study, some patients followed out to ten months began to lose their anti-HIV antibody response. The two regimens studied were AZT/3TC/ritonavir and AZT/3TC/nelfinavir. In the first study, twelve patients enrolled within 90 days of exposure (estimated mean 65 days among those who remembered a potential exposure). Mean CD4+ counts were 633 and mean HIV RNA count was 91,359/ml. One patient switched from ritonavir to indinavir after developing an allergic reaction, and three patients were discontinued from the study for non-compliance (>Bad guinea pig!=). Eight remaining patients treated for up to ten months remain plasma RNA negative and are negative by quantitative microculture; infectious virus cannot be cultured from up to ten million peripheral blood mononuclear cells (PBMCs). Eventually lymph node biopsies will be performed to assess whether HIV RNA has been cleared from lymphoid tissues and perhaps one day some of these patients will be offered the chance of terminating therapy to see if they have cleared infection from their body (Markowitz Th.B.933). A second study, using AZT/3TC/nelfinavir in 12 patients with acute primary infection, demonstrated essentially similar results. Median entry CD4+ was 253 and median baseline viral load was 81,000 copies. One patient developed a grade 4 CPK elevation and withdrew from the study; the remaining 11 became undetectable within 12 weeks. While viral load went below 500 copies/ml, median CD4+ count rose by 98 at 12 weeks; the median increase was 109 cells (Markowitz LB.B.6031). Antiretroviral-Naive Patients Two studies looked at three-drug combinations in middlestage patients who had not received previous antiretroviral treatment. One study combined AZT/ddl with the non-nucleoside reverse transcriptase inhibitor nevirapine, which previously demonstrated a rapid propensity to induce high-level resistance when used as monotherapy (Richman 1995), while the second combined AZT/3TC with the protease inhibitor nelfinavir. In the first study, 152 antiretroviral-naive patients with 200-600 CD4+ cells were randomized to AZT/ddl or AZT/ddl/nevirapine and followed for twelve months. Baseline CD4+ was 376 and viral load was 4.41 logs/ml. At 28 weeks, 70% of patients receiving triple-drug therapy had viral load below the limit of detection (500 copies/ml using the Roche PCR kit), compared with just 40% of patients on AZT/ddl. Among the patients on triple-drug therapy who did not go undetectable were several who had interrupted their ddl therapy, allowing for the rapid emergence of resistance to nevirapine and AZT (Myers Mo.B.294). The study demonstrates, however, that even three reverse transcriptase inhibitors, which are relatively weak when used as monotherapy, and to which resistance may develop quite rapidly, can provide a potent antiretroviral effect when used together on a rigorously-adhered-to regimen in antiretroviral-naive patients. In the second study, David D. Ho of Aaron Diamond presented results from a study conducted by Martin Markowitz of twelve antiretroviral-naive patients given AZT/3TC/nelfinavir. Mean baseline CD4+ count was 245 (range 26-501) and baseline viral load 56,000/ml (range 14,000-618,000). One patient was lost to follow-up. HIV RNA decreased rapidly by two logs (99%) in the first two weeks of therapy, and descended further towards the lower limit of assay detection of 400 copies/ml (using the bDNA version 2.0 test). At the same time, CD4+ counts rose by an average of 100 cells. Ho presented the two-phase viral decay model developed by Perelson et al. (Science 1996) and

Page  10 Progress Notes: Viral Load in Vancouver I demonstrated that this data, as well as Markowitz's previously-described acute primary infection data, showed curves concordant with the Perelson model. The first-phase decay represents loss of plasma virus and actively-infected circulating cells. The second-phase decay represents the loss of infected macrophages and latently-infected CD4+ T cells. At eight weeks, virus could not be cultured from up to 10 million PBMCs. Using the newer, more sensitive Chiron version 3.0 bDNA assay, which can detect viral load down to a level of 25 copies/ml, Ho demonstrated that at twelve weeks, all eleven patients remaining on study had levels below that threshold, and predicted that they were essentially at zero. The room became very quiet. You could have heard a pin drop. A collective silent sigh ensued, as the full implications of this sunk in to the thousands of scientists, reporters and activists assembled on this last late-breaker session of the Vancouver conference. People I knew and loved were in this study. Their viral load had been reduced, within three months, to virtually zero. Perhaps some of us would live, after all. David Ho proceeded relentlessly on, using the prognostic power of the Perelson two-phase decay model to predict that most if not all latently-infected cells could be cleared from the body within a range of 30-120 weeks: Duration of Treatment Before Viral Bum-Out (in weeks) Pool size (Viral copiesbody): 1 12 Decay half-life: 108 1(9 10 10" 101 2 weeks 53 60 67 73 80 Ho stated that there are an estimated one trillion CD4+ T lymphocytes in the body, of which fewer than 100 billion are activated and thus prone to infection by HIV at any given time. Of these 100 billion, perhaps no more than 10 billion can actively replicate infectious virus. Thus, a reasonable estimate for the pool size of HIV produced by the CD4+ cells of an infected host is 100 million to 1 billion copies. There are perhaps 1.3 trillion macrophages and monocytes in the body. Fewer than 1% of these are infected with HIV -- something on the order of 1.3 billion cells. 99% of macrophages in the blood turn over (or migrate to tissue) within three weeks. Using these admittedly speculative body-wide estimates, Ho figured that a minimum estimate of the time to viral bum-out would be 30 -120 weeks, based on a pool size of one billion copies/day. The estimates were more sensitive to half-life of viral decay than to pool size. Ho also cautioned that if viral replication persisted in sanctuary sites (such as the brain), there might be a much slower third-phase decay, in which case this model's predictions would be over-optimistic. Possible means of forestalling this might include more intensive antiretroviral therapy (four-drug combinations) or activating latently-infected cells with, for example, interleukin2 (IL-2) (Ho Th.B.930). Antiretrovlral-Experienced Patients While exciting, the results of the acute infection studies will not impact most currently HIV-infected persons, who have been infected for years. Many of these people are antiretroviral-experienced too, so the exciting results among antiretroviral-naive patients might not necessarily apply to them. Luckily, however, two additional studies presented in Vancouver displayed essentially identical viral load decay slopes among antiretroviral-experienced patients as in the acutely-infected and antiretroviral-naive participants described above. What is most striking about these six studies is that all demonstrate virtually identical viral decay slopes. Thus, they demonstrate the power of the hit it hard approach; they do not, however, at least yet, distinguish whether it is indeed better to hit it early. Roy "Trip" Gulick of New York University presented 48-week follow-up data from an ongoing Merck-sponsored study comparing AZT/3TC/indinavir to indinavir monotherapy and to AZT/3TC in 97 patients who entered with a median CD4+ count of 144 (range 50 -400), at least 20,000 copies of HIV RNA (median 41,385), and a mean of 2.5 years of prior AZT therapy. Nine patients developed nephrolithiasis (kidney stones) from the indinavir, and 22 had elevated bilirubin levels. 90 patients remain on study. All have been switched to open-label triple combination therapy (Gulick Th.B.931). Proportion of Patients Undetectable in AZT/3TC/lndinavir Study (Th.B.931) CD4+ change 24w 32w 44w at 44 weeks AZT/3TC 0%( 0/22) 0%( 0/23) %(0/8) +14 In a second, more preliminary study, Bill Cameron from the University of Ottawa presented six-week data on 65 patients who entered the first two strata of an ongoing study of ritonavir and saquinavir, the first study looking at two-protease regimens. Baseline CD4+ counts ranged from 100-500; patients were required to be protease-naive and to discontinue nucleosides before entering the study. The first stratum used a 400 mg dose of each drug twice daily and the second raised the ritonavir dose to 600 mg twice daily. The most common side effects included circumoral paresthesia (numbness around the mouth) in 79% (26/33) of patients, diarrhea, fatigue, nausea and flushing. 50% of the patients who remained on therapy for up to six weeks became undetectable at that time. The study is ongoing, using higher doses (Cameron Th.B.934). While none of these studies are large enough or have run long enough to demonstrate clinical benefit, taken together they raise the possibility that a treatment strategy of reducing viral load as low as possible may delay progression of disease, restore at least some immune function, and delay the emergence of drug-resistant HIV strains. Longerterm follow-up on larger numbers of patients is needed, and potential viral reservoirs 10

Page  11 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 within the body (e.g., lymphoid tissues, brain, gut) need to be assayed to determine whether peripheral blood reductions in viral load are reflected in other body compartments (Coffin 1996; Ho Th.B.930). I.A.S. RECOMMENDATIONS It's always risky to build a house when the ground is shifting under one's feet. Undeterred by the tectonic shifts taking place in HIV pathogenesis and treatment, a self-anointed group of experts from the International AIDS Society (I.A.S.) decided to expand their horizons from simply putting on the biannual AIDS conferences in order to promulate guidelines for the use of viral load-based treatment strategies. Recognizing that their first effort, published in Nature Medicine in June (Saag 1996), would be outdated by Vancouver, they released a second effort at the AIDS Conference and published simultaneously in JAMA (Carpenter 1996). Demonstrating the difficulty of trying to straddle two horses going through a raging river in opposite directions, these guidelines too were dead on arrival, and should have been subjected to a quick burial after Thursday's latebreaker session where a new treatment paradigm made its spectacular debut. Unfortunately, however, many clinicians and patients will be confused by these guidelines, which are internally inconsistent, vapidly prescriptive and riddled with contradictions. It would be more honest at this point to admit the uncertainties facing research and treatment, and design studies to resolve them. HIV Viral Load Markers in Clinical Practice: Interim IAS Guidelines, June 1996 Parameter Recommendation This matrix is rife with omissions and contradictions. What is to be done with people with 10,000-30,000 copies/ml? Nothing is said about this middle group. What is the basis for the cutoff points? Nothing in the Mellors data or anywhere else suggests a critical threshold, rather a monotonically increasing risk. Clearly viral load should be used alongside CD4+ count and clinical status. Inventing new thresholds for viral load as was done with CD4+<500 and CD4+<200 has the potential to create artificial thresholds and create potentially meaningless stratifications. At least CD4+<200 had the epidemiological evidence of a clearly increased risk for PCP and other OIs. After Vancouver, there is clearly a difference between 5,000 copies/ml and undetectable levels, so they represent two very different targets for treatment (partial suppression versus apparent complete suppression). There's nothing wrong with stating the uncertainty and proposing studies to resolve the question. Partial suppression may be more acceptable for earlier-stage patients with low viral load and higher CD4+s, whereas apparent complete suppression may be most desirable for patients at risk for AIDS. The same level of reduction, 0.5 log, is proposed both as a minimal decrease acceptable for showing antiretroviral activity and as a threshold indicating treatment failure! ddC rears its ugly head with its half-log viral reduction and its dismal clinical record. An 0.5 log will have a very different outcome for someone with over a million RNA copies than for someone with 1,000 copies/ml. The only people who should be happy with the recommended frequency of RNA testing are the manufacturers of the RNA kits. An orgy of over-sampling is suggested, with no guidance given for other factors -- e.g., intercurrent infection, immunization, immunostimulatory treatment -- which might affect viral load independently of antiretroviral treatment failure and the evolution of drug resistance. No guidance is given for patients whose viral load returns partially, but not completely, towads baseline after having been undetectable. Which drug of a three-drug regimen is failing? How can clinicans and patients find this out without removing each of the drugs in sequence and enhancing the selection pressure for resistance? The authors of the IAS guidelines provide no assistance in resolving these or many other pressing issues, and present the false impression of scientific certainty where none exists When to start >5,000-10,000 copies/ml + CD4+/clinical status suggestive of progression; Anyone with viral load >30,000 -50.00conies/ml of measurement Two baseline measurements, 2-4 weeks apart Every 3-4 months or with CD4+ counts (shorter intervals as decision points are neared) 3-4 weeks after starting/switching therapy 11

Page  12 Progress Notes: Viral Load in Vancouver I) Antiviral Therapy for HIV Infection in 1996: IAS Guidelines, July 1996 published July 10 in the Joumal of the American Medical Association. When to start *Before irreversible immunologic damage has occurred CD4+<500,though some would defer *If CD4+ 350-500 if viral load is <5,000 -*10,000. CD4+>500 and RNA >5,000 -*10,000 (no clinical evidence). *Consider for all patients with >5,000-10,000 wnen rl swi cn therapy *Treatment failure: VL rises, CD4+ falls, symptoms *VL rise to 0.3-0.5 log of baseline; (Don't measure VL within a month of an 01 or immunization) *Clinical progression *Toxicity, intolerance or non-adherence *Current use of suboptimal regimen In general, the July guidelines more openly admit the confusion and contradictions which face clinicians and people with HIV in 1996, and they frame a series of choices which may provide a useful basis for comparative studies of different treatment strategies. However, after Vancouver, several additional considerations must be mentioned. If someone wishes to go undetectable, they should not start with a regimen likely to induce only partial suppression, such as nucleoside combination therapy. A person who wishes to delay the most potent regimen, avoid the inconvenience of protease inhibitors, or save treatment options for later may do fine for several years with partial suppression. Studies are needed to sort this out. The decisions depend on treatment history, stage of disease, side effects, health care reimbursement and personal choice about how one wants to live one's life. It should be noted that the recommendations are drug or at least class-of-drug specific, whereas comparing different strategies might involve looking at partial versus apparently complete suppression regardless of how one obtained them, as the BI 1046 AZT/ddl/nevirapine study reminds us. As for when to stop, it must be remembered that two recent studies in advanced patients, Abbott's ritonavir + standard of care (SOC) versus SOC study and Roche's study of ddC vs. saquinavir vs. ddC/SQV both showed clinical benefit in advanced patients. However, in general the IAS guidelines are premature; perhaps they should wait until their next confab in Geneva, by which time things may have settled down. As the IAS rushed ahead rashly with its immediately-updated, immediatelyoutdated guidelines, the U.S. NIH and Public Health Service (PHS) postponed indefinitely their plans to convene another State-of-the-Art (SOTA) conference to revise the clearly antiquated 1993 guidelines released after Berlin. The PHS panels have the advantage of bringing outside expertise and objectivity to bear upon the promulgation of treatment guidelines; one problem with the IAS panel is that most of its members have a vested stake in the success of studies they have led, potentially interfering with their ability to temper their renewed enthusiam with an awareness of the compliance, cost, public health and toxicity issues associated with lifelong multiple-drug therapy. UNANSWERED QUESTIONS While viral load is an exciting and powerful tool, uncertainties remain on how best to use it, how often to measure it, and what sort of changes in viral load levels should be sought in using antiretroviral therapy. Undoubtedly further technical developments will improve its ability to help elucidate the pathogenesis of HIV disease, protect the blood supply, and monitor participants in treatment and vaccine studies. Among the outstanding issues are: 3wncning: For toxicity / intolerance: For treatment failure: For patients on AZT mono: For patients on two *Find a tolerable regimen *Find a more potent regimen without cross resistance *Add ddl, ddC, or 3TC; switch to ddl. *Add a protease inhibitor 12

Page  13 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Assay Development. Further development is needed to increase the sensitivity of commercially-available RNA tests to quantitate plasma HIV to lower limits of detection. In particular, new more powerful assays are needed to quantitate nonsubtype B strains, both for research purposes and to monitor viral load in natural history, treatment and vaccine studies. Protocols need to be developed and standardized for the sampling of HIV in lymphoid tissues and in genital secretions Pathogenesis. It will be important to determine whether different HIV subtypes are associated with different levels of viral load and differing transmission kinetics. Protocols need to be developed for quantifying HIV levels in the brain, CSF, gut, mucosa, semen and vaginal secretions. The contribution of host factors such as CTLs, soluble CD8-secreted antiviral factors, chemokines, cytokines and neutralizing antibodies to control of viral load over the course of disease remains to be clarified. Persistence of virus in potential sanctuary sites needs to be determined. Further work is necessary to determine the kinetics of CD4+ replenishment, the role of thymic and extra-thymic T cell maturation, and whether or not depleted antigen-specific CD4+ clones can be repleted after long-term suppressive antiretroviral therapy. Diagnosis. The US Public Health Service (PHS) should promulgate guidelines for using HIV RNA testing to screen the blood supply for people with acute infection and for detecting non-subtype 3 HIV strains. Tests should be developed which can detect all prevalent strains circulating worldwide. Transmission. There is a very real danger that people will misinterpret low viral load levels as meaning they are no longer infectious or capable of transmitting HIV sexually, intravenously or vertically. Further research is necessary to determine the impact of potent antiviral combinations on transmission, to study the transmission of drug-resistant strains, and to develop new prevention strategies and public education messages to avoid an explosion of unprotected sex. Studies of potent combination regimens in pregnant women, neonates and children remain years behind studies in adults, and need to be accelerated. Prognosis. The natural history of treated HIV infection after 1996 is likely to differ significantly from the natural history of untreated (or inadequately-treated) HIV documented by Mellors from 1985-1995. Natural history and treatment studies should therefore include long-term monitoring of viral load, treatment regimens and ultimate clinical outcomes through both observational and therapeutic research. Prognostic guidelines based on multivariate analysis from completed, ongoing and prospective cohorts should be developed and regularly updated. As Mellors pointed out, CD4+ counts and clinical status still contribute useful information to a multifactorial analysis of the risk of progression. Treatment. The duration of long-term viral suppression remains to be determined. As Ho has pointed out, there is the possibility of a very slow third-phase decay in viral replication, possibly due to antibody-bound, FDC-trapped lymphoid virions or to the persistence of HIV-infected monocytic cells in viral sanctuary sites such as the brain. Potent combination regimens which penetrate the blood-brain barrier need to be developed to avoid the persistence there of isolates no longer found in the blood. The most potent, tolerable regimen(s) for long-term suppression need to be determined, and rational sequences for potent suppression need to be defined. Studies in patients with higher CD4+ levels and relatively low viral load need to compare partial versus apparently complete plasma RNA suppression as an initial strategy, or immediate versus deferred suppression. Simpler, more convenient regimens need to be developed to enhance compliance, e.g., with the use of timerelease drugs which can be taken once a day or less often. Studies to optimize long-term compliance with complicated, inconvenient regimens need to be conducted, comparing a range of strategies in a diverse set of populations. Interventions which may contribute to replenishment of holes in the immunologic repertoire, and reconstitution of thymic and lymphoid tissue in advanced patients need to be designed and implemented. When and whether people experiencing a significant CD4+ T cell rise after combination therapy can be removed from opportunistic infection (01) prophylaxis and maintenance needs to be addressed. Finally, research needs to be conducted to determine the feasibility of treating or eradicating HIV disease among infected persons in developing nations. References Brown TM, Steketee RW, Abrams EJ, Thea D, Lambert G, Greenberg B, Schoenbaum E, Bamji M, Thomas P, Rapier JM, Orloff S, Kalish MI. Early Diagnosis of Perinatal HIV Infection Comparing DNA-Polymerase Chain Reaction and Plasma Viral Amplification. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Tu.B.2374. Burns DN, Landesman S, Rubinstein A, Waters D, Willoughby A, Goedert JJ. HIV-RNA Levels During Pregnancy and Vertical Transmission of HIV-1. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Tu.C.345. Caliendo A, Cu-Uvin S, Costello S, Murphy D, Mayer K, Flanigan T, Carpenter C. HIV-1 RNA Quantification by NASBA in Matched Plasma and Cervico-Vaginal Lavage in HIV Seropositive Women. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract LB.B.6024. Cameron W, Sun E, Markowitz M, Farthing C, McMahon D, Poretz D, Cohen C, Follansbee S, Ho D, Mellors J, Hsu A, Granneman GF, Maki R, Salgo M, Court J, Leonard J. Combination Use of Ritonavir and Saquinavir in HIV-lnfected Patients: Preliminary Safety and Activity Data. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.934. Carpenter CCJ, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding P for the International AIDS Society. Antiretroviral Therapy for HIV Infection in 1996: Recommendations of an International Panel. JAMA 1996;276:146-154. Coffin JM. HIV Viral Dynamics. Submitted, 1996. 13

Page  14 Progress Notes: Viral Load in Vancouver Condra JH, Holder DJ, Schleif WA, Chodakewitz JA, Massari FE, Blahy OM, Danovich RM, Gabryelski LJ, Graham DJ, Laird D, Quintero JC, Rhodes A, Robbins HL, Rothe E, Shivarprakash M, Yang T and Emini EA. Bi-Directional Inhibition of HIV-1 Drug Resistance Selection by Combination Therapy with Indinavir and Reverse Transcriptase Inhibitors. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.932. Condra JH, Schleiff WA, Blahy OM et al. In vivo Emergence of HIV-1 Variants Resistant to Multiple Protease Inhibitors. Nature 1995,374:569-571. Graham NMH, Astemborski J, Saah AJ, Vlahov D, Margolick JB, Farzadegan H. Infectious Viral Load Predicts Clinical Progression and Survival Among HIV Infected Adults. XI International Conference on AIDS, 1996, Abstract We.B.411. Gulick RM, Mellors J, Havlir D, Eron J, Gonzalez C, McMahon D, Richman D, Valentine F, Rooney J, Jonas L, Meibohm A, Emini E, Chodakewitz J. Potent and Sustained Antiretroviral Activity of Indinavir, Zidovudine and Lamivudine. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.931. Harrington M, Marco M, Cox S, Horn T. TAG Does ICAAC: AIDS Research Highlights from the 35th Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, 17-20 September 1995, Treatment Action Group (TAG). Ho DD, Perelson AS, Essunger P, Markowitz M. How Long Should Treatment Be Given If We Had An Antiretroviral Regimen That Completely Blocks HIV Replication? XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.930. Jurriaans, S, Vernazza PL, Goudsmit J, Boogaard J, Van Gemen B. HIV-1 Viral Load in Semen Versus Blood Plasma. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.A.4036. LefrPre JJ, Mariotti M, Morand-Joubert L, Meyohas MC, Roudot-Thoraval F. Sequential Determination of Plasma HIV-1 RNA Copy Level from the Beginning of Infection Over a Mean Eight Year Period in a Population with a Well-Defined Date of Infection. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Mo.B.1380. Markowitz M, Cao Y, Hurley A, O=Donovan R, Heath-Chiozzi M, Leonard J, Smiley L, Keller A, Johnson D, Johnson P, Ho DD. Triple Therapy with AZT, 3TC and Ritonavir in 12 Subjects Newly Infected with HIV-1. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.933 Markowitz M, Cao Y, Hurley A, O=Donovan R, Peterkin J, Anderson B, Smiley L, Keller A, Johnson P, Johnson D, Ho DD. Triple Therapy with AZT and 3TC in Combination with Nelfinavir Mesylate in 12 Antiretroviral-Naive Subjects Chronically Infected with HIV-1. Ibid., 1996, Abstract LB.B.6031. Mayers D, Saravolatz L, Winslow D, Jagodzinski L, Collins G, Hodges D, Pettinelli C, Weislow O, Stein D. Viral Burden Measurements in CPCRA 007. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.911. Mellors JW. The Contribution of Viral Load Measurements. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Mo.B.533. Mofenson L, Korelit J, Meyer W, Moye J, Rich K, Pahwa S, Bethel J, Nugent R. Relationship Between Serum HIV-1 RNA Copy Number and Mortality in HIV-Infected Children Followed in the NICHD IVIG Clinical Trial. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract We.B.315. Myers MW, Montaner JG, The Incas Study Group. A Randomized, Double-Blinded Comparative Trial of the Effects of Zidovudine, Didanosine and Nevirapine Combinations in Antiviral Naive, AIDS-Free, HIV-Infected Patients with CD4+ Counts 200-600/mm3. Ibid., 1996, Abstract Mo.B.294. Norbeck D, Kumar G, Marsh K, Rodrigues D, McDonald E, Molla A, Denissen J, Kempf D, Leonard J. Ritonavir and Saquinavir: Potential for Two-Dimensional Synergy Between HIV Protease Inhibitors. 35th Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC), San Francisco, California, 1995, Abstract LB.7. O'Brien TR, Blattner WA, Kroner BL, Goedert JJ. HIV-1 RNA Levels in Early Chronic Infection Associated with AIDS and Long-Term Non-Progression. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Mo.C.323. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time. Science 1996, 271:1582-1586. Popescu M, Wolf E, Jaegel-Guedes E, Jaeger H. HIV-1 RNA Viral Load Measurements: Are They A Good Predictor of Mortality in CDC-AIDS Patients? XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.4298. Rakusan TA, Loechelt B, Brandt C, Schutzbank T, Troy J, Sever J. Clinical and Virological Characteristics of Long Term Survivors (LTS) of Perinatally Acquired HIV Infection. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract We.B.3327. Richman DD, Havlir D, Corbeil J et al. Nevirapine Resistance Mutations of Human Immunodeficiency Virus Type 1 Selected During Therapy. J. Virol. 1994,68:1660-1666. Saag MS, Holodniy M, Kuritzkes DR, O=Brien WA, Coombs R, Poscher ME, Jacobsen DM, Shaw GM, Richman DD, Volberding PA. HIV Viral Load Markers in Clinical Practice. Nature Medicine 1996,2:625-629. Shearer WT, Quinn T, La Russa P, Lew J, Mofenson L, Almy S, Rich K, Handlesman E, Diaz C, Pagano M, Smeriglio V, Kalish L. Prospective Evaluation of Plasma HIV-1 RNA Copy Number in 106 HIV-Infected Children from the Women & Infants Transmission Study. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.910. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch et al., Viral Dynamics in Human Immunodeficiency Virus Type 1 Infection. Nature 1995, 373:117-122. Weverling GH, Keet IPM, de Jong MD, Veugelers PJ, Goudsmit J, Lange JMA, de Wolf F. HIV-1 RNA Level is Set Early in the HIV Infection and Predicts Clinical Outcome. XI International Conference on AIDS, Vancouver, B.C., 1996, Abstract Th.B.4330. Yerly S, Perneger T, Hirschel B, Matter L, Malinverni R, Perrin L. HIV Viremia Influences Survival in HIVInfected Patients. XI International Conference on AIDS, 1996, Abstract We.B.413. 14 I

Page  15 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199; 7 TREATMENTS FOR HIV INFECTION ANTIRETROVIRAL THERAPY REVERSE TRANSCRIPTASE INHIBITORS NUCLEOSIDE ANALOGUES Nucleoside Analogue Combinations see page 25 Comparing Nucleoside Analogues Combinations, see page 29 Nucleoside Analogues and NNRTIs Combinations, see page 34 Nucleoside Analogues and Protease Inhibitors Combinations, see page 42 There are currently five nucleoside analogues approved for marketing in the United States: AZT (1987), ddl (1991), ddC (1992), d4T (1994), and 3TC in combination with AZT (1995). Several more are in various stages of development. MECHANISM OF ACTION: Following phosphorylation by cellular enzymes to their respective triphosphate forms, 2',3'-dideoxynucleoside analogues have been shown in vitro to inhibit HIV in two ways. First, they compete with natural 2'-deoxynucleotides for binding to reverse transcriptase, thereby inhibiting the activity of this important viral enzyme. Secondly, they may be incorporated into newly synthesized viral DNA chains, resulting in chain termination. CLINICAL CONTEXT: AZT (zidovudine), the first antiretroviral agent to be approved, has been studied most extensively. Its clinical benefit as monotherapy is relatively short lived, on average, from several months in advanced patients to perhaps several years in individuals with higher CD4+ counts. Recently, the results of several large clinical outcomes trials were reported, which demonstrate that AZT provides more benefit when given in combination with ddl (didanosine) or ddC (zalcitabine) than when used alone, especially in patients who have not taken antiretroviral drugs previously. Although ddl monotherapy performed as well as the combination ddl/AZT in two of these trials (ACTG 175 in adults, ACTG 152 in children), it has not been studied extensively as initial therapy. ddC monotherapy has been shown to be inferior to AZT monotherapy as initial treatment, and probably should only be used in combination regimens. D4T has been studied less extensively to date, and not in any large comparative combination trials. 3TC in combination with AZT shows better laboratory surrogate marker results than other nucleoside combinations and has been shown to reduce rates of disease progression and mortality (CAESAR see page 27). In summary, although nucleoside combination regimens are more active against HIV than monotherapy (measured by quantitative plasma HIV-RNA assays), the number of different combinations that have been studied for clinical benefit are few. This section is organized to describe the results of clinical trials on each of the nucleosides as monotherapy, followed by sections on nucleoside combinations. The results of the three large comparative studies of AZT/ddl, AZT/ddC, and AZT are summarized separately. Results of combination studies with other classes of antiretroviral agents, such as the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors, are described under those headings. Finally, there are some studies of nucleoside analogues used with immune-based therapies PHYSICAL DESCRIPTION: AZT is a thymidine nucleoside analogue in which the 3'-hydroxy (-OH) group is replaced by an azido (-N3) group. AZT is approved for the treatment of all HIV+ people with a CD4+ count less than 500/mm3. Despite the results of early studies using high doses of AZT (1200 mg - 1500 mg/daily), Fischl et al. concluded in ACTG 002 that the maximum tolerated dose was 600 mg/daily. Results of recent trials indicate that combination therapy with ddl or ddC is superior to AZT monotherapy in patients who are beginning antiretroviral therapy for the first time. TRIAL RESULTS SYMPTOMATIC DISEASE The initial approval of AZT for advanced disease (CD4+ counts < 200 cells/mm3) was based on the results of a double-blind placebo-controlled trial in 282 AIDS and ARC patients (Fischl et al.). During the 24-week placebo-controlled period, one AZT recipient and 19 placebo recipients died. The study was terminated early and patients were offered open-label AZT. 15

Page  16 Antiretroviral Therapies Average time on therapy when the placebo arm was discontinued was four-and-one-half months. Two studies reported by Hamilton et al. (VA 298) and Fischl et al. (ACTG 016) demonstrated that mildly symptomatic patients with CD4+ counts 200 - 500 cells/mm3 who initiated therapy with AZT were significantly slower to develop AIDS or ARC than those who received placebo. Both trials reported were randomized, placebo-controlled studies. Follow-up data from VA 298 reported by Simberkoff et al. failed to demonstrate a significant survival benefit for patients who received AZT versus those who received placebo with baseline CD4+ counts between 200 and 500 cells/mm3. ASYMPTOMATIC DISEASE: The 1990 expanded approval of AZT for patients with CD4+ counts between 200 and 500 cells/mm3 was based on the results of two large placebo controlled studies conducted in the United States by NIAID (ACTG 016 and ACTG 019). Both ACTG 016 (Fischl et al.) and ACTG 019 (Volberding et al.) were stopped early in 1989 due to slower disease progression in AZT recipients, compared to placebo recipients, who entered the studies with CD4+ counts between 200 and 500 cells/mm3. Neither study demonstrated a significant survival benefit in this patient population. Data from clinical trials comparing AZT monotherapy to placebo in HIV+ patients with CD4+ counts > 500 cells/mm3 have not demonstrated any significant benefits in terms of survival or disease progression. ACTG 019, which compared AZT (500 mg/daily and 1,500 mg/daily) to placebo in asymptomatic patients, 1637 of whom entered with CD4+ counts > 500 cells/mm3, failed to demonstrate any significant difference in survival between the three groups after a median 4.8 years of therapy (Volberding et al., 1995). Data from ACTG 019 were corroborated by results from a European double-blind, placebo-controlled trial of AZT monotherapy versus placebo in 1749 asymptomatic patients (Concorde Coordinating Committee). In 1989, after the early discontinuation of the placebo arm in the lower (< 500) CD4+ stratum of ACTG 019 (Volberding et al.), the protocol was modified to allow patients to take AZT if their CD4+ counts fell below 500/mm3. An intent-to-treat analysis was conducted after a mean follow-up of 3 years. There were no significant differences between the two groups in terms of disease progression or survival. The three-year survival rates were 92% and 93% for the immediate and deferred groups, respectively; three-year progression rates to AIDS or death were 18% in both groups. Data suggesting a benefit of early AZT therapy versus placebo have been reported by Cooper et al. 993 HIV+ asymptomatic patients with CD4+ counts above 400 cells/mm3 (median 593) were randomized to receive AZT 1000 mg daily dose (500 mg PO bid) or placebo. The original study endpoints were progression to AIDS or advanced ARC. After the results of ACTG 019 were reported (Volberding et al.), the primary endpoints were modified to include CDC group IV disease or a CD4+ count <350/mm3. After 3 years follow-up, 6/495 AZT recipients and 10/489 placebo patients progressed to AIDS or advanced ARC (difference not significant). Progression to an endpoint (including the revised endpoints) occurred more frequently in the placebo group: 129/489 placebo recipients progressed vs 76/495 AZT recipients (P<0.001)). ACUTE PRIMARY INFECTION: Kinloch-de Loes et al. have published final results of a European/Australian pilot study that compared AZT 500 mg/day with placebo in patients presenting with acute primary HIV infection (sero-conversion episodes). Seventy-seven patients were randomized to receive AZT or placebo for six months. Endpoints include the duration of the acute syndrome, CD4+ counts and p24 antigenemia, and viral load. After six months, CD4+ counts were 150 cells/mm3 higher in the AZT group, and more patients were p24 antigenemic in the placebo group (these differences were not statistically significant). 7 clinical events occurred in the placebo group (4 candidiasis at week 6, week 19, month 9 and month 23; 2 herpes zoster at months 5 and 6; and I oral leukoplakia at month 5). One event occurred in the AZT group (oral leukoplakia at month 13). There was a statistically significant difference in event free time between the two groups (P =.0086). CHILDREN: In May 1990 AZT was approved (in a syrup formulation) for use in HIV+ children over three months old. The recommended dose at the time of approval was 180 mg/m2 PO qid. However, data from ACTG 128 (see below) have demonstrated that AZT 90mg/m2 is equally as effective and less toxic than the previously recommended dose. Moreover, data from ACTG 152 conclude that AZT monotherapy is inferior to ddl monotherapy and AZT/ddl in combination. To examine whether a lower dose of AZT was equally effective, Brady et al. conducted a randomized, double-blind study of AZT 180 mg/m2 vs. AZT 90 mg/m2 (ACTG 128) in 426 symptomatic HIV+ children. AZT in either dose was well tolerated, with no difference in efficacy or tolerance by treatment group using any clinical or laboratory parameter. The investigators concluded that for children with mild to moderate HIV-disease, a reduction of AZT to 90 mg/m2 should be the recommended dose. ACTG 152 (Englund et al.), a study comparing AZT monotherapy to ddl monotherapy to both drugs combined in HIV+ children, has been completed and 16

Page  17 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 }7 reported. NIAID and the manufacturer of AZT report that children randomized to receive AZT monotherapy were progressing faster to AIDS-defining illnesses and death than patients receiving either ddl or ddl/AZT in combination. All ACTG pediatric protocols using AZT as a control have since been stopped or altered to reflect these data. PERINATAL TRANSMISSION: Final results from ACTG 076 concluded that AZT reduces the risk of maternal-fetal HIV transmission. 477 pregnant women with CD4+ counts >200/mm3 were enrolled in the study and randomized to receive AZT or placebo after the 14th week of gestation. Medication was delivered orally until labor, and intravenously during labor. At birth, infants received AZT syrup (2 mg/kg PO 4 x qd) or placebo for six weeks according to the mother's randomization. The interim analysis included data on 363/421 infants; 180 of these infants received AZT and 183 received placebo. A total of 53 infants were found to be HIV+ by viral culture; significantly more of the infected infants had received placebo (40/53 received placebo and 13/53 received AZT). The rate of transmission at 18 months was estimated to be 25.5% in the placebo group vs. 8.3% in the AZT group (P = 0.00006). Connor et al. has reported on the long-term effect of AZT exposure among uninfected infants born to HIV+ mothers in ACTG 076. 274 infants were followed for at least 60 weeks (151 AZT treated, 123 placebo treated). Other than reversible anemia in AZT-treated children, no significant differences were reported with respect to weight, length, head circumference, CD4+ and CD8+ counts. VIRAL RESISTANCE: Two recently published articles have suggested that high-level resistance of HIV to AZT may predict more rapid clinical progression and death. Both reports (Japour et al. and D'Aquila et al.) are retrospective analyses from AZT-treated patients enrolled in ACTG 116B/117. D'Aquila et al., reported that 26 patients with strongly AZT-resistant HIV were 1.7 times more likely to die or to have an AIDS-defining event than other patients after adjustment for other predictors (CD4+ count, AIDS diagnosis, and phenotype). In a confirmatory study reported by Japour et al., the prevalence of two HIV mutations conferring AZT resistance in 188 patients who had taken AZT for at least 16 weeks was examined. After adjustment for other predictors, the combined presence of mutations at codons 215 and 41 predicted HIV progression, with relative risks of 1.82 for new AIDS-defining illnesses and 5.42 for death. The emergence of AZT-resistant HIV strains isolated from HIV+ patients treated with AZT for more than 6 months has been reported by a number of investigators. AZT-resistant HIV-1 has been isolated from persons who have never received AZT. Additionally, Erice et al. have reported that transmission of an AZT-resistant strain of HIV-1 from one person to another is possible. The clinical relevance of these in vitro findings has not been established. TOXICITY/SIDE EFFECTS: Reversible bone-marrow toxicity is the major dose-limiting toxicity of AZT treatment (anemia or leukopenia). Fatigue, rashes, severe muscle pain and inflammation (myopathy), nausea, insomnia, and headaches are also associated with AZT therapy. Side effects are generally more pronounced and frequent in patients with more advanced disease. Enlarged fatty liver and lactic acidosis have been reported in patients taking certain nucleoside analogues, including rarely, AZT. Enlarged fatty liver has been reported in at least 11 patients receiving AZT; the syndrome was fatal in eight of these patients (Freiman et al., Schuman et al.). Ten of the patients were women, and seven of these women were obese. Seven cases of lactic acidosis in HIV+ patients have been reported (Chattha et al.); four of these patients were receiving AZT. Other causes of lactic acidosis were excluded. Four patients died of cardiovascular collapse secondary to lactic acidosis. Two of the seven were obese women who were found to have extensive fatty liver. The manufacturer suggests that obese women and patients with risk factors for liver disease be followed closely while receiving AZT, and that lactic acidosis be considered when patients develop tachypnea, dyspnea, or decreased bicarbonate levels. REFERENCES: Boucher C et al. HIV-1 biological phenotype and the development of zidovudine resistance in relation to disease progression in asymptomatic individuals during treatment. AIDS 6: 1259-1264, 1992. Boyer PJ et al. Factors predictive of maternal-fetal transmission of HIV-1. JAMA 271:1925-1930, 1994. Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 343:871-8, 1994. Brady MT et al. Randomized study of the tolerance and efficacy of high- versus low-dose zidovudine in human immunodeficiency virus-infected children with mild to moderate symptoms (AIDS Clinical Trials Group 128). JID 173:1097-106, 1996. Connor EM, et al. Reduction of Maternal-Infant Transmission of HIV-1 with Zidovudine Treatment. N ENGL J MED 331(18):1173-80, 1994. Connor EM et al. Long term effect of zidovudine exposure among uninfected infants born to HIV-infected mothers in pediatric AIDS Clinical Trials Group (ACTG) protocol 076. Abstract 11, 35th ICAAC, San Francisco, 1995. Cooper DA et al. Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter. N ENGL J MED 329(5):297-303, 1993. Erice A et al. Primary infection with zidovudine-resistant human immunodeficiency virus type 1. (brief report) N ENGL J MED 328(16):1163-65, 1993. D'Aquila RT et al. Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. Ann Intern Med 122:401-8, 1995. Fischl MA et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N ENGL J MED 323(15):1009-14, 1990. 17 I

Page  18 Antiretroviral Therapies Fischl MA et al. The safety and efficacy of zidovudine (AZT) in the treatment of patients with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. A double-blind, placebo-controlled trial. Ann Intern Med 112:727-37, 1990. Hamilton JD et al. A controlled trial of early versus late treatment with zidovudine in symptomatic HIV infection. N ENGL J MED 326(7): 437-43, 1992. Japour AJ et al. Prevalance and clinical significance of zidovudine resistance mutations in human immunodeficiency virus isolated for patients after long-term zidovudine treatment. JID 171:1172-9, 1995 Kinloch-de Loes S et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N ENGL J MED 333:408-13, 1995. Lenderking WR et al. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. N ENGL J MED 330(11):738-43, 1994. Lundgren JD et al. Comparison of long-term prognosis of patients with AIDS treated and not treated with zidovudine. JAMA 271:1088-92, 1994. Mulder JW et al. Zidovudine twice daily in asymptomatic patients with HIV infection and a high risk of progession to AIDS: a randomized, double-blind placebo-controlled study. AIDS 8:;313-21, 1994. Sande MA et al. Antiretroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art conference. JAMA 270:2583-9, 1993. Schuman P et al. Fatty infiltration of the liver associated with lactic acidosis in 3 women with HIV infection. Abstract 1085, 32nd ICAAC, Anaheim, 1992. Seligmann M et al. The Concorde trial: first results. Abstract WS-B24-5, IX Intl Conf AIDS, Berlin, 1993. Simberkoff MS et al. Longterm followup of VA trial comparing early versus late AZT for symptomatic HIV infection. Abstract PoB3723, VIII Intl Conf AIDS, Amsterdam, 1992. Unadkat J et al. Pharmacokinetics of oral zidovudine (azidothymidine) in patients with AIDS when administered with or without a high-fat meal. AIDS 4:229-32, 1990. Volberding PA et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4+ cell counts of 500 or more per cubic millimeter. N ENGL J MED 333:401-7, 1995. Volberding PA et al. The duration of zidovudine benefit in persons with asymptomatic HIV infection. JAMA 272:437-442, 1994. Volberding PA et al. Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N ENGL J MED 322(14): 941-9, 1990. PHYSICAL DESCRIPTION: ddC is a cytidine nucleoside analogue. ddC was originally approved for use in combination with AZT in patients with no prior antiretroviral experience. The FDA recently approved ddC as monotherapy treatment for HIV+ people who have experienced disease progression while receiving AZT or who are intolerant to AZT. ddC monotherapy is not as effective as AZT/ddC combination therapy in prolonging life. TRIAL RESULTS ANTIRETROVIRAL-EXPERIENCED PATIENTS: ACTG 119 compared ddC (2.25 mg/day) and AZT (500 - 1200 mg/day) in AIDS/advanced ARC patients with >12 months prior AZT treatment (Fischl et al.). The study was originally designed to enroll 320 patients, but only enrolled 115. Due to this small sample size, the study has insufficient statistical power either to prove or disprove the efficacy of ddC relative to AZT in this population. Significantly more patients withdrew from AZT therapy; median treatment duration was 279 and 174.5 days in the ddC and AZT groups respectively. 19/59 (32%) ddC recipients and 17/52 (33%) AZT recipients died or developed AIDS as a first critical event. CD4+ counts declined more slowly in the ddC group (-0.08 cells/day) than in the AZT group (-0.17 cells/day) (P = 0.05). A randomized open-label study conducted through the Community Program for Clinical Research on AIDS (CPCRA 002) compared ddl to ddC as salvage monotherapies in patients who could not tolerate or whose disease had progressed on AZT therapy (Abrams et al.). The median CD4+ count was 37/mm' and patients had taken AZT for an average of 16 months. 230 patients were randomized to ddl (250 mg bid) and 237 were randomized to ddC (0.75 mg tid) and followed for at least one year. With disease progression and death as a combined endpoint, no significant difference was observed (157/230 patients on ddl and 150/237 on ddC reached endpoints, P = 0.57). Fewer patients randomized to ddC died (88 vs. 100 deaths, P = 0.09). This difference was statistically significant after adjustment for small imbalances between randomization groups (adjusted relative risk for death = 0.64, 95% confidence interval, 0.46 to 0.85; P = 0.003). Peripheral neuropathy and stomatitis occurred more frequently in the ddC group, while pancreatitis and diarrhea were more frequent in the ddl group. ANTIRETROVIRAL-NAIVE PATIENTS: A direct comparison of AZT monotherapy versus ddC monotherapy was studied in ACTG 114 (Fischl et al.) ACTG 114 was a double-blind controlled clinical trial comparing AZT and ddC in 18

Page  19 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 635 AIDS/advanced ARC patients with CD4+ counts <200 cells/mm3 and less than three months' prior AZT treatment. Patients were randomized to ddC 0.75 mg tid or AZT 100 - 200 mg qid. A one-year interim analysis, which eventually led to the closure of the trial, showed a statistically significant survival benefit for the AZT group. Results from an earlier (six-month) interim analysis showed that anti-HIV activity, determined by p24 antigen decreases and CD4+ count increases, were reported in both the AZT and ddC groups. By 6 months, 27/300 (9.0%) patients on ddC and 18/300 (6.0%) on AZT had discontinued treatment due to adverse reactions. 18/27 ddC discontinuations resulted from peripheral neuropathy and the remainder were caused by oral aphthous ulcers, elevated LFTs and neutropenia or anemia. 11/18 AZT discontinuations resulted from hematologic toxicity. CHILDREN: The safety and effectiveness of ddC in children younger than 13 years of age has not been established. Chadwick et al. has reported results on the safety, tolerability, and pharmacokinetics of ddC in a single oral dose (0.02 mg/kg) in 23 symptomatic HIV+ children. The mean age of children studied was 4.2 years. The drug was well tolerated and no side effects were noted. Plasma concentrations were lower and the half-life shorter in these children than in adults given comparable doses, suggesting that ddC may be cleared more rapidly in children than adults. VIRAL RESISTANCE: ddC resistance data has been reported (Richman et al.). Resistance is associated with a fivefold decrease in viral sensitivity and is associated with mutations at amino acids 74; conferring resistance to both ddl and ddC. TOXICITY/SIDE EFFECTS: Peripheral neuropathy and much less commonly, pancreatitis, are the most serious side effects associated with ddC. Uninterrupted use of ddC at high doses (between 0.005 and 0.06 mg/kg every 4 hours) is associated with a high incidence of peripheral neuropathy. However, reports of peripheral neuropathy are reported less frequently at the lower doses in current clinical use (between 5-10%). Fever, rash, stomatitis, and elevated liver enzymes have also been reported as side effects of ddC. Severe oral ulcers occurred in approximately 3% of patients receiving ddC in CPCRA 002; less severe oral ulcerations have occurred at higher frequencies in other clinical trials. REFERENCES: Abrams DI et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N ENGL J MED 330:657-62, 1994. Chadwick EG et al. Phase I evaluation of zalcitabine administered to human immunodeficiency virus-infected children. JID 172:1475-9, 1995. Cooney DA et al. Initial studies on the cellular pharmacology of 2',3-dideoxycytidine, an inhibitor of HTLV-III infectivity. Biochem Pharmacol 35(13): 2065-8, 1986. Fischl MA et al. Zalcitabine compared with zidovudine in patients with advanced HIV-1 infection who received prior zidovudine therapy. Ann Intern Med 118:762-9, 1993. Klecker R et al. Pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS and related disorders. J Clin Pharmacol 28: 837-42, 1988. Merigan TC et al. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. Ann Intern Med 110: 189-94, 1989. Mitsuya H et al. Inhibition of the in vitro infectivity and cytopathic effect of HTLV-III/LAV by 2',3'-dideoxynucleosides. PNAS 83: 1911-5, 1986. Sande MA et al. Antiretroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art conference. JAMA 270 2583-9, 1993. Trials, page 142, 145, 146 PHYSICAL DESCRIPTION: Dideoxyinosine is a purine nucleoside analogue ddl was the second antiretroviral approved for HIV infection (1991), originally for the treatment of adults with advanced HIV infection who have received prolonged prior treatment with AZT. The FDA recently approved ddl as first-line therapy against HIV in adults and children based on clinical endpoint data from ACTG 175 and ACTG 152. The recommended dosages are 200 mg tablets bid for adults weighing > 60 kg and 125 mg tablets bid for adults weighing < 60 kg. Two randomized dose-ranging trials concluded that higher doses of ddl were no more efficacious and significantly more toxic than the 200 mg bid dose studied (Allan et al., Darbyshire et al.) Tablets must be chewed or dissolved in water. A new formulation of ddl tablets is now available. The new formulation is smaller in size and dissolves quickly in water. A sachet (buffered powder) formulation is also available. The 200 mg bid tablet dosing schedule is equivalent to 250 mg bid buffered powder. The 125 mg bid tablet dosing schedule is equivalent to 167 mg bid buffered powder. TRIAL RESULTS ANTIRETROVIRAL-EXPERIENCED PATIENTS: Approval of ddl monotherapy was based on the successful completion of ACTG 116B/117, that demonstrated a clinical benefit of ddl 500 mg/day for asymptomatic and mildly-symptomatic patients with median prior AZT experience of 13.9 months (Kahn et al.). The median baseline CD4+ count was 95 cells/mm3. The primary endpoints of the study were death and new AIDS-defining events. 913 patients were randomized; 298 received low-dose ddl (500 mg/day), 311 received high-dose ddl (750 mg/day), and 304 received AZT (600 mg/day). After one year of therapy, the only statistically significant differences in disease progression rates were between the low-dose ddl and AZT groups (P = 0.015). Survival rates were 19 I

Page  20 Antiretroviral Therapies statistically similar between all three groups and no clinical benefits were observed in patients who entered the study with a diagnosis of AIDS. There was no correlation between duration of prior AZT treatment and clinical benefit. Clinical benefit was reported, however, in a study of 152 HIV+ patients with symptomatic disease. Patients were randomized to continue AZT (600 mg/day) and 160 were randomized to switch to ddl (600 mg/day). The main endpoints were death, AIDS-defining 01, or minor OI in concert with a CD4+ count < 50% of baseline. Spruance et al. report that significantly fewer endpoints occurred in the ddl group. The rates of progression were 53% and 75% in the ddl and AZT groups, respectively (P = 0.02). No significant difference in survival was noted; the death rates were 24% and 21% in the ddl and AZT groups, respectively. A randomized open-label study conducted through the Community Program for Clinical Research on AIDS (CPCRA 002) compared ddl to ddC for one year as salvage monotherapies in 467 patients who could not tolerate or whose disease had progressed on AZT therapy (Abrams et al.). With disease progression and death as a combined endpoint, no significant difference was observed. The difference was statistically significant after adjustment for small imbalances between randomization groups. Peripheral neuropathy and stomatitis occurred more frequently in the ddC group, while pancreatitis and diarrhea were more frequent in the ddl group. ANTIRETROVIRAL-NAIVE PATIENTS Dolin et al. reported data from a double-blind placebo-controlled phase II clinical trial (ACTG 116A) comparing two doses of ddl (sachet formulation) and AZT in 617 HIV+ patients with less than 16 weeks prior AZT treatment. AIDS/ARC patients with CD4+ count <300/mm3 and asymptomatic patients with CD4+ counts <200/mm3 were enrolled. Patients were stratified according to prior AZT exposure (0 - 8 weeks, or 8 - 16 weeks) and randomized to receive ddl 500 mg/day, ddl 750 mg/day, or AZT 600 mg/day. (Accrual into the low-dose ddl arm was terminated early to expedite enrollment. The analysis reviewed here only includes patients enrolled while all three arms remained open.) Median follow-up was 85 weeks. Overall, no difference between the three groups was observed. Several sub-group analyses were conducted which showed differences between groups. Among patients with no prior exposure (n = 380), fewer new AIDS-defining conditions or deaths occurred in the AZT group compared with high-dose ddl, but there was no statistical difference between AZT and low-dose ddl. 18% of AZT recipients, 31% of high-dose ddl recipients, and 29% of low-dose ddl recipients developed a new AIDS-defining condition or died. Among patients with 8-16 weeks' prior exposure to AZT (n = 118), fewer endpoints occurred in the low-dose ddl group compared with AZT, and there was no statistical difference between high-dose ddl and AZT. 33% of AZT recipients, 17% of high-dose ddl recipients, and 11% of low-dose ddl recipients developed a new AIDS-defining condition or died. Among patients who had less than 8 weeks' prior AZT therapy (n = 119), no statistically significant differences were observed. VIRAL RESISTANCE: The development of ddl-resistant strains has been reported in patients with prolonged ddl monotherapy (Reichman et al.). A single mutation at amino acid 74 in strains of decreased sensitivity to ddl causes resistance to ddl as well as ddC. When this mutation occurs in an AZT-resistant strain (with a mutation at amino acid 215), patients appear to regain sensitivity to AZT (St. Claire et al.). CHILDREN: The FDA originally approved ddl for the treatment of children with advanced HIV infection who are intolerant of or no longer benefitting from AZT treatment. It is now approved, both as monotherapy and in combination with AZT, as first-line therapy for HIV+ children. This approval is based on the results of ACTG 152, a clinical trial comparing AZT monotherapy to ddl monotheray to both drugs combined (Englund et al.). When compared to AZT monotherapy, both ddl and AZT/ddl significantly reduced rates of disease progression and death. So significant difference in the rates of disease progression and death were reported between the ddl monotherapy group and the combination group. DRUG INTERACTIONS: It is recommended that patients taking dapsone or ketaconazole take it two hours before taking ddl. The antacid buffer in ddl tablets may inhibit the gastric absorption of dapsone and ketaconazole, which requires acidity for dissolution. Patients receiving oral ganciclovir and ddl may be at increased risk for pancreatitis. Based on data from concluded studies, the manufacturer of oral ganciclovir reports that plasma levels of ddl are increased in patients receiving concurrent oral ganciclovir, possibly accounting for the interaction. Among more than 400 patients in clinical trials of oral ganciclovir, 7/8 who developed pancreatitis were receiving ddl. TOXICITY/SIDE EFFECTS: Potentially fatal pancreatitis and peripheral neuropathy are the most serious toxicities of ddl. Pancreatitis has been reported in about 17% of the phase I/II clinical-trial participants and about 5% of the expanded-access participants. In ACTG 116B/117, the risk of pancreatitis was dose-related, occurring in 10% of patients taking ddl 750 mg/day and 6% of patients taking ddl 500 mg/day. Pancreatitis was also found to be dose-related in the Alpha study. The single greatest risk 20

Page  21 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 '7 factor for developing pancreatitis is a prior history of pancreatitis. Other risk factors include abnormal liver function tests and abnormal renal function. Asymptomatic serum amylase levels at baseline are not strongly correlated with subsequent development of pancreatitis. Nausea and abdominal pain warrant cessation of treatment pending evaluation. Peripheral neuropathy requiring drug discontinuation occurred in 22% of the phase I/I clinical trial participants and 16% of the expanded-access participants. However, in both ACTG 116A and ACTG 116B/117, peripheral neuropathy occurred with equal frequency in the ddl and AZT groups. Neuropathy has been associated with daily ddl doses >12.5 mg/kg and cumulative ddl doses >1.5 g/kg, and especially with a prior history of peripheral neuropathy or concurrent treatment with vincristine. Most cases are mild and resolve upon cessation of the drug. Diarrhea requiring dose modification occurred in about 29% of phase I/II participants and 16% of expanded-access participants, all of whom were receiving a sachet formulation of ddl. Some investigators suggest that nausea and diarrhea is also associated with the tablet formulation. ddl may be associated with a very low rate of liver failure. One report (Lai et al.) describes a patient in a phase I trial of ddl (12 mg/kg/day PO) who died of fulminant liver failure. On autopsy, the patient's liver was enlarged with cholestasis and fatty change. The manufacturer has since analyzed a database of 45,000 ddl users and found reports of 163 patients who died with serious liver dysfunction. Whether these cases are related to ddl therapy is not known. PEDIATRIC TOXICITIES: Retinal lesions have been observed in children receiving ddl. Whitcup et al. report that these lesions appear as mottling and atrophy of the retinal-pigment epithelium and progress while ddl therapy continues. Progression stops upon cessation of ddl. Lesions are located in the mid-periphery of the fundus and may be missed upon examination by direct ophthalmoscope through undilated pupils. Therefore, the investigators suggest that all children receiving ddl be examined by indirect ophthalmoscopy through dilated pupils every four to six months. REFERENCES: Abrams DI et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N ENGL J MED 330:657-62, 1994. Allan JD et al. An efficacy study of 2'3'-dideoxyinosine (ddl) [BMY-40900] administered orally bid to zidovudine intolerant patients with HIV infection (ACTG 118). Abstract WS-B24-2, IX Intl Conf AIDS, Berlin, 1993. Butler KM et al. Prolonged dideoxyinosine (ddl) therapy in HIV+ children. VII Intl Conf AIDS, Florence. Vol. 1: 81(TU.B.94), 1991. Darbyshire JH and Aboulker JP. Didanosine for zidovudine-intolerant patients with HIV disease. Lancet 340:1346-7, 1992. ddl Iberian Study Group. Efficacy and safety of didanosine (ddl) vs. zidovudine (ZDV) in patients with HIV infection no longer benefitting from ZDV therapy. Abstract 037, 4th European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994. De Wit S et al. Efficacy and tolerability of a very low dose of didanosine (ddl) compared to a standard regimen. 33rd ICAAC, abstract #101, 1993. Dolin R et al. Efficacy of didanosine (ddl) versus zidovudine (ZDV) in patients with no or < 16 weeks of prior ZDV therapy. Abstract WS-B24-1, IX Intl Conf AIDS, Berlin, 1993. Grasela TH et al. Analysis of potential risk factors associated with the development of pancreatitis in phase I patients with AIDS or AIDS-related complex receiving didanosine. J Infect Dis 169:1250-1255, 1994. Kahn JO et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N ENGL J MED 327: 581-7, 1992. Kozal MJ et al. Didanosine resistance in HIV+ patients switched from zidovudine to didanosine monotherapy. Ann Intern Med 121:263-268, 1994. Lai KK et al. Fulminant hepatic failure associated with 2',3'-dideoxyinosine (ddl). Ann Intern Med 115:283-4, 1991. Montaner JSG et al. Didanosine compared with continued zidovudine therapy for HIV-infected patients with 200 to 500 CD4+ cells/mm3. Ann of Intern Med 123:561-71, 1995. Sande MA et al. Antiretroviral therapy for adult HIV-infected patients. Recommendations from a state-of-the-art panel. JAMA 270:2583-9, 1993. Spruance SL et al. Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clincial deterioration while receiving zidovudine. A randomized, double-blind clinical trial. Ann Intern Med 120:360-368, 1994. Whitcup SM et al. Retinal lesions in children treated with dideoxyinosine. N ENGL J MED 326: 1226-7, 1992. OTHER REPORTS: Bach MC. Clinical response to dideoxyinosine in patients with HIV infection resistant to zidovudine. N ENGL J MED 323(4): 275, 1990. Butler et al. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N ENGL J MED 324(3): 137-44, 1991. Cooley TP et al. Once-daily administration of 2'-3'-dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: results of a phase I trial. N ENGL J MED 322(19): 1340-5, 1990. Kozal MJ et al. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med 121:263-268. 1994. Lambert JS et al. 2'-3'-Dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: a phase I trial. N ENGL J MED 322(19): 1333-40, 1990. Yarchoan R et al. Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex. Lancet 336: 526-9, 1990. 21

Page  22 Antiretroviral Therapies PHYSICAL DESCRIPTION: d4T is a purine nucleoside analogue. d4T was approved (1994) by the Food and Drug Administration (FDA) for patients with advanced HIV infection who are intolerant to, or failing, approved therapies of proven clinical benefit. TRIAL RESULTS Approval was based on successful completion of a randomized, double-blind, placebo-controlled study comparing d4T 40 mg bid to AZT in patients with CD4+ counts between 50 - 500/mm3 and at least six months of prior AZT therapy (Pavia et al.). A total of 822 participants were evenly randomized to either continue AZT or switch to d4T. The primary endpoints were disease progression, survival, and a 50% drop in CD4+ count from baseline. At entry, 36% of patients were asymptomatic, 50% had symptomatic HIV disease, and 14% had AIDS. Patients had a median CD4+ count of 235 cells/mm3, with approximately 20 months prior AZT experience. Patients randomized to d4T remained on assigned therapy longer than those on AZT (79 weeks versus 54 weeks; P < 0.0001). Time to protocol-specific treatment failure, defined as AIDS-defining event, death, or greater than 50% decline in CD4+ cell count was longer in the d4T group (P = 0.002). At 93 weeks, the mean CD4+ cell drop below baseline was 79 cells/mm3 in those who continued on AZT and 53 cells/mm3 in those who switched to d4T. Reports of neuropathy were significantly higher in the d4T group. A total of 28 patients receiving d4T permanently discontinued due to peripheral neuropathy. Final analysis showed a strong trend in favor of switching to d4T in delaying progression to AIDS or death. (P = 0.06) An analysis of the expanded access protocol has also been completed (Gottlieb et al). Data in 11,784 HIV+ patients, randomized to receive one of two doses of d4T, has been reported. Patients enrolled received either 40 mg bid or 20 mg bid d4T for a median of 22 weeks. The median CD4+ count upon entry was 44 cells/mm3. Death occured in 7% of those who received high-dose d4T and in 8% of those who received low-dose d4T (P = NS). While weight gain and hematologic improvements were reported in the high-dose d4T group, these data were not statistically significant. Dose modification due to the development of peripheral neuropathy occurred in 23% of those in the high-dose d4T group and in 17% of those in the low-dose group (P < 0.0001). CHILDREN: Federici and co-workers report from an ongoing study in 38 HIV+ children that d4T 2 mg/kg/day has been safely administered with no cases of drug-related peripheral neuropathy. The most common adverse events reproted appear to reflect disease-related events. While cases of thrombocytopenia, anemia, leukopenia, and elevated liver enzymes have been reported, these have not been attributed to d4T use. TOXICITY/SIDE EFFECTS: Peripheral neuropathy is the most frequently observed toxicity of d4T, and it is dose-related. In the phase II studies, peripheral neuropathy was observed in 12, 11, and 65% of patients receiving 0.1, 0.5, 2.0 mg/kg/day respectively. In the expanded access program involving patients with advanced disease intolerant to other therapies, neuropathy was seen in 23% and 17% of patients receiving 40 mg bid or 20 mg bid respectively. This difference, which was statistically significant, led the Data Safety Monitoring Board to recommend discontinuation of the 40 mg bid arm and continue to enroll patients at 20 mg bid. In the phase III study comparing d4T vs. AZT in patients with prior AZT, toxicities overall were seen more frequently in the AZT group (especially nausea, anemia and lowered white blood cell counts). However, neuropathy did occur more frequently in the d4T group (Mellors et al.). The manufacturer has alerted investigators to anecdotal reports from patient advocates that some patients who received d4T in clinical trials or through the expanded access program have experienced sleep disorders, mania, and skin rashes. Whether these symptoms were related to d4T is unknown. However, toxicity data from the blinded d4T trials (including the parallel track) have been evaluated by an independent data and safety monitoring board. These evaluations led to the discontinuation of the highest dosing schedule (40 mg bid) in the parallel track program. REFERENCES: Browne M et al. Phase I study of d4T in AIDS and ARC. JID 167:21-29, 1993. Dudley MN et al. Pharmacokinetics of stavudine in patients with AIDS orAIDS-related complex. JID 166:480-5,1992. Gottlieb M et al. Comparison of safety and efficacy of two doses of stavudine (Zerit, d4T) in a large simple trial in the US parallel track program. 35th ICAAC, Abstract #1171, San Francisco, 1995. Katama C et al. Stavudine (d4T) in HIV-infected patients with CD4+ > 350: results of a double-blind, randomized placebo controlled study. Abstract #196, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Mellors J et al. Safety and tolerability of Zerit (stavudine, d4T) versus retrovir (zidovudine, ZDV) in HIV infected adults with < 500 CD4+ cells/mm after at least 6 months ZDV treatment. Abstract 1170, 35th ICAAC, San Francsco, 1995. Pavia AT et al. Clinical efficacy of stavudine (d4T, Zerit) compared to zidovudine in ZDV-pretreated HIV positive patients. 35th ICAAC, Abstract #1189, San Francisco, 1995. Pottage JR et al. Stavudine in the therapy of patients with advanced AIDS and < 50 CD4+ cells. Abstract #270, 2nd National Conference on Human Retroviruses, Washington DC, 1995. Merrill DP et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. JID 173:355-64, 1996. 22

Page  23 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 PHYSICAL DESCRIPTION: 3TC is composed of the (-) enantiomer of the racemic mixture 2'-deoxy-3'-thiacytidine (BCH 189). 3TC has been approved (1995) by the Food and Drug Administration (FDA) for use in combination with AZT in HIV+ patients under the accelerated approval regulations. 3TC/AZT combination data begin on page 27. The optimal dose of 3TC, when used in combination with AZT, was found to be 150 mg bid (Eron et al.). TRIAL RESULTS In a phase I/II trial reported by van Leeuwen et al. a total of 104 HIV+ patients with CD4+ counts greater than 100 cells/mm3 and less than four months prior AZT experience were randomized to receive seven dose levels, ranging from 0.5 mg/kg/day to 20 mg/kg/day; approximately 10-15 patients were randomized to each dose level. All doses were well tolerated and associated with moderate increases in CD4+ cells. All CD4+ count increases returned to baseline at week 12. VIRAL RESISTANCE: 3TC-resistant HIV-1 mutations emerge readily in vitro (Tisdale et al. and Gao et al.). Substitution of the Met 184 residue adjacent to the active site of RT confers resistance. In clinical studies, resistance to 3TC was observed in nearly all patients who received 3TC monotherapy for more than 12 weeks. However, treatment for more than 48 weeks was associated with lower HIV-RNA levels than those at baseline (Pluda et al.) TOXICITY/SIDE EFFECTS: Phase II and phase III studies of 3TC have reported the following toxicities: headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, neuropathy, neutropenia, and anemia. There have been limited anecdotal reports of alopecia, mania, and increased agitation in clinical trials of 3TC. REFERENCES: Danner S et al. 3TC in HIV positive asymptomatic or mild ARC patients. Abstract PO-B26-2054, IX Intl Conf AIDS, Berlin, 1993. Eron JJ et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N ENGL J MED 333:1662-9, 1995. Pluda JM et al. Phase I/II study of 3TC (lamivudine) in HIV-positive, asymptomatic or mild AIDS-related complex patients: sustained reduction in viral markers. AIDS 9: 1323, 1995. Tisdale M et al. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. PNAS 90: 5653-6, 1993. Van Leeuwen R et al. Evaluation of safety and efficay of 3TC in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase 1/11 study. JID 171:1166-71, 1995. Trials, pages 143 PHYSICAL DESCRIPTION: 1592U89 is a guanosine nucleoside analogue. TRIAL RESULTS No clinical endpoint data from controlled clinical trials are yet available. McDowell et al. has reported results from an initial phase I study of 1592U89 in a single-dose escalation study. In a randomized fashion, 12 patients received 1592U89 and 6 received placebo with at least 6 days between doses. The doses (100, 300, 600, 900, and 1200 mg) were administered. Six patients received an oral solution of the compound to determine the bioavailability of the tablet. At the 300 mg dose, the tablet AUC was 99% of the oral solution AUC and administration with food lowered AUC by 5% and Cmax by 35%. 1592U89 was reported to be safe and well tolerated by all patients. A phase I/I study of 1592U89 monotherapy versus 1592U89 in combination with AZT has been reported (Saag et al.). A total of 19 patients with less than 12 weeks prior antiretoriviral experience received 1592U89 (200 mg tid) for a total of four weeks. After four weeks, patients were randomized to receive either AZT or placebo in combination with 1592U89. The median CD4+ counts and HIV-RNA levels upon entry were 340 cells/mm3 and 5.14 logs/ml, respectively. A preliminary analysis of 1592U89 monotherapy at four weeks demonstrated a rise in CD4+ counts of 84 cells/mm3 and a mean decrease in HIV-RNA of 1.8 logs. Patients who then combined AZT with 1592U89 demonstrated a 2.3 log reduction at week 12. However, when compared to patients who remained on 1592U89 monotherapy, these data were not statistically significant. Preliminary results from a larger phase I/II study of 1592U89 alone and in combination with AZT have been presented (Saag et al.). Sixty patients with a median HIV-RNA count of 63,000 copies/ml and a CD4+ count of 368 cells/mm3 were evenly randomized to one of three 1592U89 dosing groups (200 mg tid, 300 mg bid, and 400 mg tid). However, patients were disproportionately randomized; the median HIV-RNA level in the 200 mg tid group was 125,000 copies/ml, whereas the median HIV-RNA levels in the other two groups was 36,000 copies/ml. At four weeks of follow-up, there was no statistically significant difference in HIV-RNA reductions between the three groups, ranging from 1.5 log in the 200 mg tid group and 2.2 log in the 400 mg tid group. After four weeks, AZT (200 mg tid) or placebo were added for an additional eight weeks. At 12 weeks, there 23

Page  24 Antiretroviral Therapies I were no statistically significant differences in HIV-RNA reductions or CD4+ count increases between those patients who received the addition of AZT or placebo. HIV-RNA reductions reported at week four were maintained throughout the twelve weeks of therapy. A median increase of 100 CD4+ cells/mm3 was reported at week 12 in all patients. Four patients were removed from the trial due to adverse events; two reported fever and rash, two reported nausea and fatigue. A fourth treatment group receiving 600 mg tid is still being treated and followed. TOXICITY/SIDE EFFECTS: Gastrointestinal disturbances (nausea and diarrhea), fever, and rash were the most common adverse events in the phase I/II studies reported. REFERENCES: McDowell JA et al. Initial phase I study of anti-HIV agent 1592U89 in a single-dose escalation design including food effect and dosage form evaluation. Abstract 1109, 35th ICAAC, San Francisco, 1995. Saag M et al. A phase I/II study of a novel nucleoside reverse transcriptase inhibitor, 1592U89 monotherapy vs. 1592U89 + zidovudine or placebo in HIV infectioned patients with CD4 counts between 200 and 500. Abstract #195, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Saag M et al. Preliminary data on the safety and antiviral effect of 1592U89, alone and in combination with zidovudine (ZDV) in HIV-infected patients with CD4+ counts 200-500 cells/mm3. Abstract Th.B.294, Vancouver, 1996. Trials, pages 144, 145 PHYSICAL DESCRIPTION: PMEA [9-(2-phosphonyl-methoxyethyl)adenine] is an adenine nucleoside analogue. It is active in vitro against many human and animal retroviruses, including HIV-1, HIV-2, CMV, as well as other human herpesviruses. BisPom PMEA (adefovir dipivoxil, GS 840) is an oral pro-drug of PMEA. LABORATORY RESULTS: De Clercq et al. reported that PMEA inhibits HIV-induced cytopathogenicity in MT-4 cells and HIV expression in H9 cells at a concentration of 1.6-2 mM. PMEA has been shown to be effective in delaying or preventing the development of retrovirus-induced diseases in mice (Balzarini et al.), cats (Egberink et al.) and monkeys (Balzarini et al.). Some in vitro results (Balzarini et al.) suggest that PMEA may be more effective at inhibiting HIV replication when administered on an intermittent schedule. In vivo, PMEA was more effective at preventing Moloney murine sarcoma virus (MSV)-induced tumors in mice when given as a single dose at the time of viral inoculation rather than divided over several administrations. This effect was observed independent of dose. TRIAL RESULTS PMEA: In a phase I/II pharmacokinetic and safety study in HIV+ patients at the NIH, the maximum tolerated dose was determined to be approximately 3 mg/kg IV qd. Daily subcutaneously administered PMEA is being studied at the University of Washington. BisPom PMEA: Deeks et al. have reported results from a phase II, randomized, placebo-controlled clinical trial of BisPom PMEA (125 mg and 250 mg qd) versus placebo in 72 HIV+ patients. The median HIV-RNA level upon entry was 4.9 log copies/ml; the median CD4+ count upon entry was 340 cells/mm3. Patients were treated for six weeks with blinded medication followed by 6 more weeks of open-label drug. At 6 weeks, the median reduction in HIV-RNA was 0.5 logs in the 125 mg group and 0.4 logs in the 250 mg group, which persisted through week 12. No significant changes were reported in placebo recipients. Median CD4+ count increases at 6 weeks were 46 cells/mm3 in the 125 mg group and 15 cells/mm3 in the 250 mg group which increased further at 12 weeks (+57 and +27 cells/mm3). CD4+ counts and HIV-RNA levels returned to baseline after drug discontinuation. TOXICITY/SIDE EFFECTS: Reversible elevated liver enzymes and neutropenia have been observed in patients receiving intravenous PMEA. No dose-limiting toxicity has been observed in BisPom PMEA recipients. REFERENCES: Balzarini J et al. Anti-retrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in vivo increases when it is less frequently administered. Int J Cancer 46:337-40, 1990. Balzarini J et al. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. PNAS 86: 332-336, 1989. Balzarini J et al. 9-(2-phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS 5:21-8, 1992. De Clercq E et al. A novel selective broad-spectrum anti-DNA virus agent. Nature 323:464-7, 1988. Deeks S et al. A randomized, double-blind, placebo controlled study of bis-POM PMEA in HIV-infected patients. Abstract #407, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Gangemi JD et al. 9-(2-phosphonylmethoxyethyl)adenine in the treatment of murine acquired immunodeficiency virus disease and opportunistic herpes simplex virus infections. Antimicrob Agents Chemother 33:1864-8, 1989. 24

Page  25 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 17 NUCLEOSIDE ANALOGUE COMBINATIONS DESCRIPTION: Many combinations of nucleoside reverse transcriptase inhibitors (RTIs) have been compared to monotherapies, especially to AZT, in relatively short term (6 months) surrogate endpoint studies. Changes in CD4+ counts and quantitative plasma HIV-RNA levels are the most commonly used laboratory markers (surrogate endpoints). The results of three large, longer (two-three years) clinical outcomes studies of AZT/ddl and AZT/ddC vs. AZT monotherapy are described in the subsequent section. The relative efficacy of the combination of ddC and AZT compared to AZT alone for initial treatment of antiretroviral naive patients was demonstrated recently by three large studies (ACTG 175, Delta, and CPCRA 007, see page 32.) TRIAL RESULTS ALTERNATING THERAPY: Skowron et al. conducted ACTG 047 to evaluate the role of alternating AZT and ddC therapy in HIV+ patients. A total of 131 unblinded patients with symptomatic disease were randomized to receive weekly or monthly alternating AZT and ddC, weekly intermittent AZT or ddC, or continuous AZT. While the study was not powered adequately to determine clinical response rates between the various treatment groups, the investigators concluded that patients alternating AZT and ddC reported fewer toxicities associated with each drug. COMBINATION THERAPY: A randomized, double-blind study (ACTG 155) comparing AZT (200 mg tid), ddC (0.75 mg tid), and the combination of AZT/ddC (200 mg tid/0.75 mg tid) has been completed. The study population included HIV+ patients (CD4+ <200/mm3 if asymptomatic and CD4+ <300 cells/mm3 if symptomatic) with more than six months prior use of AZT. 283 patients were randomized to receive AZT, 285 to ddC, and 423 to ddC/AZT. Primary endpoints of the study included occurrence of AIDS-defining events, survival, and CD4+ changes. After 17 months of follow-up there were no differences between any of the three groups (Fischl et al.). At 12 months, the probability of being free of an endpoint was 70% for the AZT group, 67% for the ddC group, and 73% for the ddC/AZT group. Preliminary results (survival) from a clinical trial (ACTG 193A) comparing AZT and ddC combination therapy to AZT alternating monthly with ddl to AZT and ddl continous therapy to the triple-combination AZT, ddl and nevaripine in patients with < 50 CD4+ cells/mm3 has been reported (Henry et al.). TOXICITY/SIDE EFFECTS: AZT and ddC do not appear to induce synergistic toxicity. In ACTG 155, ddC-associated toxicities such as peripheral neuropathy and stomatitis occurred with equal frequency in patients receiving combination ddC/AZT or ddC monotherapy. REFERENCES: Bozzette S et al. Health status and function with zidovudine or zalcitabine as initial therapy for AIDS: a randomized controlled trial. JAMA 273:295-301, 1995. Fischl MA et al. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. Ann Intern Med 122: 24-32, 1995. Held M et al. ddC versus ddC + AZT in patients with HIV-1 infection and AZT failure. Abstract PO-B26-2061, IX Intl Conf AIDS, Berlin, 1993. Meng TC, Richman DD, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced HIV infection. Ann Intern Med 116: 13-20, 1991. Moyle G et al. Safety and efficacy of zidovudine (ZDV)- zalcitabine (ddC) combination therapy in the international collaborative study. Abstract #567, 5th European Conf Clin Aspects and Treat HIV Infect, Copenhagen, 1995. Richman DD et al. Resistance to AZT and ddC during long-term combination therapy in patients with advanced infection with human immunodeficiency virus. J AIDS 7:135-8, 1994. Schooley R et al. Trial of ZDV/DDI vs ZDV/DDC in HIV-infected patients with CD4 counts less than 300: preliminary results. Abstract 052, Fourth Intl Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994. Skowron G et al. Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex. Ann Intern Med 118:321-30, 1993. OTHER REPORTS: Liu M et al. Zidovudine and dideoxycitidine differ in their effects on human immunodeficiency virus-induced pathologic activation of the immune system. JID 170:1165-1171, 1994. Trials, pages 145-148 TRIAL RESULTS ALTERNATING THERAPY: Yarchoan et al. conducted a randomized, open-label comparison of simultaneous and alternating regimens of ddl and AZT. 41 patients with AIDS or symptomatic HIV infection were randomized into two groups. One group received AZT 300 mg/day combined with ddl 250 mg/day; the second group received AZT 600 mg/day for three weeks alternating with ddl 500 mg/day for three weeks. The study concluded that simultaneous therapy provided more sustained elevations in CD4+ counts than alternating therapy over one year. Side effects occurred with equal frequency in the two groups. 25 I

Page  26 Antiretroviral Therapies Kojima et al. recently completed an investigation of viremia changes and the development of drug-related viral mutations from a subset of 26 patients in the trial conducted by Yarchoan et al. The data suggest that the simultaneous combination (AZT 300 mg/day combined with ddl 250 mg/day) is more active in decreasing virion numbers in serum than the alternating regimen (AZT 600 mg/day for three weeks alternating with ddl 500 mg/day)(P = 0.0051). COMBINATION THERAPY: Various surrogate marker studies of ddl in combination with AZT have been reported. Two studies in particular (Collier et al., Shafer et al) reported that ddl in combination with AZT produced larger and more sustained increases in CD4+ counts, more frequent decreases in HIV-RNA levels, and more stable hematologic status that AZT monotherapy. In adults, the clinical benefits of ddl in combination with AZT, compared to AZT alone, were reported in three large studies: ACTG 175, Delta, and CPCRA 007 (see page ACTG 175 ). In children, ddl in combination with AZT was compared to AZT monotherapy and ddl monotherapy (ACTG 152). Results from this trial are discussed below. CHILDREN: Both surrogate marker and clinical endpoint data from various clinical trials of ddl in combination with AZT in children are available. Husson et al., reporting from an open-label trial, demonstrated that AZT (90 - 180 mg/m2 tid) in combination with ddl (90 - 180 mg/m2 bid) was well tolerated and significantly increased CD4+ counts in HIV+ children. The relative efficacy of ddl in combination with AZT, compared to both AZT monotherapy and ddl monotherapy, was recently reported by Englund et al. ACTG 152 compared AZT (120 mg/m2 qid) in combination with ddl (90 mg/m2 bid) to AZT alone (180 mg/m2 qid) or ddl alone (120 mg/m2 bid) in symptomatic HIV+ children with < 6 months prior AZT or ddl experience. A total of 839 children were randomized, approximately half of whom were under the age of 30 months. The primary endpoints in the study were either disease progression or death. Interim analyses in February, 1995 presented to the NIAID Data and Safety Monitoring Board indicated that AZT alone was less effective than the best of the other two treatment arms and demonstrated more toxicities; 27% receiving AZT monotherapy, 19% receiving ddl monotherapy, and 18% receiving combination therapy had reached an endpoint. Rates of motor dysfunction and tendon reflex abnormalities were significantly greater in patients receiving AZT monotherapy. Patients randomized to receive either ddl monotherapy or AZT in combination with ddl were reported in the final analysis. The median follow-up for these patients was 32 months. Primary endpoints were met by 67 (24%) patients randomized to ddl monotherapy and 68 (25%) patients randomized to the combination therapy. There was no statistically significant difference between the two groups. The investigators conclude that ddl in combination with AZT is no more effective than ddl monotherapy. Both regimens, however, are significantly more effective than AZT monotherapy. The investigators also conclude, due to trends toward increased toxicities in the combination therapy group (no significant differences reported), ddl monotherapy may be favorable over combination AZT/ddl therapy. VIRAL RESISTANCE: Combination therapy with ddl and AZT does not prevent the emergence of viral resistance (Shafer et al.). Data from ACTG 143 (Ragni et al.) show that decreased sensitivity to AZT emerges with equal frequency in patients treated with AZT or combination AZT/ddl. Decreased sensitivity to ddl developed in two patients receiving ddl/AZT therapy and no patient receiving ddl monotherapy. Resistance to both ddl and AZT emerged in two patients receiving ddI/AZT combination therapy. Preliminary results (survival) from a clinical trial (ACTG 193A) comparing the combination ddl and AZT to ddl alternating monthly with AZT to ddC and AZT combination to triple-combination of AZT, ddl and nevirapine in patients with CD4+ counts < 50 cells/mm3 has been reported (Henry et al.). REFERENCES: Englund J et al. ACTG 152: Efficacy and Safety Study Results. 21st AID Clinical Trials Group Meeting, Washington, 1996. Husson RN et al. Zidovudine and didanosine combination therapy in children with human immunodeficiency virus infection. Pediatrics 93:316-22, 1994. Kojima E et al. HIV-1 viremia changes and development of drug-related viral mutations in patients receiving long-term combination therapy with AZT/ddl. Abstract #056B, X Intl Conf AIDS, Yokohama, 1994. Mukherji E et al. Differential antiviral activities and intracellular metabolism of 3'-azido-3'-deoxythymidine and 2',3'-dideoxynosine in human cells. Amnti Microb Agents and Chemother 38:1573-1579, 1994. Ragni M et al. A phase I/1I study of combination zidovudine and didanosine in HIV positive asymptomatic patients. Symposium; The Role of Didanosine in the Management of HIV Disease. Paris, 1992. Shafer RW et al. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. JID 169:722-9, 1994. Yarchoan R et al. A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. JID 169:9-17, 1994. 26

Page  27 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199i T TRIAL RESULTS Interim analysis of ACTG 290, a randomized, four-arm study of d4T vs. ddl vs AZT/d4T vs. AZT/ddl have been reported (Havlir et al.). The analysis indicated that the average CD4+ cell count of subjects in the d4T/AZT arm decreased after study entry. The median decrease from baseline at all follow-up visits ranged from 20 cells/mm3 at week 4 to 82 cells/mm3 at week 36. No unexpected changes in average CD4+ cell counts occurred in the other arms of the study. Based on this analysis the National Institute of Allergy and Infectious Diseases (NIAID) has issued an advisory to physicians recommending that they closely monitor the CD4+ cell counts of patients taking this combination. At press time there has been no explanation for this decrease and the clinical significance, if any. References: Havlir D et al. Executive summary from the interim analysis of ACTG 290. NIAID, 1996. A Note To Physicians: Important Information on the Combination of Zidovudine (ZDV) and Stavudine (d4T) in ZDV-experienced HIV-lnfected Patients. NIAID, November 1996. Trials, page 147 TRIAL RESULTS Pollard et al. have reported results from a randomized, double-blind study of d4T in combination with ddl. A total of 76 antiretroviral-naive patients with a median CD4+ count of 325 cells/mm3 and a baseline HIV-RNA level of 6,000 copies/ml were treated with one of five doses of d4T (20, 40, or 80 mg qd) and ddl (200 or 400 mg qd). Median duration of therapy was 32 weeks and 26 patients have received > 52 weeks of therapy. Data at week 28 from blinded treatment groups show a sustained median 1.3 log decrease in HIV-RNA and a median increase of 77 CD4+ cells/mm3. Follow-up at 52 weeks is available in 26 patients; a median 1.4 log decrease in HIV-RNA and a median 90 CD4+ cells/mm3 above baseline were observed in the five dosing groups as a whole. Only one case of dose-limiting peripheral neuropathy has been reported. REFERENCES: Pollard R et al. Stavudine (d4T) and didanosine (ddl) combination therapy in HIV-infected subjects: anitviral effect and safety in an on-going pilot randomized double-blinded trial. Abstract Th.B.293, Vancouver, 1996. Trials, pages 146, 149, 151, 154 3TC has been approved by the Food and Drug Administration (FDA) to be used in combination with AZT in HIV+ patients under the accelerated approval regulations (1995). TRIAL RESULTS A preliminary clinical endpoint analysis of a 1,892-patient disease progression study conducted in Canada, Australia, Europe, and South Africa (CAESAR) has been reported (Montaner et al.). This trial was a double-blind, randomized study of 3TC versus 3TC and loviride versus placebo in patients already taking an AZT-containing treatment regimen. The median CD4+ count at entry was 130 cells/mm3. At entry, 62% of all patients were taking AZT monotherapy; the remaining 38% were taking AZT with either ddl or ddC. Patients were randomized in a 1:2:1 fashion: 482 received placebo, 935 received 3TC, and 475 received 3TC and loviride. The primary endpoints were either disease progression (a new AIDS-defining 01) or death. Disease progression or death were reported in 81/482 (17%) patients receiving placebo, 80/935 (9%) patients receiving 3TC, and 38/475 (8%) patients receiving 3TC and loviride. The difference in the two arms receiving 3TC was not statistically significant, however a significant difference between 3TC and placebo was reported (54% reduction in progression to AIDS or death, P < 0.001). The 3TC arms also showed a significant survival benefit, numbers of deaths were: 22.482 (4.6%) in the placebo group, 22/935 (2.4%) in the 3TC group, and 13/475 (2.7%) in the 3TC and loviride group (53% reduction in mortality when compared to placebo, P < 0.01). The investigators conclude that, compared to placebo, 3TC added to AZT-containing regimens significantly reduced progression to AIDS or death and increased survival. While this trial was not adequately powered to determine a statistically significant clinical benefit of adding loviride, the investigators conclude that the addition of loviride to AZT and 3TC containing regimens does not provide additional clinical benefit. Bartlett et al. compared two doses of 3TC (300 mg and 150 mg) in combination with AZT (200 mg) with a combination of ddC and AZT in AZT-experienced HIV+ patients with CD4+ counts between 100 and 300 cells/mm3. All patients were evenly randomized into the three groups. At week 24 of therapy, no significant difference in viral RNA decreases were reported; decreases below baseline were 0.6 logs in the AZT/ddC group, 0.8 logs in the high-dose 3TC/AZT group, and 0.6 logs in the low-dose 3TC/AZT group. No significant difference was reported between the high-dose 27

Page  28 Antiretroviral Therapies I 3TC/AZT group and the AZT/ddC group in sustained CD4+ count increases at week 24; both groups reported a mean 15 cells/mm3 increase at 24 weeks. Results from a randomized, double-blind trial comparing two doses of 3TC (150 mg bid and 300 mg bid) in combination with AZT (200 mg tid) versus monotherapy treatment with either 3TC (300 mg bid and 200 mg tid) or AZT (200 mg tid) in AZT-naive patients with CD4+ counts between 200 and 500 have been reported (Eron et al.). A total of 364 patients were randomized. Sustained CD4+ count increases above baseline at week 24 in the AZT monotherapy group, 3TC monotherapy group, low-dose 3TC combination group, and high-dose combination group were 8 cells/mm3, 15 cells/mm3, 36 cells/mm3, and 58 cells/mm3, respectively. Decreases in viral RNA by quantitative PCR of 1.0 versus 0.8 were reported in the high-dose and low-dose combination groups, respectively. While these data are not statistically significant, significant differences were found when comparing decreases in viral RNA between the combination groups and monotherapy groups at week 24. Results in 59% of patients who remained on study drug at week 52 have recently been reported (Eron, et al.). At week 52, 50% of patients on 3TC/AZT had a 1.0 log decrease from baseline HIV-RNA levels, compared HIV-RNA levels that returned to baseline in the AZT and 3TC monotherapy groups. Clinical endpoint data (disease progression or survival) has not yet been reported. In a randomized, double-blind trial reported by Staszewski et al., two doses of 3TC (300 mg and 150 mg) in combination with AZT (200 mg) were compared to AZT alone in patients with at least 6 months prior AZT experience. A total of 223 patients were randomized to each of the three study groups. No significant differences between the two 3TC doses in combination with AZT were reported. At 24 weeks of therapy, both combination groups reported a median increase in CD4+ counts of 33 cells/mm3 above baseline (P = NS). Katlama et al. have reported the results of a double blind safety and efficacy trial of the combination of 3TC and AZT vs. AZT alone in AZT-naive HIV+ patients. One hundred and twenty nine patients with CD4+ counts between 100 and 400 cells/mm3 with less than 4 weeks prior AZT use were randomized to receive either 3TC & AZT ( 300mg bid/200mg bid) in combination or AZT (200mg) monotherapy for 24 weeks. After 24 weeks all patients were given open-label 3TC & AZT and followed for an additional 24 weeks. Baseline characteristics were similar in both treatment groups (mean CD4+ cell count was 251 cells/mm3). At 8 weeks of treatment, median CD4+ cell counts increased in the combination group 85 cells/mm3 above baseline and remained 80 cells above baseline at week 24. In the AZT monotherapy group, median CD4+ cell counts increased 38 cells/mm3 above baseline at week 8, which fell to 7 cells below baseline at 24 weeks. (P < 0.001). While CD4+ cell counts in the combination group maintained an increase of 39 cells/mm3 at week 48, these data were not statistically significant. A subset of patients have been tested for HIV RNA by quantitative PCR assays. At week 4, a log reduction of 1.5 was reported in the combination group, with a log reduction of 0.7 in the monotherapy group. At week 24, viral RNA maintained a reduction of 1.0 in the combination group, while viral burden levels had returned to baseline in the monotherapy group. Data on survival and disease progression were not reported. ONGOING PEDIATRIC TRIALS: ACTG 300 is comparing AZT/3TC in combination to AZT/ddl in combination to ddl monotherapy. A second similar study is enrolling patients at the National Cancer Institute (NCI). Another study in children at the NCI is examining the combination of AZT/3TC with the protease inhibitor, indinavir. REFERENCES: Bartlett J et al. A randomized, double-blind multicenter comparative trial of lamivudine (3TC)/zidovudine (ZDV) combination therapy versus zidovudine/dideoxycytidine (ddC) combination therapy in ZDV experienced patients with CD4 cells 100-300. Abstract LB35, 2nd National Conference on Human Retroviruses, Washington DC, 1995. Eron JJ et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N ENGL J MED 333:1662-9, 1995. Eron JJ et al. 52 Week follow-up of NUCA 3001: 3TC, zidovudine, or both in the treatment of HIV-positive patients with CD4 cell counts of 200-500. Abstract #198, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Gao Q et al. The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine. Antimicrob Agnts Chemo 37(6): 1390-2, 1993. Katlama C et al. Combination 3TC (lamivudine) vs ZDV monotherapy in ZDV naive HIV-positive patients with CD4 of 100-400 cells/mm 3. Abstract #7.5, 2nd Intl Cong Drug Ther in HIV Infect, Glasgow, 1994. Montaner J et al. CAESAR: Confirmation of the clinical benefit of 3TC (Epivir) in HIV-1 disease: preliminary results. Abstract LB6, 36th ICAAC, New Orleans, 1996 Staszewski S et al. Combination 3TC/ZDV vs. ZDV monotherapy in ZDV experienced HIV-1 positive patients with a CD4 of 100-400 cells/mm 3. Abstract LB32, 2nd National Conference on Human Retroviruses, Washington DC, 1995. OTHER REPORTS: Larder BA et al. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269:696-99, 1995. 28

Page  29 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 COMPARING COMBINATIONS OF NUCLEOSIDE ANALOGUES DESCRIPTION: Three large randomized, double-blind, controlled trials comparing combination nucleoside therapy (AZT/ddC and /ddl) with AZT monotherapy (in all three trials) and with ddl monotherapy (in one trial) were recently reported. All of the drugs were administered at standard doses in all of the trials (AZT at 200 mg tid, ddl at 200 mg bid, and ddC at 0.75 mg tid). All three studies were designed to follow patients for several years, until clinical endpoints (progression to AIDS or death) occurred in a sizeable proportion of patients. The three trials enrolled patients at somewhat different, but overlapping, stages of disease, and all enrolled both antiretroviral naive patients and AZT-experienced patients. Toxicities that were reported from all of these trials were those expected based on previous studies of these drugs. These three trials are all consistent in demonstrating the clinical superiority (prolonging time to AIDS events and death) of combination therapy with AZT/ddl or AZT/ddC over AZT monotherapy in patients who have not taken antiretroviral therapy previously, regardless of CD4+ count at the time of initiating therapy. Interpretation of the results for AZT-experienced patients is less clear. However, it would appear that, on average, the earlier the change is made from AZT monotherapy to one of the combination regimens, the better. In advanced patients, there does not appear to be an advantage to switching from AZT alone to one of these combinations, and other options should be considered. All of these trials are limited, of course, to statements about these two particular combination regimens. Of great interest currently is the comparative safety and efficacy of newer combinations, including AZT/3TC and those containing protease inhibitors. TRIAL RESULTS ACTG 175 was an American study sponsored by NIH and reported by Hammer et al.. It enrolled 2467 mostly asymptomatic patients with CD4+ counts between 200 and 500, 1067 of whom were AZT-naive (median CD4+ of 372 at entry), and 1400 who had taken AZT for a median of 18 months prior to enrollment (median CD4+ of 338). Median follow-up was 143 weeks. Nearly 20% of the patients were lost-to-follow-up (status unknown) at the end of the study, and over half of the patients had switched off of their originally assigned treatment before reaching a clinical endpoint, complicating interpretation of the results. In the overall analysis, both combination arms and the ddl monotherapy arm had better clinical outcomes (progression to AIDS or death) than the AZT monotherapy arm. Similar results were reported in the subgroup analysis of AZT-naive patients, with ddC/AZT performing best. In the AZT-experienced patients, both ddI/AZT and ddl alone were clinically superior to AZT monotherapy, but AZT/ddC was not statistically different from AZT alone. REFERENCES: Hammer S et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with with CD4 cell counts from 200 to 500 per cubic millimeter. N ENGL J MED 335:1081-90, 1996. TRIAL RESULTS The Delta trial was an international study of 3248 HIV+ patients with CD4+ counts between 50 and 350 (3207 evaluable patients), conducted in Europe and Australia and reported by Yeni et al (1995) and updated recently by Gazzard (1996). The study compared the two combinations to AZT monotherapy, and stratified patients by history of prior AZT use into two separately monitored studies (Delta 1 and Delta 2). Patients were followed for a median of 30 months. Loss to follow-up was 15%, and the switch rate off of the originally assigned therapy was very high, over 75%. Delta 1 enrolled 2131 (2124 evaluable patients) AZT naive patients with a median CD4+ count of 213 cells/mm3. In the updated intent to treat analyses of data through Sept 1995 (death in all patients, and AIDS or death in patients with AIDS at entry), both combination groups were confirmed to be superior to AZT monotherapy. 1117 (1083 evaluable) AZT-experienced patients were enrolled into Delta 2 (median CD4+ count of 189 cells/mm3). In the updated analyses, the three groups continued to look similar except for ddl/AZT versus AZT, which, while not reaching conventional levels of statistical significance, trended strongly in favor of ddl/AZT (P = 0.065) for mortality in all patients. Final analyses for all endpoints, including time to progression to an AIDS event or death in all patients (analogous to CPCRA 007 endpoints), are currently in progress. REFERENCES: Rresults of the Yeni P et al. Preliminary European/Australian delta trial: Based on data up to 31st May 1995. 5th Euro Conf on Clin Aspects and Treat of HIV Infect, Copenhagen, 1995. Gazzard B et al. Further results from the European/Australian Delta Trial. Abstract LB5a, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. 29

Page  30 Antiretroviral Therapies TRIAL RESULTS Saravolatz et al. have reported final results of the American CPCRA study, which was the last of these trials to be completed. It also compared the two combination regimens with AZT monotherapy, in 1113 patients with CD4+ counts under 200 (median of 92). Over 75% of these advanced patients were AZT experienced, with a median duration of prior AZT use of 12 months. Overall, there was no difference in time to AIDS or death among the three treatment groups. A subgroup analysis of the 250 AZT-naive patients showed statistical superiority of the two combination groups compared to AZT montherapy, whereas there was no difference among treatment groups in the AZT experienced patients. Loss to follow up in this community based study was very low (less than 5%). REFERENCES: Saravolatz L et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic milliliter. N ENGL J MED 335:1099-1106, 1996. Figure 1: Tabular summary of results for all three studies (ACTG 175, Delta, and CPCRA 007). All results reported herein are final and published in peer-reviewed journals. ACTG 175 DETLA# CPCRA 007 STUDY DRUGS AZT/ddl AZT/ddC JAZT ddl AZT/ddl AZT/ddC AZT ZT/ddl AZT/ddC AZT ALL PATIENTS n = 2467; Median CD4+ Count = 350cells/mm n = 3214; Median CD4+ Count = 200 cells/mm3 n = 1113; Median CD4+ Count = 92 cells/mm3 AIDS or Death 11%* 12%t 16% 11%* 29%* 34% 37% 62%t 62% 65% Death 5%* 7%t 9% 5%* 18%* 21%* 25% 48% 49% 51% NAIVE n = 1067; Median CD4+ Count = 372 cells/mm3 n = 2131; Median CD4+ Count = 212 cells/mm3 n = 254; Median CD4+ Count = 93 cells/mm3 AIDS or Death 8%t 6%* 12% 9% 22%* 29%* 34% 49%* 51%t 57% Death 4% 3%t 7% 4% 13%* 15%* 21% 31% 39% 41% EXPERIENCED n = 1400; Median CD4+ Count = 338 cells/mm3 n = 1083; Median CD4+ Count = 189 cells/mm3 n = 859; Median CD4+ Count = 92 cells/mm3 AIDS or Death 13%* 17% 18% 14%t 42% 42% 45% 65% 66% 68% Death 6%* 9% 10% 5%* 28%t 32% 35% 53% 53% 55% *P<0.05 for pairwise comparison with AZT monotherapy t0.05<P<0.10 for pairwise comparison with AZT monotherapy MAIDS or death endpoint in Delta study was calculated for subset of patients without AIDS at entry (2766 overall, 1862 naive, 904 experienced NON - NUCLEOSIDE ANALOGUES REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) DESCRIPTION: The NNRTIs are structurally diverse, but all bind near the catalytic site of HIV-1 reverse transcriptase, and are quite specific (unlike the nucleoside RTIs, they have no activity against HIV-2). As noncompetitive inhibitors of reverse transcriptase, their in vitro antiviral activity is additive or synergistic with most nucleoside analogues. The principal limitation of NNRTIs is the rapid development of viral resistance, which is seen both in cell culture systems and in patients on therapy. Combination therapy with a nucleoside analogue tends to slow down the development of resistance. One NNRTI, nevirapine, has been approved under the Food and Drug Administration's accelerated approval guidelines. Another NNRTI, delavirdine, is currently being reviewed by the FDA; delavirdine is available under an expanded access protocol. Results using a third NNRTI in earlier stages of development, DMP-266, are also reported. The following section describes the compounds and the results of monotherapy studies. The results of combination studies of NNRTIs with nucleoside analogues are described in a section, beginning on page 34. 30

Page  31 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1991 7 Trials, page 149 PHYSICAL DESCRIPTION: Delavirdine is a BHAP (bis(heteroaryl)-piperazine) compound, one of several non-nucleoside chemicals with anti-HIV-1 activity. MECHANISM OF ACTION: BHAP compounds non-competitively inhibit HIV-1 (RT), probably through direct binding with the enzyme (Romero et al.). It has been reported that delavirdine inhibits HIV-1 in vitro at lower concentrations than ateverdine and is synergistic in combination with ddC and AZT (Chong et al.). U-87201E is active against clinical HIV-1 isolates (Campbell et al.). Resistance to BHAP compounds develops rapidly in vitro and in vivo. BHAP-resistant virus results from a single amino-acid substitution at codon 236 (Sardana et al.). The development of high-level resistance to BHAP compounds has been reported to sensitize HIV-1 RT to inhibition by other non-nucleoside RT inhibitors (Dueweke et al.). TRIAL RESULTS Results from a dose-escalating clinical trial (ACTG 260) of delavirdine (at a starting dose of 400 mg tid) versus either AZT or ddl have been reported (Para et al.). A total of 115 patients with CD4+ counts between 200 and 500 cells/mm3 were eligible, of which half were antiretroviral-naive. The highest tolerated dose was 2550 mg/day. Of 84 patients who received delavirdine, 30 developed rash, seven of which were severe. ONGOING CLINICAL TRIALS: ACTG 261 is comparing delavirdine/AZT, delavirdine/ddl and delavirdine/AZT/ddl in patients with CD4+ counts between 100 - 350 cells/mm3; enrollment has been closed with 549 HIV+ patients enrolled. Another study being sponsored by the manufacturer in 1,350 patients with CD4+ counts between 200 and 500 cells/mm3 is still enrolling. AZT/3TC/delavirdine is being compared to AZT/3TC and AZT/delavirdine combinations. An expanded access program for delavirdine has been established. HIV+ patients with CD4+ counts < 300 cells/mm3 currently receiving at least one other antiretroviral therapy are eligible. DRUG INTERACTIONS: According to the manufacturer, several phase I studies have demonstrated that fluconazole, AZT, TMP/SMX, and clarithromycin have no significant effect on delavirdine clearance. Therapy with delavirdine is contraindicated in patients receiving rifampin and rifabutin. TOXICITY/SIDE EFFECTS: Side effects to delavirdine include skin rash and reversible elevations in liver enzymes and bilirubin. RERENCES: Chong KT et al. A novel BHAP, U-90152, is synergistic with 3'azido-2'3'-dideoxythymidine (AZT) and 2'3'-dideoyxcytidine (ddC) against HIV-1 replication in vitro. Abstract PO-A25-0606, IX Intl Conf AIDS, Berlin, 1993. Dueweke T et al. A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. PNAS 90: 4713-4717, 1993. Para MF et al. ACTG 260: randomized phase I/II concetration-controlled trial of the anti-HIV activity of delavirdine. Abstract LB9, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Romero DL et al. Nonnucleoside reverse transcriptase inhibitors that potently and specifically block HIV-1 replication. PNAS 88: 8806-10, 1991. Sardana W et al. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Bio Chem 267(25): 17526-30, 1992. OTHER REPORTS: Anstadt FJ et al. Preclinical pharmacokinetic evaluation of several BHAP analogs, novel non-nucleoside reverse transcriptase inhibitors. 31st ICAAC, abstract #1337, 1991. Dueweke TJ et al. The binding of a novel bisheteroarylpiperazine mediates inhibition of HIV-1 reverse transcriptase. J Biol Chem 267: 27-30, 1991. Vasudevachari MB et al. Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors. Virology 190: 269-77, 1992. 31

Page  32 Antiretroviral Therapies Trials, page 150-151 PHYSICAL DESCRIPTION: DMP-266 is a non-nucleoside reverse transcriptase inhibitor, which has a mechanism of action similar to that of other NNRTIs. LABORATORY RESULTS: DMP-266 is capable of inhibiting, with 95% inhibitory concentrations of 1.5 mM, a panel of NNRTI-resistant mutant HIV, each of which expressed a single reverse transcriptase amino acid substitution (Young et al.). TRIAL RESULTS A trial of DMP-266 alone and in combination with indinavir has been completed. Mayers et al. have reported data on thirty patients who completed an initial two weeks of therapy with either DMP-266 (200 mg qd) or placebo. The median CD4+ count at entry was 249 cells/mm3. The median viral load at entry was 131,000 HIV-RNA copies/ml (5.12 log copies). Following two weeks of monotherapy with DMP-266, a mean reduction in HIV-RNA of 1.68 log and an increase in CD4+ count of 96 cells/mm3 was reported. In contrast, no significant changes in these markers were observed for placebo-treated patients. After two weeks of DMP-266 monotherapy, open-label indinavir (800 mg tid) was added. At 12 weeks on the combination, an HIV-RNA reduction of 3.2 log was reported. These data were not statistically signficant when compared to patients receiving indinavir monotherapy. The area under the indinavir plasma concentration time curve (AUC) was observed to be approximately 37% lower in patients on DMP-266. A second study examining the surrogate marker activity of DMP-266 in combination with AZT and 3TC is still underway. REFERENCES: Mayers D et al. A double-blind pilot study to evaluate the antiviral activity, tolerabilityand pharmacokineticsof DMP-266 alone and in combinationwith indinavir.Abstract LB8a, 36th ICAAC, New Orleans, 1996. Young SD et al. L-743,726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Abstract Mo.A. 1077, XI International Conference on AIDS, Vancouver, 1996. PHYSICAL DESCRIPTION: An Alpha-APA (a-anilino-phenylacetamide) derivative. These derivatives are synthetic compounds with selective anti-HIV-1 activity. MECHANISM OF ACTION: Loviride has a mechanism of action similar to that of other non-nucleoside RT inhibitors such as nevirapine and delavirdine. TRIAL RESULTS Results from a clinical trial comparing a combination of AZT, 3TC, and loviride to AZT and 3TC combined to AZT alone has been completed (CAESAR). The primary endpoints were disease progression and death. The addition of loviride to AZT/3TC did not confer any additional clinical benefit over AZT/3TC alone, although the trial was not powered adequately to make this determination. Complete results from the CAESAR study begin on page 27. Youle et al. enrolled 56 HIV+ patients with varying prior AZT experience and CD4+ count between 200-500/mm3 in a randomized, double-blind trial comparing four treatment arms: loviride monotherapy, AZT monotherapy, loviride/AZT in combination, and 3 months placebo followed by 3 months loviride monotherapy. While no clinically relevant differences were observed among the treatment groups, HIV-RNA in peripheral blood measured by quantitative PCR decreased an average of 80% (greater than 1 log drop) from baseline to week 8 in the combination group. Staszewski et al. enrolled 114 antiretroviral naive asymptomatic patients with CD4+ count > 400 cells/mm3 in a placebo-controlled study. Patients were randomized to receive loviride (200 mg tid), loviride (100 mg tid) or placebo for 6 months. A 15% increase in CD4+ cells over baseline was observed in the loviride group after 8 weeks and sustained during the 6 months of treatment. When compared to the placebo group the difference in CD4+ count was significant (P =.005). Clinical resistance to loviride was not observed in this study. TOXICITY/SIDE EFFECTS: Rash and pruritis. REFERENCES: De Brabander et al. Loviride induces a prolonged rise of the CD4 count in asymptomatic HIV-1+ patients. Abstract #PB0242, X Intl Conf AIDS, Yokohama, 1994. 32

Page  33 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 07 Pauwels R et al. Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of a-anilophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. PNAS 90: 1711-1715, 1993. Staszewski S et al. Evaluation of the efficacy and tolerance of R18893, R89439 (loviride) and placebo in patients infected with HIV-1. An interim analysis. Abstract 041: 170, Fourth European Conference on the Clinical Aspects and Treatment of HIV Infection. Milan, 1994. Youle M et al. Randomized double-blind trial of loviride [R89439] (L), zidovudine (Z) and the combination in HIV-1 infected patients. Abstract LB6A, 2nd National Conference on Human Retroviruses, Washington, 1995. Trials, page 152 PHYSICAL DESCRIPTION: Nevirapine is a non-nucleoside dipyridodiazepinone derivative with in vitro activities comparable to other non-nucleoside reverse transcriptase inhibitors (e.g. BHAP compounds). However, all these compounds have unique structures. MECHANISM OF ACTION: Wu et al. reported that nevirapine is a selective noncompetitive inhibitor of HIV-I reverse transcriptase; Richman and co-workers report that it binds to HIV-1 RT at the same site as other non-nucleoside RT inhibitors. Richman et al. report that HIV-1 resistant to nevirapine emerges rapidly in vitro. These strains are cross-resistant with other non-nucleoside RT inhibitors, but not nucleoside-analog RT inhibitors. Nevirapine has been approved under the Food and Drug Administration's acclerated approval mechanism for use in combination with approved nucleoside analogues. Results from clinical trials of nevirapine in combination with approved nucleoside analogues begin on page 34. TRIAL RESULTS Sixty-four patients with CD4+ counts below 400 cells/mm3 enrolled in a dose-escalation safety, and activity study of nevirapine 12.5 - 600/mg day PO (ACTG 164). Transient decreases in p24 antigenemia were observed in the first week of therapy (Cheeseman et al.). High-level viral resistance emerged rapidly in most patients, and correlated with the loss of viral activity (Richman et al.). According to the manufacturer, a subset of patients in the 400 mg/day group experienced sustained reductions in p24 antigenemia. PREGNANT WOMEN: Mirochnick et al. recently studied nevirapine (100 mg or 200 mg) in HIV+ pregnant women in active labor, a median of 5.8 hours prior to delivery. Median maternal serum drug levels at delivery were similar in the two dose groups. Nevirapine is eliminated slowly and readily crosses the placenta. Following maternal dosing, newborns may require 1 postnatal dose to maintain serum levels > 100 ng/ml throughout the first week of life. Median breast milk nevirapine concentrations (4 samples from 3 women) were 76% of maternal serum concentrations. The investigator concluded that nevirapine can be safely administered to women in labor. VIRAL RESISTANCE: Reduced susceptibility to nevirapine has been studied with both laboratory and clinical isolates. Data on 115 patients have been evaluated from a number of trials (Myers et al.). Resistance to nevirapine is consistently associated with amino acid changes in the reverse transcriptase gene at positions 103, 106, 108, 181, 188, and 190. In patients previously treated with nucleoside analogues, reduced susceptibility to nevirapine was observed in the majority of isolates by week 8 of nevirapine treatment. There is no particular order in which mutations emerge. There is a predominance of the 181 mutation in nevirapine monotherapy patients, however this mutation was not observed when patients are concurrently receiving AZT (Meyers et al.). TOXICITY/SIDE EFFECTS: Maculopapular rash has been observed at higher doses of nevirapine (400 mg/day and above). Fourteen of 32 (44%) patients who received initial therapy with nevirapine 400 mg/day experienced side effects; 11/14 permanently discontinued treatment as a result (8 rash, one thrombocytopenia, and two fever). Protocols studying higher doses of nevirapine currently use a two week lead in regimen of 200 mg/day; the manufacturer states that rash occurs in 24% of patients treated with this regimen. One patient who received nevirapine 600 mg/day had a severe reaction including facial edema and inability to swallow. Stevens-Johnson syndrome has been confirmed in two patients. de Jong et al. noted liver enzyme abnormalities in 4/20 nucleoside-naive individuals receiving nevirapine monotherapy. Discontinuation of drug followed. DRUG INTERACTIONS: Nevirapine undergoes extensive oxidative metabolism in humans. Nevirapine metabolism is mediated primarily by P450 isozymes of the 3A family, with additional contribution of 2B6. Drug interactions involving inhibition or induction of P450 are a potential concern. Myers et al. have monitored nevirapine plasma levels in patients concurrently taking drugs which themselves induce or inhibit P450 (macrolide antibiotics, rifabutin, ketoconazole, and H-2 blockers). Of all compounds tested, only ketaconazole had a significant inhibitory effect on nevirapine metabolism. Myers et al. also report that nevirapine has a low potential to inhibit the metabolism of other compounds. 33 I

Page  34 Antiretroviral Therapies I ONGOING PROTOCOLS: Several trials of nevirapine are still underway. In one trial, eligible patients will be randomized to treatment with nevirapine 200 mg/day for two weeks and then 200 mg bid in combination with open label 3TC 150 mg bid or nevirapine placebo in combination with 3TC. All patients must be on stable nucleoside therapy for the duration of the study. A total of 2000 HIV+ patients with < 200 CD4+ cells/mm3 will be studied. The primary endpoints will be death and/or disease progression. Other studies open and enrolling include a phase II, double-blind, placebo-controlled, open-label, trial of nevirapine/AZT/ddl vs. AZT/ddl/3TC in 225 HIV+ patients with CD4+ counts between 200 and 500 cells/mm3 ACTG 244 is a phase II/III randomized, dose-escalating, double-blind, placebo-controlled trial of nevirapine/AZT/ddl vs. AZT/ddl, vs. AZT in HIV+ patients with CD4+ counts between 300 and 600 cells/mm3. ONGOING PEDIATRIC PROTOCOLS: ACTG 245 is a phase I/II randomized, placebo-controlled, double-blind, trial of nevirapine, ddl, and AZT vs. nevirapine and ddl vs. ddl and AZT in children, ages 6 months to 17 years, with greater than 24 weeks prior antiretroviral therapy. It is active, fully enrolled. ACTG 180 is a phase II, open-label pharmacokinetics and safety trial of nevirapine vs. nevirapine/AZT in children age one day to 18 years. This trial has recently been completed. Entry CD4+ requirements for both pediatric trials were age-dependent. REFERENCES: Chow YK et al. HIV-1 error revealed. Nature 364:679, 1993. Chow YK et al. Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature 361:650-4, 1993. de Jong MD et al. Antiviral response to nevirapine monotherapy in nucleoside naive persons. Abstract PB0847, X Intl Conf AIDS, Yokohama, 1994. Henry K et al. Presentation of primary analysis (survival) for ACTG 193A. 22nd AIDS Clinical Trial Group Meeting, Washington, DC, 1996 Larder BA et al. Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature 365:451-3, 1993. Myers M et al. Combination antiviral therapy with Viramune (nevirapine). 21st ACTG Meeting, Washington, 1996. Mirochnick M et al. Safety and pharmacokinetics of nevirapine in HIV-infected pregnant women and their newborns. Abstract #403, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Richman D et al. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. PNAS 88: 11241-5, 1991. Richman D et al. Loss of nevirapine activity associated with the emergence of resistance in clinical trials. Abstract PoB 3576, VIII Intl Conf AIDS, Amsterdam, 1992. OTHER REPORTS: Merluzzi VJ et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250:1411-3, 1990. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR AND NUCLEOSIDE ANALOGUE COMBINATIONS Trials, page 149 TRIAL RESULTS Interim results from a clinical trial comparing AZT monotherapy to three combinations of AZT and delavirdine (either 200, 300, or 400 mg tid) have been reported (Carberry et al.). The median CD4+ count at entry was 310 cells/mm3. After a median 52 weeks of therapy in 800 patients, 60% of whom were antiretroviral naive, the AZT/delavirdine (300 or 400 mg tid) groups had between 35 to 70 cells/mm3 higher CD4+ count than the group randomized to receive AZT monotherapy. Combination therapy also resulted in an median 0.5 log reduction in HIV-RNA for at least 60 weeks. REFERENCES: Carberry PA et al. Delavirdine (DLV) combined with zidovudine (ZDV) or didanosine (ddl) produces sustained reductions in viral burden and increases in CD4+ counts in early and advanced HIV-1 infection. Abstract Mo.B.295, XI International Conference on AIDS, Vancouver, 1996. TRIAL RESULTS A clinical trial of delavirdine, in combination with ddl, was recently reported after being terminated by the manufacturer; no clinical benefit was associated with the use of delavirdine/ddl, compared to ddl alone, in patients with advanced HIV-disease. However, an earlier analysis of this study suggested that significant (prolonged) reductions in HIV-RNA log copies/ml highly correlates with slower HIV-disease progression. Interim results from 870 patients enrolled in a randomized, double-blind study of ddl monotherapy versus a combination of delavirdine (400 mg tid) and ddl has been reported (Carberry et al.). All patients reported at least one year of prior antiretroviral therapy and entered the trial with a median CD4+ count of 135 cells/mm3. The CD4+ cell counts of patients on combination therapy remained about 5-20 cells/mm3 above ddl monotherapy during the first 40 weeks, and above or near baseline for at least 1 year. HIV-RNA levels declined 0.9 logs at week 4 of combination therapy (2-fold greater than with ddl monotherapy). Delavirdine/ddl combination resulted in long-term 34

Page  35 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 HIV-RNA reduction of 0.5 logs for at least 60 weeks. Neither of the differences in CD4+ counts or HIV-RNA levels between the two groups were statistically significant. Moreover, rates of progression to AIDS and death were similar between the two groups. An analysis of 1700 patients who are currently enrolled in two delavirdine phase II studies indicates that significant decreases in HIV-RNA correlates with reduced HIV-disease progression (Freimuth et al.). Baseline HIV-RNA levels of < 5 logs, 5-6 logs, and > 6 logs correspond to about a 1%, 6%, and 24% risk of clinical progression during the > 1 year study period. In addition, reduction in viral burden caused by treatment was correlated with a significantly lower incidence of clinical endpoints. Sustained HIV-RNA levels of 0.5 logs or greater were highly correlated with better clinical outcome. In patients with > 5 logs of HIV-RNA, a 0.5 log or greater decrease sustained for at least 8 weeks was assocated with a reduction in the incidence of disease progression of more than 50%. These findings were more highly correlated with clinical outcome than were CD4+ changes (P < 0.0001). REFERENCES: Carberry PA et al. Delavirdine (DLV) combined with zidovudine (ZDV) or didanosine (ddl) produces sustained reductions in viral burden and increases in CD4 counts in early and advanced HIV-1 infection. Abstract Mo.B.295, XI International Conference on AIDS, Vancouver, 1996. Freimuth WW et al. HIV-1 RNA viral burden at baseline or its reduction following antiretroviral therapy is highly correlated with reduced HIV-1 disease progression. Abstract LB8c, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996 TRIAL RESULTS Eighty-three patients with CD4+ counts below 400 cells/mm3 enrolled in a dose-escalation study of the combination of nevirapine (12.5- 600 mg/day) and AZT (ACTG 168). Transient decreases in p24 antigen were observed in the first week. Murphy et al. recently reported that significant declines in median p24 antigen were sustained through week 16 in the nevirapine 400 mg group (P = 0.008) and through week 24 in the nevirapine 600 mg group (P = 0.03). 8/26 patients in the 600 mg nevirapine group discontinued therapy due to severe rash. A second randomized, placebo-controlled study comparing nevirapine and AZT to AZT alone in 60 HIV+ patients with CD4+ counts between 200 and 500 c ells/mm3 and prior AZT therapy (3 - 24 months) has been completed (Myers et al.). A significant difference of 45 CD4+ cell/mm3 was reported between the two groups, in favor of nevirapine, at week 28 (P = 0.009). No significant differences in HIV-RNA levels were reported between the two groups. de Jong et al. report that an alternating regimen of one week of nevirapine and three weeks of AZT neither prolongs nerivapine activity nor prevents the emergence of viral resistance. In a study involving 20 nucleoside-naive individuals, de Jong noted that 18 patients showed a mean 50% reduction in p24 antigen titers after 4 weeks of receiving nevirapine monotherapy at 400 mg/day. The duration of these declines, however, was variable. Transient CD4+ count increases also occurred, followed by a return to baseline values within 12 weeks. ONGOING STUDIES: A multi-center study is underway to compare immediate and deferred nevirapine 400 mg/day with or without AZT; 250 patients with CD4+ counts between 200 - 500 cells/mm3 are projected to be enrolled. REFERENCES: Cheeseman SH et al. Nevirapine alone and in combination with zidovudine: safety and activity. Abstract MoB 0053, VIII Intl Conf AIDS, Amsterdam, 1992. de Jong MD et al. Alternating nevirapine and zidovudine treatment of human immunodeficiency virus type 1-infected persons does not prolong nevirapine activity. JID 169: 1346-50, 1994. Murphy R et al. Safety, immunologic and virologic activity of nevirapine in combination with AZT therapy in HIV-infected patients. Abstract #262, 2nd National Conference on Human Retroviruses, Washington DC, 1995. Myers M et al. Combination antiviral therapy with Viramune (nevirapine). 21st ACTG Meeting, Washington, 1996. TRIAL RESULTS Results from ACTG 241, a randomized, double-blind, placebo-controlled trial of nevirapine, AZT, and ddl vs. AZT and ddl have been reported. A total of 398 HIV+ patients with median CD4+ counts of 138 cells/mm3, HIV-RNA levels of 39,000 copies/ml, and 25 months prior antiretroviral therapy were randomized and studied for 48 weeks. At 48 weeks, the triple combination showed an improvement of 21 CD4+ cells/mm3 above baseline (P = 0.003). A 0.25 log difference between the triple and double combination groups were reported in HIV-RNA levels at week 48, again, with the nevirapine group remaining slightly below baseline (P = 0.003). No significant differences in disease progression or death were reported between the two groups (14% of patients receiving AZT/ddl and 17% of patients receiving triple combination therapy reached a clinical endpoint), although it was not powered to detect these endpoints. Results from a clinical trial comparing AZT/ddl/nevirapine to combinations of AZT/ddl and nevirapine/AZT in 151 HIV+ antiretroviral-naive patients have been reported (Myers et al.). The median baseline HIV-RNA level at entry was 35,704 35

Page  36 Antiretroviral Therapies copies/ml. The median baseline CD4+ count at entry was 376 cells/mm3. At 28 weeks, 75% of patients receiving the triple combination reported undetectable plasma HIV-RNA levels, compared with 45% in the AZT/ddl group and 0% in the nevirapine / AZT group. These data are statistically significant. Signicant differences in CD4+ count increases were also reported. At week 28, patients receiving the triple combination reported an increase of 125 CD4+ cells/mm3 above baseline, compared to 75 cells/mm3 in the AZT/ddl group and 10 cells/mm3 in the nevirapine/AZT group. Preliminary results (survival) from a clinical trial (ACTG 193A) comparing the triple-combination of nevirapine/AZT/ddl to AZT/ddC combination therapy to AZT alternating monthly with ddl to combination AZT/ddl in patients with CD4+ cell counts < 50 cells/mm3 have been reported (Havlir et al.). This study was a randomized double-blind, placebo-controlled trial designed to compare survival between these four treatment arms. Data on 1313 patients were included in the analysis (325 patients in the AZT/ddl alternating treatment, 332 patients in the AZT/ddl combination treatment, 326 in the AZT/ddC combination group and 330 in the triple-combination AZT/ddl/nevaripine group. The median CD4+ cell count at entry was 20 cells/mm3 and 56% of all patients had less than 18 months prior antiretroviral experience. Only 26% of all patients who received study drug remained in their assigned treatment group for the duration of the trial or until death. The majority of the discontinuations were unrelated to toxicities or side effects. A total of 536 deaths were reported during the study period with 118 (36%) deaths on nevirapine/AZT/ddl, 148 (45%) deaths in the AZT/ddI alternating monthly group, 128 (39%) deaths in the AZT/ddl combination group and 142 (43%) in the AZT/ddC treatment group. The survival times differed between the four treatment arms (P = 0.018) and in pairwise comparison, survival was significantly longer statistically on AZT/ddl/nevirapine compared to AZT/ddC combination and AZT/ddl alternating monthly but not significantly different compared to AZT/ddl combination therapy. CD4+ cell count and HIV RNA data have not yet been presented. CHILDREN: Burchett et al. recently treated 186 children with advanced HIV infection with either AZT, ddl, and nevirapine, AZT and ddl, or ddl and nevirapine. It was reported that combination therapy is well tolerated for greater than 8 weeks in pediatric patients. The only toxicity reported was rash, all occuring in the first month on study drug. A total of 8% of nevirapine recipients discontinued due to severe rash. ONGOING STUDIES: ACTG 193A, compares the combination of AZT/ddl/nevirapine with several different two-drug combinations of nucleoside analogs in patients with CD4+ counts below 50 cells/mm3; both enrollment and the study have been concluded. A clinical trial in pregnant women (ACTG 250), studying nevirapine in combination with AZT to prevent perinatal transmission, is underway. ONGOING PEDIATRIC STUDIES: A multi-center trial (ACTG 245) to compare different combination regimens (AZT/ddl, AZT/ddl/nevirapine, or ddl/nevirapine) in children with advanced HIV disease is underway and fully enrolled. The National Cancer Institute (NCI) is conducting a trial of nevirapine in children. The NCI trial is an open-label dose escalation trial of nevirapine in combination with AZT and ddl. REFERENCES: Burchett SK et al. Early toxicity experience in combination therapy of advanced pediatric disease. Abstract 1264, 35th ICAAC, San Francisco, 1995. Myers M et al. Combination antiviral therapy with Viramune (nevirapine). 21st ACTG Meeting, Washington, 1996. PROTEASE INHIBITORS Three protease inhibitors (indinavir, ritonavir, and saquinavir) have been approved in the United States. The manufacturer of a fourth protease, nelfinavir, has recently submitted an NDA with the FDA seeking approval for an adult formulation as well as a pediatric powder formulation. Two expanded access programs for nelfinavir are open. One is for patients who cannot take either ritonavir or indinavir. The second program is open to children ages 2 to 13 years. One other protease inhibitor (141 W94) is in earlier stages of clinical development. MECHANISM OF ACTION: The protease inhibitors comprise a structurally heterogeneous class of compounds that target a later stage of the viral life cycle than do the reverse transcriptase inhibitors. The protease inhibitors bind to the catalytic site of the viral protease enzyme, which plays a critical role in cleaving the large polyproteins of the immature virus, as it buds off from the infected cell. The virus only becomes infectious if the protease enzyme is successful in cleaving the final viral protein elements before they are assembled into mature virions. Because they act at an entirely different site in the viral life cycle than the reverse transcriptase inhibitors, the protease inhibitors in combination with nucleoside analogues, demonstrate at least additive and often synergistic activity against HIV in vitro. Cross resistance has not been reported between the two classes of drugs. However, there is reason for concern, based on in vitro data, that cross resistance between different protease inhibitors may be a problem with some of these compounds. There are no clinical data as yet from patients switching from one protease inhibitor to another to provide information on the potential for this 36

Page  37 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 problem developing in the clinic. If it does, it may limit the number of different protease inhibitors that can be used successfully by an individual patient. As a group, the protease inhibitors are generally well tolerated, and have not been reported to cause anemia, leukopenia, or peripheral neuropathy, common toxicities of the nucleoside analogues. However, because they are metabolized in the liver, and some are potent inhibitors of an important hepatic enzyme system (cytochrome p450), there is the potential for drug-drug interactions with other compounds metabolized by or affecting this system. The following section describes the individual compounds and the results of monotherapy trials; combination therapy results are described in the subsequent section. Trials, page 153, 154 PHYSICAL DESCRIPTION: Indinavir is a peptide-based protease inhibitor. Indinavir was approved by the Food and Drug Administration (FDA) under its accelerated approval regulations for use as monotherapy or in combination with approved nucleoside analogues in patients with HIV infection; clinical efficacy has not been established. TRIAL RESULTS Mellors et al. recently reported data on 16 patients, all of whom received AZT during a comparative trial comparing indinavir and AZT. All patients had a median CD4+ count of 110 cells/mm3 and HIV-RNA levels greater than 50,000 copies/ml prior to receiving treatment with indinavir 600 mg four times daily. At weeks 12, 24 and 36, median CD4+ counts were increased from baseline by 104, 105, and 126 cells/mm3, respectively. Median CD4+ counts were sustained above baseline at 52 weeks. At 8 weeks, there was a median 1.98 log reduction in serum RNA levels. A greater than 2 log reduction was reported in 5 patients. To evaluate the efficacy and safety of indinavir at increasing doses, a clinical trial in 70 HIV+ patients was recently reported (Mellors et al. 1996). Patients with CD4+ counts between 150 and 500 cells/mm3 and HIV-RNA levels greater than 20,000 copies/ml received one of three indinavir doses; 800 mg tid, 800 mg qid, and 1000 mg tid, for 24 weeks. Differences between groups were not statistically discernable. At 24 weeks of therapy, a mean 2.5 log redution was reported in all patients, indpendent of dose. ONGOING STUDIES: ACTG 320, a randomized, double-blind study comparing indinavir to placebo with open-label AZT and 3TC in patients with less than 200 CD4+ cells and greater than 6 months prior AZT experience is underway. Disease progression and death are the primary endpoints of this study. ONGOING PEDIATRIC STUDIES: A six-month dose-escalating study in 54 HIV+ children is currently underway. Patients are randomized to receive either indinavir alone or in combination with AZT and 3TC. This trial is being conducted by the National Institutes of Health in Bethesda, Maryland. VIRAL RESISTANCE: In the early trials of indinavir, in which lower, suboptimal doses (200 and 300 mg qid) were used, resistance developed between 12 and 24 weeks of therapy (Mellors et al.). Increasing the dose of indinavir to 600 mg qid or 800 mg tid, currently believed to be the optimal dose, did not overcome resistance. Starting patients on the higher doses intitially did prevent the development of resistance in most patients for at least 24 weeks. Laboratory and human studies indicate that phenotypic resistance (reduced sensitivity to the drug) develops over time as multiple amino acid substitutions (genotypic resistance) occur. Lower plasma levels of indinavir seem to select for resistant mutants, so it is important to initiate and maintain indinavir dosing at the prescribed higher doses. Amino acid changes at positions 32, 46, 71, and 82 have been reported in vitro. In vivo, mutations at positions 10, 20, 24, 46, 54, 63, 64, 71, 82, 84, and 90 have been reported. Mutations at postions 32, 46, and 82 result in a 3-fold reduced susceptibility to indinavir. Mutations at positions 10, 46, 63, and 82 result in a 4-fold reduced susceptibility; the addition of a mutation at position 84 results in an 8-fold reduced susceptibility. Mutations at positions 32, 46, 71, and 82 results in a 14-fold reduced susceptibility. There is complete cross resistance between HIV strains with phenotypic resistance to indinavir and the protease inhibitor, ritonavir. Approximately two-thirds of indinavir-resistant viral strains that have been studied by the manufacturer are cross resistant to saquinavir, but all saquinavir-resistant strains that have been studied thus far are fully sensitive to indinavir, at least initially. Cross resistance with the protease inhibitor nelfinavir appears one-sided; mutations at the key mutations with indinavir confers cross-resistance to nelfinavir. Mutations at the key protease positions while taking nelfinavir may still confer (reduced) sensitivity to indinavir. TOXICITY/SIDE EFFECTS: Elevated liver enzymes and bilirubin have been observed in less than 10% of patients receiving 400 mg PO four times daily for 12 weeks. Urolithiasis is also associated with indinavir treatment (< 5% of patients) and can minimized by liberal intake of fluids. REFERENCES: Chodakewitz J et al. Antiviral activity exerted by crixivan (MK-639) an oral HIV protease inhibitor. Abstract 76, 5th EACS, Copenhagen, 1995. 37

Page  38 Antiretroviral Therapies Condra JH et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 374:569-71, 1995. Mellors J et al. A randomized, double-blind study of the oral HIV protease inhibitor, L-735,524 vs. AZT in p24 antigenemic, HIV-1 infected patients with < 500 CD4 cells. Abstract #183, 2nd National Conference on Human Retroviruses, Washington DC, 1995. Mellors J et al. Antiretroviral activity of the oral protease inhibitor, MK-639 in p24 antigenemic, HIV-1 infected patients with < 500 CD4+ cells. Abstract 1172, 35th ICAAC, San Francisco, 1995. Mellors J et al. Efficacy and Safety of the HIV protease inhibitor indinavir sulfate at escalating dose. Abstract #146, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Stein DS et al. A 24-week open-label phase 1/11 evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 10:485-92, 1996. Teppler H et al. Pharmacokinetics and tolerability studies of L-735,524, a new HIV protease inhibitor. First National Conf. Human Retrov abstract L8: 152, 1993. Trials, page 155 PHYSICAL DESCRIPTION: Nelfinavir is a non-peptidic protease inhibitor, which is highly bioavailable after oral administration. TRIAL RESULTS A dose-ranging pilot study of nelfinavir conducted in Britain has been completed (Moyle et al.). Twenty-two patients with a median CD4+ count of 400 cells/mm3 and viral RNA > 20,000 copies/ml were randomized in an open-label fashion to receive either 770 mg/day or 1030 mg/day for 28 days. All patients completed the initial 28 days of therapy. At 28 days of therapy, 2/10 at 770 mg/day and 4/12 at 1030 mg/day had a greater than 1 log reduction in viral HIV-RNA levels (P = 0.01). A rise of 150 CD4+ cells/mm3 at day 28 were reported in 6/10 and 4/12 patients on the 770 and 1030 mg/day doses. The six patients deemed responders at 28 days continued on an open-label extension of the study using 1030 mg/day. All six patients reported a sustained decrease in HIV-RNA of one log through day 120. Results from a dose-ranging phase I/II study in HIV+ patients with no prior AZT experience have been reported (Markowitz et al.). Thirty patients with CD4+ counts between 200 and 500 cells/mm3 and greater than 20,000 copies/ml HIV-RNA were randomized in an open-label fashion to receive one of three doses of nelfinavir. Twice-daily doses of 500 mg, 600 mg, or 750 mg resulted in average maximum reductions HIV-RNA levels of one log or greater. A dose escalation study of nelfinavir 500, 750, and 1000 mg tid has recently been completed (Chapman et al.), showing a greater than 2 log reduction in HIV-RNA at the highest dose. ONGOING STUDIES: A number of clinical trials have recently opened for enrollment. Two of them are phase I pharmacokinetics and safety trials. One, sponsored by the manufacturer, is investigating the safety, tolerability and pharmacokinetics of a pediatric powder formulation in HIV+ children and exposed infants. The second phase I studied is sponsored by the AIDS Clinical Trials Group (ACTG # 353) which will study the effects of nelfinavir co-administered with AZT & 3TC in HIV+ pregnant women and their newborns.. The manufacturer has also recently opened a safety and efficacy and pharmacokinetic profile study of nelfinavir in combination with d4T & 3TC in HIV+ women. The Terry Beirn Community Program for Clincal Research on AIDS (CPCRA #042) is enrolling a trial of nelfinavir vs ritonavir when added to background antiretroviral therapy. A number of other studies are investigating the effects on clinical outcome of nelfinavir in addition to standard induction and maintenance therapy for CMV retinitis, MAC, and KS. Additionally the manufacturer is conducting drug interaction studies of nelfinavir with the protease inhibitors: saquinavir, indinavir, ritonavir, and 141W94; with the non-nucleoside RT inhibitors: delavirdine, loviride, DMP266, and nevaripine; and 1592U89, a nucleoside analogue. A second phase III double-blind, trial in patients with CD4+ cell count <100 is studying the addition of nelfinavir (750 mg tid) to individual patients' current standard of care antiretroviral treatment. VIRAL RESISTANCE: Amino acid changes at positions 30, 46, 71, and 82 have been reported in vitro. In vivo, mutations at positions 30, 36, 46, 71, 77, and 88 have been reported. A mutation at position 84 results in a 5-fold reduced susceptibility. Mutations at positions 30 and 71 result in a 7-fold reduced susceptibility. Mutations at positions 46, 63, 71, and 84 results in a 30-fold reduced susceptibility. Cross resistance with the protease inhibitors indinavir and ritonavir appear one-sided; mutations at the key amino acid positions associated with ritonavir and indinavir confers cross-resistance to nelfinavir. Mutations at the key protease positions while taking nelfinavir may still confer (partially-reduced) sensitivity to both ritonavir and indinavir. TOXICITY/SIDE EFFECTS: Diarrhea, loose stools and elevated liver enzymes have been reported. REFERENCES: Chapman S et al. Oral presentation on nelfinavir. New York University Medical Center Forum on Protease Inhibitors. New York, 1996. 38

Page  39 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Markowitz M et al. Phase 1/11 dose range-finding study of the HIV protease inhibitor AG1343. Abstract LB-4, 35th ICAAC, San Francisco, 1995. Moyle G et al. A phase II dose escalation study of the Agouron protease inhibitor AG 1343. Abstract LB-3, 35th ICAAC, San Francisco, 1995. Quart BD et al. Phase I safety, tolerance, pharmacokinetics and food effect studies of AG1343 - A novel HIV protease, 2nd National inhibitor. Abstract LB3Conference on Human Retroviruses, Washington DC, 1995. - -~ Trials, page 156 PHYSICAL DESCRIPTION: Ritonavir is a peptide-based protease inhibitor. Ritonavir was approved by the Food and Drug Adminstration (FDA) for use alone or in combination with approved nucleoside analogues in patients with advanced HIV infection. Approval was based on data demonstrating delays in disease progression and death in one short-term placebo-controlled trial. Ritonavir was also approved by the FDA under its accelerated approval regulations for patients with earlier HIV infection, based on reductions in HIV-RNA levels and increases in CD4+ counts. TRIAL RESULTS A four week phase I/1, dose-ranging trial of ritonavir was conducted in Europe in which 84 patients were randomized to one of four doses of ritonavir or placebo in 2 groups (Danner et al.). In group I, 39 patients were randomized to placebo, 300 mg bid, or 400 mg bid; in dose group II, 45 patients were randomized to placebo, 500 mg bid, or 600 mg bid. There were significant decreases in viral RNA and p24 antigen at one week that were sustained through week 4 in all four ritonavir groups. There were mean decreases of 0.78, 0.83, 0.97 and 1.13 log in viral RNA at week 4 in the groups receiving 300, 400, 500, and 600 mg of ritonavir, respectively (P < 0.01). After two weeks of treatment, increased CD4+ counts were observed in the groups receiving 400, 500, and 600 mg of ritonavir every 12 hours; these increased counts continued through week 4 and were significantly higher at all measurements than those in the placebo groups (P < 0.05). Increased counts were also found among the patients with low CD4+ counts at baseline: among 29 patients with baseline CD4+ counts below 100 cells/mm3, 22 had maximal increases of more than 100 cells/mm3, and 8 of these had increases of at least 200 cells/mm3. During a blinded extension of this four-week trial conducted by Danner et al., patients receiving placebo were randomized to receive one of two doses of ritonavir studied in their original group. Viral load data was provided in 76/84 patients. The mean concentrations of HIV-RNA in the 300 and 400 mg groups approached baseline values at 16 weeeks. Concentrations of viral RNA in the 500 mg group started to return towards baseline at 20 weeks, whereas those in the 600 mg group remained constant. At 36 weeks, those in the 600 mg group reported a mean decrease in HIV-RNA from baseline of 0.81 log (P = 0.01). A twelve-week phase I/I trial has been reported by Markowitz et al. Using two groups, a total of 62 patients were randomized to receive one of four dosages of ritonavir or placebo for four weeks, followed by an 8-week dose-blinded phase. In group I, 31 patients were randomized to placebo, 200 mg tid, or 300 mg tid; in dose group II, 31 patients were randomized to placebo, 200 mg qid, or 300 mg qid. Fifty-five patients completed the first four weeks of the study. The most common adverse events reported were diarrhea and headache in both the treatment and control groups. The administration of ritonavir was associated with at least a doubling of the serum triglyceride concentration in 25% of ritonavir patients. Statistically significant decreases in HIV-RNA were found in all four treatment subgroups. A maximal antiviral effect consisting of a decrease of 0.86 to 1.18 log of HIV-RNA was seen by day 15 (P < 0.001). At four weeks, the ritonavir-treated patients had a mean reduction of 0.83 log of HIV-RNA. At the end of 12 weeks, a persistent reduction of 0.5 log in the viral load was maintained at all dose levels. Overall, the median increase in CD4+ cells was 74 cells/mm3 at four weeks of therapy. An international randomized, controlled phase III clinical trial of ritonavir in 1090 antiretroviral-experienced patients with fewer than 100 CD4+ cells and over 9 months of prior antiretrovial therapy has been completed (Cameron et al.) The primary endpoint was progression to AIDS or death. 543 patients were randomized to ritonavir (600 mg bid) and 547 patients were randomized to placebo. Patients were permitted to remain on non-protease inhibitor antiretroviral therapy per standard of care. Crossover to open-label ritonavir following an AIDS event was permitted after four months on study. The median HIV-RNA level upon entry was 5.3 log copies/ml; the median CD4+ count upon entry was 31 cells/mm3. After a median duration of seven months of treatment, disease progression or death occurred in 85/543 (15.7%) patients in the ritonavir group and 181/547 (33.1%) in the placebo group (P < 0.001). The total number of deaths reported were 26 (4.8%) in the ritonavir group and 46 (8.4%) in the placebo group (P = 0.021). Nausea, vomiting, and diarrhea occurred more frequently in the ritonavir group. The investigators conclude that ritonavir therapy prevents AIDS complications and prolongs life in patients with advanced HIV over a six month period of treatment. An ongoing phase III clinical trial is testing ritonavir alone and in combination with AZT in patients with CD4+ counts between 200 and 700 cells/mm3; the trial has completed enrollment. 39

Page  40 Antiretroviral Therapies VIRAL RESISTANCE: The emergence of ritonavir-resistant HIV strains isolated from HIV+ patients have been reported (Koreyeva et al. and Gao et al.). Amino acid changes at positions 46, 63, 71, 82, and 84 have been reported in vitro. In vivo, mutations at positions 20, 36, 46, 54, 63, 71, 82, 84, and 90 have been reported. A mutation at postions 82 and 84 results in an 8-10-fold reduced drug susceptibility. Mutations at positions 46, 63, 71, 82, and 84 result in a 27-fold reduced susceptibility. Reduced sensitivity to ritonavir is associated with multiple and variable amino acid substitutions at the genotypic level, similar to the resistance patterns that develops to indinavir. There is complete cross-resistance between these two drugs in vivo. Cross resistance with the protease inhibitor nelfinavir appears one-sided; mutations at the key amino acids associated with ritonavir confers cross-resistance to nelfinavir. Mutations at the key protease positions while taking nelfinavir may still confer (reduced) sensitivity to ritonavir. TOXICITIES/SIDE EFFECTS: Nausea, parasthesia, and elevated liver enzymes were the most commonly found adverse events in preliminary safety studies. The original, liquid based formulation was not well tolerated. Thus, the manufacturer has switched to oral capsule formulation. DRUG INTERACTIONS: Ritonavir is a potent inhibitor of the liver's cytochrome p450 metabolic enzyme system and so care must be taken in using ritonavir at the same time as other drugs that are metabolized by this pathway (antihistimines, antidepressants, antibiotics). It is very important to consult the labeling (package insert) for drug-drug interaction information before prescribing. REFERENCES: Danner SA et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N ENGL J MED 333:1528-33, 1995. Gao Q et al. Specific mutations in HIV-1 protease that confer diminished susceptibility to ABT-538. Abstract 1282, 35th ICAAC, San Francisco, 1995. Cameron B et al. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. Abstract LB6a, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Korneyeva et al. Phenotypic and genotypic evolution of HIV-1 in AIDS patients undergoing therapy with the protease inhibitor ABT-538. Abstract 1175, 35th ICAAC, San Francisco, 1995. Markowitz M et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N ENGL J MED 333:1534-9, 1995. OTHER REPORTS: Kelleher AD et al. Alterations in the immune response of human immunodeficiency virus-infected patients Saquinavir (Invirase, Ro 31-8959 treated with an HIV-specific protease inhibitor, ritonavir. JID 173:321-9. 1996. Trials, page 156, 157 PHYSICAL DESCRIPTION: It is a peptide-based protease inhibitor., which has potent in vitro inhibitory activity against HIV. However, it is poorly absorbed when given orally (from 0% when fasting to 4% after a full fatty meal), the levels in the body are relatively low, limiting its antiviral activity in vivo. Saquinavir was approved by the Food and Drug Administration (FDA) under its accelerated approval regulations for use in combination with approved nucleoside analogues in patients with advanced HIV infection, based on reductions in HIV-RNA levels and increases in CD4+ counts. A recently reported study shows a statistically significant clinical benefit of the combination of saquinavir and ddC over ddC monotherapy in advanced patients with prior AZT experience There was no difference observed between ddC and saquinavir monotherapies in this trial. TRIAL RESULTS Three phase I/II dose-finding trials of saquinavir in HIV+ patients were conducted in the U.K., France and Italy. In France 61 advanced HIV patients with CD4+ count between 50 - 250 cells/mm3 (mean = 150 cells/mm3) received saquinavir at doses of 75, 200 or 600 mg PO tid for 16 weeks. Dormont et al. report that dose-related increases in CD4+ counts were seen in patients receiving the highest dose (P = 0.006). The maximum median increase was 32 cells/mm3 at the higher dose. In the U.K. 49 asymptomatic and mildly symptomatic patients with CD4+ counts <500 cell/mm3 enrolled in a randomized double-blind dose-ranging trial and received saquinavir at 25, 75, 200 or 600 mg PO tid for 16 weeks (Kitchen et al.). As in the French study, increased CD4+ counts were observed in the 600 mg treatment group in the first four weeks. The maximum median increase was 51 cells/mm3. To evaluate whether even higher doses of saquinavir monotherapy would give better antiviral activity, a small study of 40 patients was conducted, half of whom received 1200 mg tid and half 2400 mg tid. The 20 patients receiving the lower dose of saquinavir demonstrated a maximum mean decrease in HIV-RNA of 1.1 log and a sustained decrease of 0.5 log at week 24, whereas the first 14 patients receiving the higher dose of saquinavir experienced a maximum drop of 1.5 log and prolonged suppression with the viral load remaining 0.9 log below baseline at week 24. CD4+ cell count increases in the higher dose group also showed a more durable response with elevations lasting throughout the study, averaging 100 cells/mm3 above baseline at week 24, as compared to a 3l1cell/mm3 increase at the lower dose. Mild liver function test elevations and gastrointestinal distress were more common in the higher dose group. 40

Page  41 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Due to poor bioavailability associated with saquinavir therapy, a clinical trial of a new soft gelatin capsule oral formulation of saquinavir is ongoing. Three thousand patients with HIV are currently enrolled in a phase III clinical trial. The trial being conducted is comparing AZT monotherapy to combinations of AZT/saquinavir and AZT/ddC/saquinavir in HIV+ patients with CD4+ counts 50-350 cells/mm3. This trial is now closed to enrollment. VIRAL RESISTANCE: Amino acid changes at positions 48, 84, and 90 have been reported in vitro. In vivo, mutations at positions 10, 48, 63, 71, and 90 have been reported. A mutation at position 84 in a 5-fold reduced drug susceptibility; the addition of a mutation at position 90 confers a greater than 100-fold reduced susceptibility to saquinavir. A majority of the patients treated with the currently available formulation of saquinavir in the clinical trials that have been completed do not develop phenotypic resistance or genotypic resistance after one year of therapy. In laboratory studies on saquinavir-resistant viruses, there is no detectable cross resistance with indinavir or ritonavir. However, concern has been raised that treatment with saquinavir may result in more rapid development of resistance to indinavir or ritonavir used later. There is no clinical data at present to address this theoretical concern. TOXICITY/SIDE EFFECTS: In its currently marketed formulation, saquinavir is generally well tolerated, with GI disturbances (nausea and diarrhea) being the most commonly reported side effect. DRUG INTERACTIONS: Saquinavir is metabolized by the body by the liver's cytochrome p450 enzyme system, so plasma levels of the drug are easily altered by other drugs that either increase of decrease the activity of this important metabolic pathway. For example, azole drugs (ketaconazole, fluconazole, itraconazole, etc.) and ritonavir, another protease inhibitor, are potent inhibitors of p450. When taken together, these drugs raise the concentration of saquinavir in the blood and tissues. On the other hand, inducers of this enzyme system, such as rifampin and rifabutin, result in increased enzyme activity and metabolism of saquinavir, lowering the already modest levels achieved in most patients. Therefore, these drugs should not be used by patients taking saquinavir, or only with the knowledge that the anti-HIV activity of saquinavir is likely to be reduced. A laboratory study in rats recently concluded by Norbeck et al. reported that plasma concentration levels of saquinavir, when used in combination with ritonavir, may be increased 18-fold. The AUC (area under the curve), a better estimate of total body exposure to the drug, was increased 200-times. REFERENCES: Dormont J et al. a phase 1/11 dose-ranging study of the safety and activity of Ro 31-8959 (HIV-proteinase inhibitor) in previously zidovudine (ZDV) treated HIV-infected individuals. Abstract WS-B26-3, IX Intl Conf AIDS, Berlin, 1993. Food and Drug Administration (FDA). Antiviral Drugs Advisory Committee hearing on saquinavir for the treatment of HIV infection. November, 1995. Johnson VA et al. Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2'3'-deoxycytidine, or recombinant interferon alpha against zidovudine-sensitive or -resistant HIV-1 in vitro. JID 166: 1143-1146, 1992. Kitchen VS et al. Safety and activity of saquinavir in HIV infection. Lancet 345: 952-55, 1995. OTHER REPORTS: Ashorn et al. An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and spread of infection. PNAS 87(19): 7472-6, 1990. Craig JC et al. Antiviral properties of Ro 31-8959, an inhibitor of HIV proteinase. Antivir Res 16: 295-305, 1991. Trial, page 153 PHYSICAL DESCRIPTION: 141W94 (formerly VX-478) is a peptide-based protease inhibitor. Laboratory studies in rats indicated that 141W94 crosses well into the central nervous system, and that the drug is found in higher concentrations in lymph tissues than in plasma (St. Clair et al.). Oral bio-availability has been estimated at greater than 70%. The concentrations of 141 W94 in plasma at 8 and 12 hours are several hundred times higher than the concentrations needed to inhibit the virus in vitro (St. Clair et al.). Recent data from a clinical trial reported by Schooley et al. demonstrated that CNS penetration in humans is less significant; only 1% of the drug crosses the blood-brain barrier (Schooley et al.). TRIAL RESULTS Results from an open-label, dose-ranging study of 141W94 have been completed (Schooley et al.). 42 patients with a median CD4+ count of 282 cells/mm3 and a median HIV-RNA count of 4.83 log were assigned to receive one of four 141 W94 doses: 300 mg bid, 300 mg tid, 900 mg bid, and 1200 mg bid. At four weeks of therapy, the median change in HIV-RNA levels from baseline were 0.58 log, 1.025 log, 1.69 log, and 1.95 log, respectively. CD4+ count increases were also reported at week four; 64, 85, 35, and 110 cells/mm3, respectively. Three patients discontinued due to adverse events (2 due to rash, 1 due to worsening colitis). Diarrhea was the most commonly reported adverse event. 41 I

Page  42 Antiretroviral Therapies VIRAL RESISTANCE: In vitro resistance has been reported by Kim et al. The drug appears to induce a genotypic resistance profile that is different from other protease inhibitors approved and in development, suggesting that cross resistance may be less of a problem. REFERENCES: Kim EE et al. Structural analysis of the basis of viral resistance to VX-478. Abstract 1278, 35th ICAAC, San Francisco, 1995. Sadler et al. The safety and pharmacokinetics of 141W94: an HIV protease inhibitor. Abstract #564, 5th EACS, 1995. Schooley et al. Preliminary data on the safety and antiviral efficacy of the novel protease inhibitor 141W94 in HIV-infected patients with 150 to 400 CD4+ cells/mm3. Abstract LB7a, 36th ICAAC, New Orleans, 1995. St. Clair M et al. Oral presentation on VX-478. New York University Medical Center Forum on Protease Inhibitors. New York, 1995. PROTEASE INHIBITOR AND NUCLEOSIDE ANALOGUE COMBINATIONS TRIAL RESULTS Two hundred sixty six antiretroviral-naive patients with a median CD4+ count of 258 cells/mm3 and median HIV-RNA of 22,000 copies/ml were randomized to indinavir 600 mg q6h, AZT 200 mg q8h, or both for 24 weeks (Chodakewitz et al.). At week 24, patients randomized to receive AZT alone reported no increase in CD4+ counts and a median 0.3 increase in HIV-RNA. In the indinavir monotherapy group, patients reported a median 100 CD4+ cell/mm3 increase and an HIV-RNA reduction of median 1.2 logs. In patients receiving indinavir and AZT, a median CD4+ increase of 80 cells/mm3 and a median reduction in HIV-RNA of 1.3 logs were reported. Results from a second trial conducted in Brazil comparing AZT, indinavir, and a combination of both has been reported (Chodakewitz et al.). A total of 224 patients with a median CD4+ count of 139 cells/mm3 and a median HIV-RNA level of 29,000 copies/ml were enrolled. At 24 weeks of therapy, no increase in CD4+ cells/mm3 and an increase of 0.3 logs in HIV-RNA levels were reported in patients receiving AZT monotherapy. In the indinavir monotherapy group, a median increase of 100 CD4+ cells/mm3 and a median decrease of 0.8 logs were reported at 24 weeks. In the combination group, a median increase of 100 CD4+ cells/mm3 and a decrease of 1.3 logs were reported. EFERENCES: Massari F et al. A double-blind, randomized trial of indinavir (MK-639) alone or with zidovudine vs. zidovudine alone in zidovudine naive patients. Abstract LB-6, 35th ICAAC, San Francisco, 1995. Chodakewitz J et al. Presentation before the FDA's Antiviral Drugs Advisory Committee, March 1, 1996. TRIAL RESULTS Results from a phase II, open-label, randomized study of indinavir in combination with AZT and ddl have been reported (Mellors et al.). A total of 78 antiretroviral-naive patients received either indinavir (600 mg qid) and AZT (200 mg tid) and ddl (200 mg bid) or indinavir monotherapy alone or a combination of AZT and ddl. At baseline, median CD4+ counts were 150 cells/mm3 and median HIV-RNA was approximately 5 log. Maximum median declines in RNA were 3.1 log, 1.9 log and 1.5 log for the three groups, respectively. Most HIV-RNA levels began to elevate towards baseline at week 24. Maximum median increases in CD4+ counts, reported at week 24, were 110, 100 and 70 cells/mm3, respectively. REFERENCES: Mellors J et al. A phase II open-label, randomized study of the triple combination of indinavir, AZT and ddl versus indinavir alone and AZT/ddl in antiretroviral naive patients. Abstract #200, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Trials, page 153, 154 TRIAL RESULTS A randomized, double-blind study comparing indinavir (800 mg tid), AZT (200 mg tid), and 3TC (150 mg bid) to indinavir alone and AZT/3TC in combination has been reported (Gulick et al.). A total of 97 antiretroviral-experienced (greater than 6 months) patients with CD4+ counts between 50 and 400 cells/mm3 and HIV-RNA levels > 20,000 copies/ml were randomized. At week 12, the percentage of patients who reported a decrease in HIV-RNA below the level of detection (500 HIV-RNA copies/ml) were 88% in the triple combination group, 41% in the 42

Page  43 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 indinavir monotherapy group, and 8% in the AZT/3TC combination group. At week 24, the percentages were 86%, 44%, and 0%, respectively. Data at 32 weeks are available in 68 patients. At 32 weeks, the number of patients (and percentage) of patients with undetectable HIV-RNA levels were 19/23 (83%), 8/22 (36%), and 0/23 (0%), respectively. Nine patients reported nepholithiasis, eight of whom were receiving indinavir. All patients have now been switched to open-label indinavir/AZT/3TC therapy. REFERENCES: Gulick R et al. Potent and sustained antiretroviral activity of indinavir in combination with AZT and 3TC. Abstract Th.B.931, XI International Conference on AIDS, Vancouver, 1996. TRIAL RESULTS Thirty three HIV+ patients have been enrolled in an ongoing open-label, dose-ranging study of the safety and efficacy of nelfinavir (500, 750, or 1000 mg tid) and d4T versus d4T alone. Patients enrolled were d4T- and nelfinavir-naive with a median HIV-RNA level of 68,000 copies/ml and a mean CD4+ count of 350 cells/mm3. Therapy was well tolerated in all four treatment arms. Adverse events reported were diarrhea and fatigue. After two months, those patients receiving d4T monotherapy began receiving nelfinavir. At five months of combination therapy, mean reductions in HIV-RNA levels of 1.6 log were reported. CD4+ counts rose (mean average) by 97 cells/mm3 at five months. REFERENCES: Gathe Jr J et al. A randomized phase II study of viracept, a novel HIV protease inhibitor, used in combination with stavudine (d4T) vs. stavudine (d4T alone. Abstract Mo.B.413, XI International Conference on AIDS, Vancouver, 1996. Trial, page, 155 TRIAL RESULTS Results from an open-label study of nelfinavir in combination with AZT and 3TC have been reported by Ho et al. Eleven antiretroviral-naive patients with a mean HIV-RNA level of 156,000 copies/ml and a median CD4+ count of 245 cells/mm3 were treated. At 16 weeks, HIV-RNA levels were below the level of detectability in all patients (< 25 HIV-RNA copies/ml)/ An increase in 100 CD4+ cells/mm3 at 16 weeks was also reported in all patients. ACUTE INFECTION: A study of nelfinavir in combination with AZT and 3TC is currently underway in 12 patients recently infected with HIV. Preliminary data have been reported by Markowitz et al. Median HIV-RNA level for all patients at entry was 81,000 copies/ml. Median CD4+ counts at entry was 253 cells/mm3. One patients has withdrawn from the study due to severe abdominal cramping. Of the eleven patients remaining, all reported undetectable HIV-RNA in plasma (< 500 copies/ml) within 12 weeks. All patients in this study still continue to report undetectable levels in plasma HIV-RNA. REFERENCES: Ho D et al. How long should treatment be given if we had an antiretroviral regimen that completely blocks HIV replication? Abstract Th.B.930, XI International Conference on AIDS, Vancouver, 1996. Markowitz M et al. Triple therapy with AZt and 3TC in combination with nelfinavir mesylate in 12 antiretroviral-naive subjects chronically infected with HIV-1. Abstact LB.B.6031, XI International Conference on AIDS, Vancouver, 1996. TRIAL RESULTS Three hundred fifty six HIV+ patients with a mean CD4+ count of 361 cells/mm3 and mean HIV-RNA levels of 68,000 copies/ml were randomized to receive AZT, ritonavir, or a combination of both (Leonard et al.). At 16 weeks, patients receiving AZT monotherapy reported a mean increase in CD4+ counts of 15 cells/mm3; mean HIV-RNA levels in this group decreased 0.4 logs. Significant differences, favoring ritonavir monotherapy, were reported in patients receiving ritonavir alone and a combination of ritonavir and AZT. In the ritonavir monotherapy group, the mean CD4+ count increase reported was 75 cells/mm3 and the mean HIV-RNA decrease was 1.2 logs. In the combination group, the mean CD4+ count increase reported was 45 cells/mm3 and the mean HIV-RNA level decrease was 1.0 log (P < 0.05). REFERENCES: Leonard J et al. Hearing of the FDA's Antiviral Drugs Advisory Committee on the NDA for ritonavir, Gaithersberg, MD, February 29, 1996. 43

Page  44 Antiretroviral Therapies TRIAL RESULTS Results from a French study of ritonavir in combination with AZT and ddC have been presented (Mathez et al.). 32 patients with a median CD4+ count of 175 cells/mm3 were treated in an open-label fashion to receive ritonavir (600 mg bid), AZT (200 mg tid), and ddC (0.75 mg tid). The mean HIV-RNA level upon entry was 50,100 copies/ml (4.7 log); the mean CD4+ count at baseline was 170 cells/mm3. During the first six months of therapy, 15/32 (49%) patients discontinued the triple combination due to adverse events (primarily gastrointestinal disturbances and nausea. At week 60, the 17 patients who remain on triple combination continue to report a 2 log reduction in HIV-RNA; 8/17 patients' HIV-RNA levels remain undetectable at week 60. The mean increase in CD4+ counts at week 60 was 182 cells/mm3. REFERE NCES: Mathez D et al. A triple combination of ritonavir + AZT + ddC as a frist line treatment of patients with AIDS: Update. Abstract Mo.B.175, XI International Conference on AIDS, Vancouver, 1996. TRIAL RESULTS Twelve patients with acute HIV infection (infected with HIV within 90 days of study enrollment) are being treated with ritonavir (600 mg bid), AZT (200 mg tid), and 3TC (150 mg bid). Preliminary results at week 16 were recently presented (Markowitz et al.). At entry, the median HIV-RNA level was 91,289 (5 log); the median CD4+ count was 564 cells/mm3. One patient was switched to indinavir after reporting an allergic reaction to ritonavir. Three patients were discontinued due to non-compliance. At 16 weeks, all remaining patients had HIV-RNA levels below the level of detectability (< 25 HIV-RNA copies/ml) and all patients reported an increase of > 200 CD4+ cells/mm3. All patients in this study will continue to be followed for at least one year. REFERENCES: Markowitz M et al. Triple therapy with AZT, 3TC, and ritonavir in 12 subjects newly infected with HIV-1. Abstract Th.B.933, XI International Conference on AIDS, Vancouver, 1996. TRIAL RESULTS Clinical endpoint data have been presented from a randomized, double-blind comparison of saquinavir vs ddC vs. saquinavir and ddC. 978 patients with a median baseline CD4+ count of 170 cells/mm3 were evaluable. The median duration of prior AZT therapy was lower in the saquinavir/ddC group (68 weeks) than in the monotherapy groups (74 weeks). For the primary endpoint, time to first AIDS-defining event or death, there was statistically significant benefit of combination saquinavir and ddC treatment over ddC monotherapy treatment, with 85 patients reaching an endpoint on ddC, and 46 patients reaching an endpoint in the combination group (P = 0.0002). There was no significant difference between the saquinavir monotherapy group and the ddC monotherapy group. For the secondary endpoint of survival alone, a total of 28 deaths were reported in the ddC monotherapy group and 9 deaths in the combination group (P = 0.002). A total of 34 deaths were reported in the saquinavir monotherapy group. There was no statistically significant difference between the ddC monotherapy group and the saquinavir monotherapy group. Results from a randomized, double-blind study of saquinavir and ddC have been reported (ADAC, 1995). 451 HIV+ patients with a CD4+ count between 50-100 cells/mm3, and a minimum of 16 weeks prior AZT therapy, were randomized to receive ddC 0.75 mg q8h, saquinavir 600 mg q8h or saquinvavir 600 mg and ddC 0.75 mg. Data were evaluable in 423 patients. 137 patients in the combination group reported a sustained median increase of 30 CD4+ cells/mm3 at 16 weeks, whereas patients treated with either ddC or saquinavir monotherapy returned to baseline at weeks 9 and 12, respectively (P = 0.001). Similarly, combination therapy produced a greater and more sustained decrease in viral load than either monotherapy (P < 0.001). REFERENCES: Hearing of the FDA's Antiviral Drugs Advisory Committee (ADAC) on Saquinavir, November 7, 1995. 44

Page  45 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 TRIAL RESULTS Three hundred and two patients with advanced HIV disease and CD4+ counts between 50 - 300/mm3 were randomized to receive saquinavir/AZT, saquinavir/AZT/ddC, or AZT/ddC for 24 weeks in a double-blind trial (ACTG 229). All regimens used saquinavir 600 mg tid, ddC 0.75 mg tid and AZT 200 mg tid. All patients received at least 4 months prior AZT. Primary endpoints included changes in CD4+ counts, reduction in HIV viral load (measured by quantitative PBMC virus cultures) and safety and tolerance. Collier et al. reports that CD4+ counts rose during the first 8 weeks of study but then gradually declined in all treatment groups. The rate of increase of CD4+ was greater in the triple combination group than in the AZT/ddC group (P = 0.001) and in the saquinavir/AZT group (P = 0.08). The proportion of patients who sustained a 50 cell or a 50% rise from baseline was 37/96 (39%) on the triple combination, 27/98 (28%) on saquinavir/AZT and 21/100 (21%) on AZT/ddC. In HIV PBMC co-culture, there was a significantly greater reduction in viral burden in the triple drug arm compared with the other treatment arms. However, levels increased to 35% of baseline levels at week 24. 1 13 patients (37%) had one or more adverse events, including symptoms of disease progression. There were no major differences in toxicities among the three arms. Collier et al. subsequently reported follow-up data from ACTG 229. Of patients enrolled in the initial study, 96% completed the initital 24-week study and 244/302 (82%) of these completed an additional 24 week follow-up; 218/302 (73%) remained on study until completion. At week 48, 3 patients in the triple combination, 8 patients in the AZT/saquinavir group, and 7 patients in the AZT/ddC group reported the development of an AIDS defining illness or death (NS). CD4+ cell counts remained above baseline in 111 patients in the triple combination group, 74 patients in the AZT/saquinavir group, and 72 patients in the AZT/ddC group (P = 0.013). Mean PBMC titers were 0.5 log below baseline in the triple combination group, compared with less than 0.25 log in either the AZT/saquinavir or AZT/ddC groups (NS). REFERENCES: Collier AC et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N ENGL J MED 334:1011-7, 1996. Collier AC et al. Extended treatment with saquinavir, zidovudine, and zalcitabine vs. saquinavir and AZT vs. AZT. 35th ICAAC, Abstract #1173, San Francisco, 1995. TRIAL RESULTS A total of 33 antiretroviral-naive HIV+ patients were enrolled into an open-label safety and antiviral activity study of saquinavir (600 mg tid), AZT (200 mg tid), and 3TC (150 mg bid). At entry, the mean HIV-RNA level was 95,499 copies/ml (4.99 log); the mean CD4+ count was 326 cells/mm3. Data at four weeks are available in 30 patients. A median 1.96 log reduction in HIV-RNA has been reported, along with a CD4+ count increase of 107 cells/mm3. No serious adverse events have been reported thus far. REFERENCES: Baruch A et al. Efficacy and safety of triple combination with Invirase (saquinavir/SQV/protease inhibitor), Epivir (3TC, lamivudine), and Retrovir (ZDV/zidovudine) in HIV-infected patients. Abstract Mo.B.172, XI International Conference on AIDS, Vancouver, 1996. PROTEASE INHIBITOR COMBINATION TRIAL RESULTS Because ritonavir is a cytochrome p450 inhibitor, saquinavir plasma concetration are profoundly increased when coadministered with ritonavir. A laboratory study in rats concluded by Norbeck et al. reported that plasma concentration levels of saquinavir, when used in combination with ritonavir, may be increased 18-fold. The AUC, a better estimate of total body exposure to the drug, was increased 200-times. In HIV-negative study patients, saquinavir plasma concentrations were profoundly increased when coadministered with ritonavir (Hsu et al.). The pharmacokinetics of ritonavir did not change when coadministered with saquinavir. Preliminary results from a randomized, open-label study of saquinavir in combination with ritonavir have been reported (Cohen et al.). A total of 136 patients were divided among two groups. The first group (n = 71) was randomized to receive either ritonavir (400 mg bid)/saquinavir (400 mg bid) or ritonavir(600 mg bid)/saquinavir (400 mg bid). At entry, the median HIV-RNA level was 4.63 log and the median CD4+ count was 268 cells/mm3. At 12 weeks of therapy, the median reduction in HIV-RNA was 2.74 log and 3.06 log, respectively. Median CD4+ count increases at 12 weeks were 91 and 113 cells/mm3, respectively. The second group (n = 65) was randomized to receive either ritonavir (400 mg tid)/saquinavir (600 mg tid) or ritonavir 45

Page  46 Antiretroviral Therapies I (600 mg bid)/saquinavir (600 mg bid). Median HIV-RNA decreased from baseline by 2.09 and 2.19 log, respectively, after six weeks of therapy. Median CD4+ count increases were 74 and 88 cells/mm3, respectively. No statistically significant differences in HIV-RNA reductions and CD4+ count increases were reported between the four randomized groups studied. Circumoral parasthesia, nausea, and diarrhea were reported by 50-90% of patients enrolled in the study. 9/136 (6.6%) withdrew from the study due to adverse events, five of whom were receiving ritonavir (400 mg tid)/saquinavir (400 mg tid). Results from an open-label study of ritonavir in combination with saquinavir in patients with advanced HIV infection have been reported (Hirschel et al.). Nine patients with a median baseline HIV-RNA count of 107,151 copies/ml and a median CD4+ count of 10 cells/mm3 were treated with ritonavir (600 mg bid)/saquinavir (600 mg bid). One patient died from Mycobacterium tuberculosis while on study drugs and a second patient required dose modification because of serious adverse events (diarrhea and nausea). At eight weeks, a median reduction in HIV-RNA of > 1 log was reported in seven evaluable patients; however these data were not statistically significant when compared to baseline HIV-RNA levels, presumably because of the small number of patients and high variability in baseline HIV-RNA levels. Moreover, HIV-RNA levels began to increase towards baseline levels between week 8 and 13 in five patients. REFERENCES: Cohen C et al. Ritonavir-saquinavir combination treatment in HIV-infected patients. Abstract LB7b, 36th ICAAC, New Orleans, 1996. Hirschel BJ et al. Treatment of advanced HIV infection with ritonavir plus saquinavir. Abstract LB.B.6030, XI International Conference on AIDS, Vancouver, 1996 Hsu A et al. Assemssment of single- and multiple dose interactions between ritonavir and saquinavir. Abstract LB.B.6041, XI International Conference on AIDS, Vancouver, 1996. INTEGRASE INHIBITORS DESCRIPTION: HIV requires integration of a double-stranded DNA copy of the RNA genome into the host cell chromosome for productive infection. The viral enzyme integrase mediates the integration of retroviral DNA. Integrase is one of three retroviral enzymes; the other two are reverse transcriptase and protease. One inhibitor of HIV integrase is now in the clinical stages of development. Trials, page 158 PHYSICAL DESCRIPTION: AR-177 is synthetic DNA composed of 17 nucleosides and containing phosphorothioate linkage at the 3' and 5' terminal bonds. It is formulated as a sterile buffered solution for intravenous administration. MECHANISM OF ACTION: AR-177 is an integrase inhibitor with an IC50 in the 30-50 nanomolar range (Ojwang et al.). Inhibition of HIV-1 binding to CD4+ cells and inhibition of cell fusion have also been observed at micromolar concentrations of AR-177. Inhibition of gpl20 binding to CD4+ in vitro, and inhibition of reverse transcriptase were observed only at high concentration of AR-177. LABORATORY RESULTS: AR-177 demonstrated anti-HIV activity at micromolar concentrations with clinical isolates and prevented cytopathic effects of HIV-1. Inhibition of the infection of macrophages was seen from below I tM to above 50 [tM. The activity varied among HIV-I strains, but was consistently active. Resistance develops after approximately three months in vitro. AR-177 has weak antiviral activity against HIV-2. Long plasma and tissue half-lives (greater than 2 weeks) of AR-177 were observed in rats. The terminal plasma half-life was determined to be 24 hours. In rats, the primary organs in which AR-177 concentrates are the kidney, liver, spleen, bone marrow and lymph nodes. (Bishop et al.). TRIAL RESULTS Results from a single-dose safety and pharmacokinetics study of AR-177 in HIV+ patients has been reported (Deeks et al.). Four patients enrolled in each dose group studied; 0.75 mg/kg, 1.5 mg/kg, and 3.0 mg/kg. AR-177 was well tolerated at all doses studied. AR-177 also displayed dose-dependent pharmacokinetics and 46

Page  47 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 suggest a three times a day dosing schedule. A multiple-dose study of AR-177 is currently underway. TOXICITY/SIDE EFFECTS: There have been no reports of mortality, histopathological, or cardiovascular events in animals (Cornish et al.). No adverse events have been described in human patients who have been dosed so far. REFERENCES: Bishop J et al. Intramolecular G-quartet motifs confer nuclease resistance to a potent anti-HIV oligonucleotide. J Biol Chem 271:5698-703, 1996. Cornish KG et al. Cardiovascular effects of phosphorothioate oligonucleotide with sequence antisense to p53 in the conscious rhesus monkey. Pharmacol Commun 3:239-47, 1993. Deeks S et al. Phase I study of AR-177 (zintevir), an HIV-1 inhibitor with significant activity against integrase protein: safety, pharmacokinetics, immunologic and virologic activity. Abstract Th.B.946, XI International Conference on AIDS, Vancouver, 1996. Galbraith WM et al. Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res Dev 4:201-6, 1994. Ojwang J et al. T30177, an oligonucleotide stabilized by an intramolecular guanosine-octet, is a potent inhibitor of laboratory strains and clinical isolates of the human immunodeficiency virus type 1. Antimicrob Agents Chemother 39:2429-35, 1995. Rando et al. Suppression of human immunodeficiency virus activity in vitro by oligonucleotides which form intramolecular tetrads. J Biol Chem 270 1754-60, 1995. OTHER ANTIRETROVIRAL COMPOUNDS The following compounds represent a heterogeneous group of agents with in vitro anti-HIV activity, which do not fit into any of the previously described classes. None are approved for use against HIV at this time. PHYSICAL DESCRIPTION: ALX40-4C is the code-name for a nine-residue peptide. MECHANISM OF ACTION: In vitro and animal studies have shown ALX40-4C to inhibit replication of HIV by inhibiting the action of the HIV enzyme Tat. Tat upregulates HIV expression through interaction with the transactivating region (TAR) found on all HIV-1 transcripts. It is believed that ALX40-4C binds to the active site of TAR. The manufacturer states that ALX40-4C inhibits the replication of both clinical and laboratory isolates at a wide range of concentrations depending on the viral isolate. TRIAL RESULTS Twenty eight asymptomatic HIV+ people with CD4 cell count >300/mm3 received single doses of ALX40-4C intravenously (Sahai et al.). Doses ranged from 0.002 pg/kg to 0.70 pig/kg. According to the investigators, no toxicities or side effects attributable to the drug were seen. A phase I/II open-label dose-ranging safety and activity trial is open at the Ottawa General Hospital in Ontario, Canada. Forty HIV+ patients will be randomized according to CD4+ cell count to one of five dose levels. Patients will receive 20 minute intravenous infusions three times a week. A second phase I/II open-label dose-ranging safety and efficacy trial is open at the Toronto Hospital in Canada. Forty patients with late-stage HIV disease and CMV viremia, but no CMV disease, will be examined for their CMV and HIV response to the drug. Dose levels and drug administration are the same as in the Ottawa protocol. REFERENCES: Delling U et al. The number of positively charged amino acids in the basic domain of Tat is critical for trans-activation and complex formation with TAR RNA. PNAS 88:6234-8, 1991. Sahai J et al. A phase I, sigle dose evaluation ofALX404C in HIV-postive patients. 35th ICAAC, Abstra #A127, San Franisco, 1995. Sumner-Smith M et al. ALX404C: AnHIV, Cel Uplake, Pharmaod4netc Analyses. Abstrac 425A X IntlConf AIDS, Yokohama, 1994. Sumner-Smith M et al. Critical chemical features in trans-acting-responsive RNA are required for interaction with human immunodeficiency virus type 1 Tat protein. J Virol 65:5196-202, 1991. PHYSICAL DESCRIPTION: Antisense is a general term to describe short synthetic DNA strands (oligomers, or deoxyoligonucleotides) which are complementary to specific messenger RNA transcripts. MECHANISM OF ACTION: Antisense DNA oligomers specifically bind complementary segments of messenger RNA molecules, thereby preventing gene expression. The success of early attempts to inhibit HIV replication in vitro with unmodified phosphodiester DNA oligomers was limited because these molecules were rapidly degraded by cellular nucleases (Zamecnik et al. and Goodchild et al.). Recently, chemically modified oligomers have been developed which are resistant to cellular nucleases. LABORATORY RESULTS: Lisziewicz et al. reported the results of in vitro experiments with several phosphorothioate-modified DNA oligomers. All oligomers were 28 bases long. Several different sequences, targeted against tat, 47

Page  48 Antiretroviral Therapies rev, and gag, were evaluated and compared to a random control sequence. All HIV-1 specific sequences inhibited HIV-1 type-IlII replication in infected MOLT-3 cells at pM concentration. High levels of viral replication were observed in cells treated with random control sequences. In another assay, uninfected cells were simultaneously challenged with HIV-1 and treated with antisense DNA oligomers at a 5 pM concentration. No apparent viral replication was observed, suggesting that these compounds may inhibit a pre-integration step in HIV replication. It has since been reported that phosphorodithioate DNA oligomers can inhibit HIV-1 reverse transcriptase through direct binding (Marshall and Caruthers). Agrawal and Tang reported the results of in vitro experiments with a 25-mer phosphorothioate-modified DNA oligomer code-named GEM 91. The oligomer is complementary to a segment of the gag mRNA at the site of codon initiation. GEM 91 was tested in CEM, H9, and MOLT 3 cells acutely infected with HIV-1 (strains Ills or MN). The ED50 ranged from 0.1 - 0.3 VpM. Higher concentrations (22.5 p.M) were required to inhibit HIV-l replication in chronically infected cells. Results from two in vitro studies reported by Bym et al. A total of 14 samples were collected; HIV-I strains with different in vitro phenotypes with respect to syncytium induction, AZT sensitivity, or ddl sensitivity were included. Sensitivty was high for all HIV-1 clinical isolates tested, with a range of IC50 from 1.6 pLM to <.04 pM. Bym et al. have also reported that HIV resistance to GEM 91 has not been observed in vitro. TRIAL RESULTS A phase I safety and pharmacokinetics study has concluded in France. 23 patients with CD4+ counts between 200 and 500 cells/mm3 received alternating bi-weekly intravenous (IV) and subcutaneous (SC) administrations of GEM 91 at 0.1, 0.3, 0.5 or 1.0 mg/kg. According to the manufacturer, the treatment was well-tolerated, with local reactions observed with SC administration. Urine tests revealed limited degradation of the drug. Blood levels of GEM-91 in the SC arms were highly variable, thus questioning the viability of SC administration. A follow-up study in 12 patients using single dose infusions up to 2.5 mg/kg showed plasma concentrations identical to those achieved in vitro with no clinically significant intolerance. A phase I single-dose pharmacokinetic study of radiolabled GEM 91 has finished at the University of Alabama. S-labeled GEM-91 was administered to 6 HIV+ patients via infusion at a dosing level of 0.1 mg/kg. Urinary excretion represented the major pathway of elimination with approximately 50% eliminated after 24 hours and approximately 70% after 96 hours. No toxicity was observed. Sereni et al. (1995) recently reported prelimary results from a phase Ib study of GEM 91 in 30 HIV+ patients. At baseline, CD4+ counts ranged from 100-500 cells/mm3 and > 25,000 HIV-RNA copies/ml. Nine patients received GEM 91 0.5 mg/kg, 9 received 1.0 mg/kg, and 12 received 2.0 mg/kg every other day for 27 days. To date, the 0.5 mg/kg/day and 1.0 mg/kg/day have been well tolerated. No significant changes in viral RNA have been observed. Phase II trials have begun in France and the United States. An oral compound equivalent to GEM-91 has been found to be highly bioavailable in laboratory animals. Clinical studies of an oral formulation are being developed by the manufacturer. REFERENCES: Agrawal S and Tang JY. GEM 91 - an antisense oligonucleotide phosphorothioate as a therapeutic agent for AIDS. Guest editorial, Antisense Res and Devel 2:261-6, 1992. Byrn RA et al. Failure to generate HIV-1 resistance in vitro to the antisense therapeutic agent GEM 91. Abstract #469, 2nd National Conference on Human Retroviruses, Washington, 1995. Byrn RA et al. In vitro antiviral activity of GEM 91 against diverse clinical isolates of HIV-1. Abstract #477, 2nd National Conference on Human Retroviruses, Washington, 1995. Goodchild J et al. Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides. PNAS 85:5507-11, 1988. Lisziewicz J et al. Specific inhibition of human immunodeficiency virus type 1 replication by antisense oligonucleotides: an in vitro model for treatment. PNAS 89:11209-13, 1992. Marshal WS and Caruthers MH. Phosphorodithioate DNA as a potential therapeutic drug. Science 259:1564-70, 1993. Sereni D et al. An open-label safety and pharmacokinetic study of single intravenous or subcutaneous ascending doses of GEM 91 in untreated, adult, HIV positive, asymptomatic human volunteer patients. ICAAC, abstract M10: 217, 1994. Sereni D et al. An open-label, multiple-dose, safety, pharmacokinetics and preliminary antiviral activity study of GEM 91 administered by intermittent intravenous infusions in HIV-positive adults. Abstract 1177, 35th ICAAC, San Francisco, 1995. Zamecnik PC et al. Inhibition of replication and expression of human T-cell lymphotropic virus type III in culture cells by exogenous synthetic oligonucleotides complementary to viral RNA. PNAS 83:4143-5, 1986. Zhang, R et al. Human Pharmacokinetics of an anti-HIV antisense oligonucleotide phosphorothionate (GEM 91) in HIV-infected individuals. Abstract A/5, 34th ICAAC, Orlando, 1994. OTHER REPORTS: Agrawal S et al. Pharmacokinetics, distribution, and stability of oligodeoxynucleotide phosphorothioate in mice. PNAS 88:7595-9, 1991. Kilkuskie RE et al. GEM 91 - an antisense inhibitor of HIV-1 replication. Abstract PO-A25-0572, IX Intl Conf AIDS, Berlin, 1993. 48 L

Page  49 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 07 Trials, page 162 PHYSICAL DESCRIPTION: Hydroxyurea, a member of the family of cellular deoxynucleotide (dNTP) modulators, is an oral antineoplastic agent indicated for the treatment of leukemia and inoperable ovarian cancer. MECHANISM OF ACTION: Hydroxyurea inhibits deoxynucleotide synthesis by blocking the cellular enzyme ribonucleotide reductase. LABORATORY RESULTS: Gao et al. (1993) reported that hydroxyurea inhibits HIV-1 DNA synthesis in activated peripheral blood lymphocytes in vitro. Lori et al. demonstrated the antiviral effect of hydroxyurea by using non-toxic dose levels (1 PM or 0.1 pM) to block HIV-1 replication in acutely infected quiescent and activated lymphocytes/macrophages as well as in in vivo infected cells obtained from HIV+ patients. Lori et al. also reported that hydroxyurea was found to be synergistic with AZT and ddl in vitro. Gao et al. (1995) reported that hydroxyurea increased phosphorylation of AZT and ddC but not ddl. However, Rana et al. reported that adding hydroxyurea to AZT did not increase anti-HIV activity in vitro. TRIAL RESULTS Lori et al. have presented results from a randomized, controlled study of hydroxyurea (500 mg bid) in combination with ddl (200 mg bid) in patients with CD4+ counts > 250 cells/mm3 and HIV-RNA levels > 20,000 copies/ml. 40 patients were randomized to receive the combination and 20 were randomized to receive ddl monotherapy. At week 2, both treatment groups reported a median 1 log reduction in HIV-RNA. At 24 weeks, patients receiving hydroxyurea and ddl reported sustained HIV-RNA decreases (median 1.3 log reduction) whereas HIV-RNA levels in patients receiving ddl monotherapy had turned towards baseline. No significant differences in CD4+ count increases were reported between the two groups. Various small, non-randomized, open-label studies of hydroxyurea, either alone or in combination with ddl, have been reported (Vilas, et al., Clotet et al., Biron et al., Mole et al., Williams et al., Simonelli et al.). All non-randomized studies have reported durable results similar to the study conducted by Lori et al. ONGOING STUDIES: Two studies of hydroxyurea in combination with ddl are currently enrolling. ACTG 307 is a randomized, double-blind study comparing ranging doses of both hydroxyurea and ddl. Approximately 140 patients will be enrolled. AmFAR's CBCT Network is conducting an open-label study of hydroxyurea in combination with ddl; target accrual is 80 patients. TOXICITY/SIDE EFFECTS: As a cancer treatment, hydroxyurea has induced bone marrow depression (leukopenia, anemia), gastrointestinal disturbances (anorexia, nausea, vomiting), and dermatological reactions (maculopapular rashes, facial erythema). Headaches, fevers, chills, malaise, and elevation of liver enzymes have also been reported. In HIV+ patients, there have been reports of anemia, leucopenia, thrombocytopenia, increased MCV, hyperpigmentation of the palms, paresthesis, and minor mouth ulcerations. REFERENCES: Biron F et al. Anti-HIV activity of the combination of didanosine and hydroxyurea in HIV-1 infected individuals. Acq Immun Def Syn 10(1):36-40, 1995. Gao W et al. Low levels of deoxynucleotides in peripheral blood lymphocytes: A strategy to inhibit human immunodeficiency virus type I replication. Proc Natl Acad Sci 90:8925-8928, 1993. Gao W et al. A comparison of the potentiation mechanisms of anti-HIV-1 activities of 2',3'-dideoxynucleosides by hydroxyurea. Abstract #82, 2nd National Conference on Human Retroviruses, Washington, 1995. Lori F et al. Sustained absence of viral rebound consistently observed in patients treated with combination of hydroxyurea and didanosine. Abstract Th.B.942, XI International Conference on AIDS, Vancouver, 1996. Mole, L and Holodniy, M. A pilot study of the tolerance and potential antiviral activity of hydroxyurea alone and in combination with ddl in HIV-infected patients, Abstract #1 110, 35th ICAAC, San Francisco, 1995. Lori F et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 266:801-805, 1994. Rana KZ et al. Exposure to hydroxyurea in combination with zidovudine does not increase activity against HIV in vitro. Abstract #83, 2nd National Conference on Human Retroviruses, Washington, 1995. Simonelli G et al. Hydroxyurea as an antiretroviral drug in HIV infected patients: clinical, immunological and virological evaluation. Abstract #84, 5th Euro Conf on the Clin Aspects and Treat of HIV, Copenhagen, 1995. Williams S et al. A pilot study of the effect of ddl plus hydroxyurea on HIV viral burden. Abstract #1 111, 35th ICAAC, San Francisco, 1995. 49

Page  50 Antiretroviral Therapies MECHANISM OF ACTION: Castanospermine, and its analog MDL 28,574A inhibit the enzyme glucosidase I and thereby inhibit HIV replication and syncytium formation by modifying the glycosylation of the viral envelope gpl20. LABORATORY RESULTS: Sunkara et al. reported that MDL 28,574A inhibited syncytium formation by HIV-1 in vitro; the IC50 was 0.15 g/mL (compared with an IC50 of 6.5 g/mL for castanospermine). No host cell toxicity was observed at concentrations up to 200 g/ml, and no toxicity was observed when the compound was administered to mice for 2 weeks at 200 mg/kg daily. TRIAL RESULTS A phase I clinical trial designed to evaluate the safety of single doses of MDL 28,574A delivered orally has been completed. According to preliminary results from the manufacturer (1995), the maximum tolerated dose reported was 400 mg/day. Preliminary results from two clinical trials of MDL 28,574A have been reported. The first trial has enrolled 200 HIV+ patients with CD4+ counts between 100 and 300 cells/mm3 (Zolnouri et al.). The second trial has enrolled 170 HIV+ patients with CD4+ counts between 300 and 500 cells/mm3 (Richmond et al.). Drop-out rates are 19% and 14%, respectively. Drop-out rates from the study are attributed to voluntary withdrawl and noncomliance. The investigators report that no significant treatment-related serious adverse events have been associated with MDL 28,574A. Both studies will continue to enroll patients. TOXICITIES/SIDE EFFECTS: Bloody diarrhea and flatulence are the primary dose-limiting toxicities reported in the phase I and two phase II studies. REFERENCES: Richmond GJ et al. Efficacy and safety of MDL 28,574A in HIV-positive patients with baseline CD4 values of 301-500. Abstract Mo.B.1145, XI International Conference on AIDS, Vancouver, 1996. Sunkara PS et al. Anti-HIV activity of castanospermine analogues. Lancet volume 1:1206, 1989. Zolnouri P et al. Efficacy and safety of MDL 28,574A in HIV-positive patients with baseline CD4 values of 100-300. Abstract Mo.B.1138, XI International Conference on AIDS, Vancouver, 1996. OTHER REPORTS: Tyms AS and Taylor DL. Activity of glucosidase inhibitors against HIV infection. J Antimicrob Chemother 22:271-4, 1988. Ruprecht RM et al. In vivo analysis of castanospermine, a candidate antiretroviral agent. J AIDS 2:149-157, 1989. 50

Page  51 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 1997 TREATMENTS FOR HIV INFECTION IMMUNE-BASED THERAPIES DESCRIPTION: HIV/AIDS is a progressive immunodeficiency disease, therefore researchers have long been interested in developing ways to improve immune defenses in HIV+ patients. Many different approaches have been tried; none have yet been proven to be of clinical benefit. One approach is the use of therapeutic vaccines, with the objective of inducing beneficial immune responses. Another approach is to administer pharmacologic doses of certain cytokines. The most promising result so far is with IL-2, which boosts the CD4 count substantially in some individuals at less advanced stage of disease (i.e. CD4+ cell count >200). A third approach is to administer compounds with anti-TNF activity. The following section describes the results to date of clinical studies of the immune-based therapies, referred to above and others with a variety of rationales and purported mechanisms of action. CYTOKINES Trials, page 165 PHYSICAL DESCRIPTION: IL-12 is a heterodimeric cytokine encoded by two separate genes, p40 and p35. It is naturally produced by macrophages and B lymphocytes. A recombinant version is under clinical investigation. MECHANISM OF ACTION: IL-12 has a wide variety of biological activities. It stimulates the production of interferon-g from T and natural killer (NK) cells (Scott, 1993) and is required for T-cell-independent triggering of NK cells by intracellular parasites such as T gondii (Gazzinelli et al.). It has been proposed as a treatment for HIV disease because it stimulates a subset of CD4+ cells called TH I, which may be important for preventing disease progression in HIV+ people. Two subsets of CD4+ cells, called TH, and TFL, have been characterized. THi cells produce IL-2 and interferon-y and facilitate cell-mediated immunity. TH, cells produce IL-4, IL-5, and IL-10, and are associated with humoral immunity (antibodies). Recently, investigators have proposed that progression to symptomatic HIV infection is associated with a switch from a dominant TH, response to a dominant TH2 response (Shearer). In one model, IL-12 has been demonstrated to induce THi development in naive CD4+ cells undergoing primary activation (Hsieh et al.). LABORATORY RESULTS: Two in vitro studies conducted at the University of Colorado Health Science Center have reported the effects of IL-12 on natural killer cell activity and antigen specific lymphoproliferative responses. The first study (McFarland et al.) studied IL-12 activity in peripheral blood mononuclear cells (PBMC) from HIV+ and HIV-negative children. Although NK activity in both unstimulated and IL-12 stimulated PBMC from uninfected children was higher than in PBMC from infected children, the mean increase in NK activity after IL-12 stimulation was similar for uninfected and infected children. The second study (Uherova et al.), conducted on 13 HIV+ PBMC isolates stimulated with IL-12, demonstrated varied antigen-specific responses. Assays were collected from patients with a broad range in CD4+ cell counts (0 - 1200 cells/mm3). Increased antigen-specific responses to streptokinase and candida were reported in PBMC isolated from patients with > 500 CD4+ cells/mm3; PBMC isolated from patients with >200 CD4+ cells/mm3 demonstrated increased responses to tetanus toxoid. PBMC from patients with fewer than 200 CD4+ cells/mm3 did not demonstrate significant increases in antigen-specific responses. Clerici et al. have reported that IL-12 augments the in vitro production of cytokines associated with THi responses (IL-2 and interferon-y) in HIV+ individuals. PBMCs were cultured from 40 HIV+ individuals unable to produce IL-2 in response to envelope peptides of HIV-1 (Env). When these cells were Env-stimulated in the presence of IL-12, increased IL-2 production was observed in 28/40 (70%). Env-stimulated IL-2 production was not seen in PBMCs from 9 HIV-negative individuals studied as a control. PHA-stimulated interferon-y production was diminished in 8 HIV+ subjects; IL-12 incubation augmented interferon-y production in 6/8 individuals. Finally, PBMCs from HIV+ people were stimulated in vitro with non-HIV antigens (influenza virus and HLAdisparate PBMCs); IL-12 increased the T helper cell response to these 51

Page  52 Immune-Based Therapies I antigens. Elevated responses to these antigens were not observed in cells from HIV-negative subjects. McLeod et al. report that IL-12 has neither a direct inhibitory nor stimulatory effect on HIV replication in vitro. TRIAL RESULTS Two phase I clinical trials of IL-12 in HIV+ patients with CD4+ counts between 100 and 300 cells/mm3 and 300 and 500 cells/mm3 have been completed. Single doses of 3, 10, 100, 300, 1000, 3000, and 4000 ng/kg were found to be safe in both clinical trials. However, one study (Jacobson et al.) reported no marked effects on HIV-RNA levels or CD4+ counts in patients receiving single dose treatment. Due to a high number of hospitalizations and deaths possibly resulting from IL-12 administration in a non-AIDS kidney cancer study, additional phase I studies for oncology and HIV are being developed. A phase II/III randomized, double-blind, placebo-controlled dose escalating trial in patients with CD4+ counts between 100 and 300 cells/mm3 is currently underway at St. Luke's/Roosevelt Hospital in New York. All patients will recieve one of three doses: 30, 100, 300 SC ng/kg biw. REFERENCES: Clerici M et al. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science 262:1721-4, 1993. Gazzinelli RT et al. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon-y by an intracellular parasite and induces resistance in T-cell-deficient hosts. PNAS 90:6115-9, 1993. Hsieh CS et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547-9, 1993. Jacobson MA et al. Phase I trial of recombinant human IL-12 in HIV-infected subjects. Abstract #309, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. McFarland EJ et al. Interleukin-12 enhances natural killer cell activity in peripheral blood mononuclear cells from HIV-infected infants and children. Abstract #406, 2nd National Conference on Human Retroviruses, Washington DC, 1995. McLeod GX et al. Effects of interleukin (IL)-12 on HIV-1 replication in vitro. Abstract 54, 1st Natl Conf on Human Retroviruses, Washington DC, 1993. Scott PS. IL-12: Initiation cytokine for cell-mediated immunity. Science 260:496-7, 1993. Shearer G. Protective cell-mediated immune responses. Oral presentation, Roundtable for the Development of Drugs and Vaccines against AIDS, Institute of Medicine, 1993. Uherova P et al. The effects of rhlL-12 on the in vitro antigen-specific lymphoproliferative responses in HIV-infected individuals. Abstract #407, 2nd National Conference on Human Retroviruses, Washington DC, 1995. OTHER REPORTS: Locksley RM. Commentary: Interleukin 12 in host defense against microbial pathogens. PNAS 90:5879-80, 1993. Seder RA et al. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon- production and diminishes interleukin 4 inhibition of such priming. PNAS 90:10188-93, 1993. Trials, pages 166, 167 PHYSICAL DESCRIPTION: Interleukin-2 (IL-2) is a natural glycoprotein generated by T lymphocytes following antigenic and mitogenic stimulation. A recombinantly produced form is being studied in clinical trials. PEG-IL-2 (polyethylene-glycol derivatized IL-2) is a modified form of IL-2 with a prolonged half-life in vivo. MECHANISM OF ACTION: IL-2 is a lymphokine central to the immune response; it promotes the proliferation and expansion of activated T lymphocytes, potentiates B cell growth and activates monocytes and natural killer cells. Based on studies examining the use of interferon-alpha, an immunomodulatory compound, it was hypothesized that patients with higher CD4+ counts would be more likely to have a CD4+ response to IL-2 than patients with more severely impaired immune systems; this hypothesis has been confirmed by Kovacs et al. (reported below). TRIAL RESULTS Results from a phase I trial of IL-2 in HIV+ patients have been published (Kovacs, 1995). In the initial dose-escalation part of the study, 23 patients with CD4+ counts greater than 200 cells/mm3 were treated with IL-2 administration as a continuous infusion at a dosage of 6 to 18 million IU/day for 5 days every 8 weeks. The maximum tolerated dosage of IL-2 used in combination with AZT was 12 million IU/day when administered for 21 days and 18 million IU/day when administered for 5 days. Capillary leak, severe flu-like symptoms, hepatic and renal dysfunction, thrombocytopenia, and neutropenia were the primary dose-limiting toxicities reported. In the second part of the study, 10 patients with similar baseline characteristics were treated with IL-2 beginning at a dose of 18 million IU/day once every two months for 5 days. Most patients in part 2 received concomitant AZT (500 mg/day). Six patients required dose reduction to 12 million IU/day and two to 6 million IU. Two of these 8 patients permanently withdrew from the study. The baseline CD4+ count increased by more than 50% in 6 of these 10 patients, one and two months after a course of IL-2. The expanded CD4+ cells were examined in vitro and thought to result from a broad based, rather than selective expansion of cells. No significant changes in CD4+ counts occurred in the other 4 patients. No consistent changes in the plasma viral load, as measured by p24 antigen or plasma viremia, were detected during the multiple courses of IL-2 therapy during 24-40 months of follow-up. However, 4 patients reported consistent but transient increases in plasma viral load by bDNA immediately following a round of IL-2; these increases subsequently returned to baseline levels by the next follow-up visit. 52

Page  53 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 )7 In 15 patients with fewer than 200 CD4+ cells/mm3 at baseline who were treated, side effects were reported to be more severe; dose reduction was required in 12 patients. The other 3 patients were unevaluable. Among the six patients who could be evaluated and who had initial CD4+ counts between 100-200 cells/mm3, two had CD4+ cell increases of more than 50%. In contrast, none of the six patients with CD4+ counts under 100 cells/mm3 had increased CD4+ counts. Moreover, sustained increases in p24 antigen or HIV-RNA were noted in 10 of the 12 patients. The authors conclude that intermittent IL-2 infusions with concomitant antiretroviral therapy result in sustained, significant increases in CD4+ counts in some patients with baseline CD4+ counts > 200 cells/mm3, and that larger controlled trials with clinical endpoints are warranted. Final data from a trial of IL-2 plus any approved antiretroviral therapy versus antiretroviral therapy alone in 60 HIV+ patients have been published (Kovacs et al., 1996). A total of 31 patients were randomized to receive IL-2 in combination with antiretroviral therapy. 42% of IL-2 recipients reported fatigue. Only 2/31 (6.5%) IL-2 patients completed the trial without a reduction in the IL-2 dose of 18 million IU/day. In patients receiving IL-2, the mean CD4+ count increased from 428 to 916 cells/mm3 at month 12, while in the control group the mean CD4+ count decreased from 417 to 349 cells/mm3. The mean rate of change per month in the IL-2 recipients was significantly significant (P < 0.001). Increases in HIV-RNA levels did not differ significantly between the two groups. McMahon et al. enrolled sixteen symptomatic HIV+ subjects in a phase I study of the combination of subcutaneous IL-2 and AZT. All subjects received AZT 600 mg/day with six patients receiving IL-2 200,000 U/m2 daily, six receiving IL-2 700,000 U/m2 daily and 4 receiving IL-2 2 million IU/m2 daily. Treatment duration was five days. Lymphopenia occurred at all dose levels by the second day of treatment, with a rebound above baseline apparent by the eighth day of the study. Significant changes in viral titer were not observed. Significant increases in circulating IL-2 receptors and transient increases in NK cell activity were observed. 2/4 patients receiving IL-2 at 2 MU/m2 stopped therapy because of side effects (hypotension and rigors). PEG IL-2: Three studies of polythylene glycol (PEG) IL-2 have been published. Wood et al. reported significant CD4+ cell increases in 19 HIV+ patients enrolled in a phase I/II open-label trial of PEG IL-2 (weekly infusions of 10 million IU/m2). Virologic monitoring showed no evidence of increased HIV activation. However, two reports by Teppler et al. failed to demonstrate significant changes in CD4+ counts, although a non-significant trend towards increased CD4+ counts in patients with greater than 400 CD4+ cells/mm3. IL-2 & INDINAVIR: Falloon et al. has reported results of IL-2 therapy with concomitant indinavir. A total of 36 patients with < 300 CD4+ cells/mm3 were randomized to receive either 12 million IU IL-2 for 5 days every 8 weeks and indinavir 600 mg qid; 12 million IU IL-2 for 5 days every 8 weeks and indinavir 600 mg qid for 10 days every 8 weeks (pulsed dose); or indinavir monotherapy 600 mg qid. Median CD4+ counts at entry were 186, 164, and 144 cells/mm3 at baseline, respectively. At week 14 of therapy, CD4+ counts were 382, 205, and 229, respectively. In all patients treated, HIV-RNA levels remained below baseline after 14 weeks. A trial (ACTG 236) of the combination of AZT + IL-2 + alpha thymosin is underway at Stanford University. A phase II, randomized trial (ACTG 248) is underway, studying low-dose SC IL-2 in combination with antiretroviral therapy versus antiretroviral therapy alone in 104 HIV+ patients with at least 3 months stable antiretroviral therapy; 64/104 patients are enrolled. A number of IL-2 studies are underway at the National Institutes of Health. IL-2 in these studies are to be administered subcutaneously and intravenously, with concomitant antiretroviral therapy. TOXICITY/SIDE EFFECTS: Mild hematologic toxicity (neutropenia and anemia), chills, fevers, muscle pains, fatigue, headache, nausea, loose stools and elevated liver-function tests have been observed. REFERENCES: Falloon J et al. MK-639 (Merck HIV protease inhibitor) with interleukin -2 (IL2) in HIV. Abstract 1176, 35th ICAAC, San Francisco, 1995. Kovacs JA et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N ENGL J MED 335:1350-6, 1996. Kovacs JA et al. Increases in CD4 lymphocytes with intermittent courses of interleukin -2 in patients with human immunodeficiency virus infection: a preliminary study. N ENGL J MED 332:567-75, 1995. McMahon D et al. A phase I study of subcutaneous recombinant interleukin-2 in patients with advanced HIV disease while on zidovudine. AIDS 8:59-66, 1994. Teppler H et al. Prolonged immunostimulatory effect of low-dose polythelene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection. J Exp Med 177:483-92, 1993. Teppler H et al. Efficacy of low doses of the polythelene glycol derivative of interleukin-2 in modulating the immune response of patients with human immunodeficiency virus type 1 infection. JID 167:291-8, 1993. Wood R et al. Safety and efficacy of poythylene glycol-modified interleukin-2 and zidovudine in human immunodeficiency virus type 1 infection: A phase 1/11 study. JID 167:519-21, 1993. OTHER REPORTS: Cunningham-Rundles C et al. Brief Report: Enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethylene glycol-conjugated interleukin-2. N ENGL J MED 331:918-921, 1994. Ramachandran RV et al. Long-term effects of interleukin-2 on CD4 cell counts in human immunodeficiency virus-infected patients. J Infect Dis 170:1044-1046, 1994. Schwartz DH et al. Safety and effects of interleukin -2 plus zidovudine in asymptomatic individuals infected with human immunodeficiency virus. JAIDS (4): 11-23, 1990. 53

Page  54 Immune-Based Therapies GENE TRANSFER THERAPY Trial, page 168 DESCRIPTION: Gene transfer therapy involves the delivery of altered genes to target cells, providing the opportunity for the replacement or inactivation of disease-causing genes, augmentation of normal gene functions, or provision of cellular markers. One delivery mechanism utilizes murine retroviral vectors, which are genetically engineered retroviruses. These vectors are non-pathogenic, produce no proteins of their own, and are non-replicating. Other delivery mechanisms under investigation include DNA virus vectors, liposomes, particle-mediated DNA injection, and direct naked DNA injection. In the development of gene transfer therapy for AIDS patients, two major approaches are being studied. The first relies on the enhancement of the body's own immune response while the second provides interference with the HIV life cycle through inhibition of viral replication events. Of the many strategies currently being pursued, four are in clinical trials. These include immunotherapeutics, adoptive T-cell transfer, dominant negative inhibition, and hairpin ribozymes. MECHANISM OF ACTION: IMMUNOTHERAPEUTICS uses genetically engineered cells that overproduce HIV antigens, thus stimulating a host humoral and cellular immune response. Foreign proteins produced intracellularly induce class I MHC-restricted CTL (cytotoxic T-lymphocyte) responses. Induction of CTL responses and neutralizing antibodies may prevent HIV-1 spread by recognizing and lysing virally-infected cells or inhibiting the ability of HIV to infect cells. ADOPTIVE T-CELL TRANSFER is a strategy for augmenting the immune response in individuals with persistant viral infections. The approach is to isolate CTLs of defined specificity; then, with or without gene marking, the cells are expanded ex vivo and adoptively transferred. DOMINANT NEGATIVE INHIBITION is a process that interferes with the functioning of essential viral gene products by expression of transdominant forms of viral proteins, which bind to wild type viral proteins and inactivate them. For HIV, several transdominant protein targets have been identified, including the rev and tat proteins and viral group-specific antigens (GAG). RIBOZYMES are fragments of RNA that possess an enzyme activity that cleaves other RNA molecules in a sequence-dependent manner. Hairpin ribozymes (so-called because of their shape) can be engineered to match a target genetic sequence. Through enzymatic cleavage of viral substrates, these hairpin ribozymes have been shown to inactivate HIV expression within cells. TRIAL RESULTS IMMUNOTHERAPEUTICS: A phase I safety trial was conducted by Galpin and co-workers in California. Four HIV+ asymptomatic patients, all with CD4 counts >500mm3, received monthly injections of their own genetically altered fibroblasts. Fibroblasts were removed from HIV+ patients, genetically altered ex vivo with the murine retroviral vector HIV-IT(v), then readministered to the donor. The vector is designed to deliver to target cells the genes that code for the production of the HIV envelope proteins env and rev, thus mimicking an infection and stimulating a cell-mediated immune response. A second phase I placebo-controlled, dose-ranging study in California administered HIV-IT(v) through direct intramuscular injections to multiple locations in the arms and legs of 21 asymptomatic HIV+ volunteers with CD4 counts above 400/mm3 (Merritt et al.). Patients received a series of 3 treatments over 3 months and will be followed for 3 years for evidence of the safety and immunological activity of the treatment. HIV-IT(v) was shown to be well tolerated and immunogenic at monthly x 3 schedule at the highest dose studied (17 cfu/ml purified vector). ADOPTIVE T-CELL TRANSFER: A phase I placebo-controlled, dose-ranging study conducted by the National Institutes of Health of adoptive transfer of genetically modified cytotoxic T lymphocytes (CTL) in HIV-discordant identical twins has been reported (Walker et al.). The study was designed to determine the safety and activity of adoptive transfer of antigen specific syngeneic CD8 cells genetically engineered, using ex vivo retroviral transduction, to express a chimeric receptor (CD4 zeta) containing the extracellular and transmembrane domains of human CD4 (providing anti-gpl20 specificity) and the intracytoplasmic domain of CD3-zeta (to allow for CD4 cell activation). A total of 10 patients received transduced adoptive transfers; 4 patients received non-transduced infusions. All infusions were well tolerated. Preliminary data revealed evidence of gene transfer persisting in vivo for as long as 4 weeks post infusion. DOMINANT NEGATIVE INHIBITION: Nabel and co-workers at the University of Michigan will treat 12 patients using transdominant gene transduction. CD4+ cells will be isolated from asymptomatic HIV+ patients with CD4+ counts between 400 and 500/mm3. These cells will be stimulated to provide preferential proliferation, genetically altered ex vivo with a control gene or a mutant form of the rev gene, Rev M10, and then readministered to the donor. Rev is an important regulatory protein which controls the export of viral RNA from the 54

Page  55 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 nucleus to the cytoplasm of infected cells. Rev M10, a transdominant mutant form of the rev gene, has shown in vitro inhibition of viral replication and does not appear to interfere with normal cellular functions. Six patients will receive cells transduced with Rev M10 or a control vector using the murine retroviral vector approach while six patients will receive Rev M10 or control constructs using particle-mediated gene delivery, microspheres of gold embedded with the desired DNA. HAIRPIN RIBOZYMES: Wong-Staal and co-workers at the University of California-San Diego plan to insert the gene for hairpin ribozymes, isolated from the tobacco ringspot virus, into peripheral blood lymphocytes removed from six HIV+ volunteers with CD4 counts between 200 and 500/mmr. TOXICITY/SIDE EFFECTS: No significant side effects have been reported. REPORTS: Bridges SH and Sarver N. Gene therapy and immune restoration for HIV disease. Lancet 345:427-32, 1995. Britton S et al. Ribozyme based gene therapy against HIV/AIDS. Abstract #577, 5th Euro Conv on the Clin Aspects and Treat of HIV, Copenhagen, 1995. Chada S et al. Cross-reactive lysis of human targets with prototypic and clinical human immunodeficiency virus type 1 (HIV-1) strains by murine anti-HIV-l senv-specific cytotoxic T lymphocytes. J Virology: 3409-17, 1993. Chang H et al. Gene therapy strategies for HIV-1 infection. Jrnl Physicians Ass AIDS Care: 20-26, 1994. Cotton P. High-tech assault on HIV: Gene Therapy. JAMA 272:1235-36, 1994. Hardy LM et al. From the Institute of Medicine: Gene Therapy for HIV Infection. JAMA 272:423, 1994. Merritt J et al. HIV-IT(v) stimulates HIV-1 specific cytotoxic T lymphocytes following intramuscular administration to HIV-seropositive volunteers. Abstract 176, 35th ICAAC, San Francisco, 1995. Pomerantz RJ et al. Genetic therapies for HIV infection: promise for the future. AIDS 9: 985-93, 1995. Walker RE et al. Adoptive transfer of gentically modified, HIV-1 specific, syngeneic cytotoxic T lymphocytes (CTL) in HIV-discordant identical twins. Abstract #E16, 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Wong-Staal F et al. Gene therapy for HIV infection. Abstract PS18, X Intl Conf AIDS, Yokohama, 1994. TUMOR NECROSIS FACTOR INHIBITORS Trials, page 168 PHYSICAL DESCRIPTION: An oral inotropic agent used in Japan as a treatment for mild to moderate congestive heart failure. MECHANISM OF ACTION: OPC-8212 reduced the viral cytopathic effect of HIV-1 in acutely infected T cells in vitro (ICso = 8.55 - 15.8pg/ml), and inhibits virus production in acutely and chronically infected macrophages (Maruyama et al.). OPC-8212, at concentrations greater than 3[pg/ml, inhibited the production ofTNF-a from stimulated peripheral blood mononuclear cells in vitro. TNF-a (sometimes referred to as cachectin) is a naturally occurring cytokine with many functions in the human immune system. It has been reported by Lahdevirta et al. that in HIV+ people, TNF-a levels are elevated and may be implicated in the progression of the disease as well as the wasting syndrome associated with HIV infection. Folks et al. reported that in vitro, recombinant TNF-a upregulates HIV-1 expression in chronically infected T-cell lines, and Ito et al. showed that TNF-c antagonizes the anti-HIV effect ofAZT. TRIAL RESULTS Preliminary results from a phase I clinical trial in 24 asymptomatic HIV+ patients have been reported. Patients are randomized to receive either 60 or 90 mg/day OPC-8212. Preliminary data are available in 16 patients. 4/16 patients discontinued; 2/4 due to neutropenia and the remaining 2 as a result of consent withdraw. No significant effect was observed in plasma RNA viremia, CD4 or CD8 counts, TNF, IL6, or beta-2-microglobulin in the two groups. TOXICITY/SIDE EFFECTS: In patients with heart failure, neutropenia and agranulocytosis have been reported. These effects generally resolved upon discontinuation of the treatment. REFERENCES: Gatell M et al. Vesnarinone in asymptomatic HIV patients. Abstract 1106, 35th ICAAC, San Francisco, 1995. Ito M et al. Tumor necrosis factor antagonizes inhibitory effect of azidothymidine on HIV replication in vitro. Biochem Biophys Res Comm 166:3, 1095-1101, 1990. Lahdevirta J et al. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85: 289-91, 1988. Maruyama B et al. Vesnarinone inhibits production of HIV-1 in cultured cells. Biochem & Biophys Res Comm 195:1264-71,1993. Mitsuyasu, R et al. Preliminary results of a Phase I study of Vesnarinone (OPC-8212) in HIV-infected persons with CD4 > 300 cells/mm3. Abstract 005B, X Intl Conf AIDS, Yokohama, 1994. 55 ~

Page  56 Immune-Based Therapies PHYSICAL DESCRIPTION: Pentoxifylline is a tri-substituted xanthine derivative approved for the treatment of patients with intermittent claudication and chronic peripheral arterial disease. MECHANISM OF ACTION: Fazely et al. report that pentoxifylline reduces the replication of HIV-1 in vitro in acutely infected PBMC and cultured human T cells. Pentoxifylline indirectly inhibits HIV-1, possibly through inhibition of the NF-KB binding protein (Biswas et al.). Pentoxifylline also inhibits the production of tumor necrosis factor (TNF, cachectin), a naturally occurring cytokine with many functions in the human immune system. Folks et al. reported that recombinant TNF upregulates HIV-1 expression in vitro in chronically infected T-cell lines. Ito et al. showed that TNF antagonizes the anti-HIV effect of AZT in vitro. Lahdevirta et al. reported that in HIV+ people, TNF levels are elevated and may be implicated in the progression of the disease as well as the wasting syndrome associated with HIV infection. A recent study found that pentoxifylline exerts a broad antiretroviral effect, inhibiting HIV replication in both acutely infected PBMC and chronically infected promonocytic cells (Fox et al.). This group reported that pentoxifylline inhibited both the synthesis and action of several cytokines, and that it inhibited viral expression at both the transciptional and post-transcriptional levels. Pentoxifylline has also been reported to downregulate the production of TNF-y, TNF-a, and GM-CSF in CD8+ cytotoxic lymphocytes (CTL) (Heinkelein et al). Investigators further noted that the ability to stimulate cell surface antigen and HIV expression was significantly reduced in pentoxifylline-treated CTL. Zhang et al. report that in vitro, pentoxifylline enhances the anti-HIV effect of ddl. TRIAL RESULTS An open-label study (ACTG 160) of pentoxifylline 400 mg or 800 mg three times daily was completed. The patient population included HIV+ patients with CD4 counts below 300/mm3 and elevated TNF RNA levels. All patients also received anti-retroviral nucleoside therapy. Twenty-five AIDS patients enrolled in the first dose level (400 mg three times daily). Dezube et al. analyzed data from 17/25 patients who completed at least eight weeks of therapy. Eight patients withdrew early (2 due to noncompliance, 2 due to KS, 3 due to Ols, and one due to an adverse reaction). Among the 17 patients analyzed, significant decreases in TNF levels were observed. A trend towards a decrease in fasting triglycerides (a surrogate marker for cytokine activation) was also reported. The median CD4+ cell count, which was 34/mm3 at baseline, remained unchanged. Another 30 patients have since been enrolled at the second dose level (800 mg three times daily). Reductions in LPS-induced TNF expression and TNF mRNA levels have been observed in the sixteen patients completing 8 weeks of treatment. Thirteen percent of the patients enrolled at this dose level discontinued therapy due to gastrointestinal toxicity. Investigators also concluded that pentoxifylline had no effect on HIV-RNA levels. Forty-five HIV+ patients with CD4 counts below 300/mm3 enrolled in a randomized double-blind placebo-controlled study of pentoxifylline 400 mg three times daily at Community Research Initiative on AIDS (CRIA) in New York City. Peripheral blood mononuclear cells from all enrolled patients spontaneously produced high levels of TNF when cultured ex vivo. Sonnabend et al. reported preliminary data on 32 patients who have completed the protocol. Significant reductions in TNF production ex vivo were observed at eight weeks in the pentoxifylline group compared with the placebo group. Significant reductions in HIV titers were not observed. Eleven mildly symptomatic patients who had never received anti-retroviral therapy enrolled in an open-label study of pentoxifylline 800 mg tid (Mole et al.). Nine patients received treatment. These patients were not screened or selected for elevated TNF RNA levels. No changes in serum TNF RNA, plasma HIV RNA, or CD4 counts were observed after more than three weeks of treatment. TOXICITY/SIDE EFFECTS: discontinued pentoxifylline due to reported that side effects requiring emesis) occurred in 3/9 patients when 800 mg tid. One person in ACTG 160 recurrent fevers. Mole et al. discontinuation (nausea, fevers, pentoxifylline was administered at 56

Page  57 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 REFERENCES: Biswas DK et al. Pentoxifylline inhibits HIV-1 LTR-driven gene expression by blocking NF-KB action. J AIDS, 6:778-86, 1993. Dezube B et al. High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. JID 171:1628-32, 1995. Dezube B et al. Pentoxifylline decrease TNF in AIDS patients. Abstract PB0285, X Intl Conf AIDS, Yokohama, 1994. Dezube B et al. Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in patients with AIDS (ACTG 060). J AIDS, 6:787-94, 1993. Fazely F, Dezube B, et al. Pentoxifylline (Trental) decreases the replication of the human immunodeficiency virus type 1 in human peripheral blood mononuclear cells and in cultured T cells. Blood 77: 1653-6, 1991. Folks TM et al. umor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. PNAS 86: 2365-2368, 1989. Fox LM et al. Pentoxifylline inhibits HIV replication in acutely infected primary cells and chronically infected U1 cells through multiple mechanisms. Abstract 362, 1st Natl Conf on Hum Retrovir, 1993. Heinkelein M et al. Pentoxifylline reduces cytokine releases and the ability to stimulate cell surface antigen and HIV-1 expression by CD8+ Cytotoxic T lymphocytes (CTL). Abstract PA0232, X Intl Conf AIDS, Yokohama, 1994. Lahdevirta J et al. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85: 289-91, 1988. Ito M et al. Tumor necrosis factor antagonizes inhibitory effect of azidothymidine on human immunodeficiency virus (HIV) replication in vitro. Biochem Biophys Res Comm 166:3, 1095-1101, 1990. Mole L et al. The use of pentoxifylline alone in HIV-infected patients. J AIDS 7:519-21, 1994. Sonnabend J et al. Pentoxifylline (PTX) as a TNF inhibitor in HIV+ individuals, Abstract PA0285, X Intl Conf AIDS, Yokohoma, 1994. Zhang L et al. Pentoxifylline (Trental) enhances the antiretroviral activity of didanosine (dideoxyinosine, ddl). Abstract PoA 2326, VIII Intl Conf AIDS, Amsterdam, 1992. OTHER REPORTS: Dezube B et al. Pentoxifylline for the Treatment of Infection with Human Immunodeficiency Virus. CID 18:285-87, 1994. Dezube B et al. Cytokine dysregulation in AIDS: in vivo over-expression of mRNA of tumor necrosis factor-alpha and its correlation with that of the inflammatory cytokine GRO. J AIDS 5:1099-104, 1992. Dezube B et al. Pentoxifylline (Trental) decreases tumor necrosis factor and HIV replication in patients with AIDS. Abstract MoB0019, VIII Intl Conf AIDS, Amsterdam, 1992. Luke DR et al. Phase 1/11 study of pentoxifylline with zidovudine on HIV1 growth in AIDS patients. Intl J Clin Pharmacol 31:343-50, 1993. Strieter RM et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Comm 155: 1230-6, 1990. PHYSICAL DESCRIPTION: Thalidomide is the racemic mixture of the D and L isomers of N-pthalimidoglutarimide. It was widely used in Europe as a sedative prior to the discovery of its teratogenicity, at which time it was removed from the market. MECHANISM OF ACTION: In vitro, Makonkawkeyoon et al. have shown that thalidomide suppresses HIV and TNF-cx expression in stimulated, chronically infected promonocytic UI cells and in PBMC isolated from HIV+ patients. Effective concentrations of thalidomide ranged from 5 - 50 PLg/ml, depending on the HIV-1 inducer used. Thalidomide did not suppress HIV expression in stimulated ACH-2'T cells. The anti-TNF activity of thalidomide is also being studied as a treatment for AIDS-related wasting syndrome. For results from these trials, see page 137. TRIAL RESULTS A phase I, placebo-controlled, dose-escalating study (ACTG 267) of the safety and pharmacokinetics of thalidomide in 36 HIV+ patients is temporarily closed to enrollment. Thalidomide has also been shown, when compared to placebo, to be an effective treatment for oral aphthous ulcers (ACTG 251). For results from these trials, see page 135. TOXICITY/SIDE EFFECTS: Thalidomide can induce severe congenital abnormalities in developing fetuses. The most frequent side effect in adults is sedation. Thalidomide is associated with neurotoxicity, and may exacerbate pre-existing peripheral neuropathy in patients with HIV infection (Gunzler et al.). REFERENCES: Gigliotti G et al. Thalidomide: treatment of choice for aphthous ulcers in patients seropositive for human immunodeficiency virus. J Am Acad Dermatol, 28:271-2, 1993. Gunzler V. Thalidomide in human immunodeficiency virus (HIV) patients: a review of safety considerations. Drug Saf 7:116-34, 1992. Makonkawkeyoon S et al. Thalidomide inhibits the replication of human immunodeficiency virus type 1. PNAS 90:5974-8, 1993. OTHER REPORTS: Sampaio EP et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 173:699-703, 1991. 57

Page  58 Immune-Based Therapies PHYSICAL DESCRIPTION: TNFR:Fc is a recombinantly produced dimer composed of two molecules of the tumor necrosis factor (TNF) receptor linked by the Fc portion of immunoglobulin. MECHANISM OF ACTION: Tumor necrosis factor-alpha (TNF-a, cachectin) is a naturally occurring cytokine with many functions in the human immune system. TNF-c levels are elevated in people with HIV, and several investigators have reported that TNF-o may play a role in the pathogenesis of HIV disease: it upregulates HIV-1 expression in vitro (Folks et al.) and antagonizes the anti-HIV effect of AZT in vitro (Ito et al.). TNF-c levels may also be implicated in the wasting syndrome associated with HIV infection (Lahdevirta et al.). In vitro, TNFR:Fc has been shown by Howard et al. to inhibit TNF-a induced expression of HIV-1 and limit the activation of the HIV-long terminal repeat transcription in chronically infected human cell lines. TNFR:Fc binds both to TNF-a and TNF-y (lymphotoxin), whereas anti-TNF antibodies bind largely to TNF-a. TRIAL RESULTS Walker et al. has reported results from a dose-ranging safety study in which TNFR:Fc was administered subcutaneously twice a week for eight weeks in HIV positive subjects with CD4 counts <200 cells/mm3. A total of 12 patients were enrolled. While the three doses studied were well tolerated, no improvements occurred in immunologic or virologic parameters. TOXICITY/SIDE EFFECTS: Two HIV negative subjects receiving a single intravenous dose of TNFR:Fc developed skin rashes and chest tightness. REFERENCES: Folks TM et al. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. PNAS 86: 2365-2368, 1989. Howard OMZ et al. Soluble tumor necrosis factor receptor: inhibition of human immunodeficiency virus activation. PNAS 90: 2335-2339, 1993. Lahdevirta J et al. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85: 289-91, 1988. Ito M et al. Tumor necrosis factor antagonizes inhibitory effect of azidothymidine on human immunodeficiency virus (HIV) replication in vitro. Biochem Biophys Res Comm 166:3, 1095-1101, 1990. Walker RE et al. Safety and preliminary activity of a TNF receptor fusion protein in patients with advanced HIV infection. Abstract 178, 35th ICAAC, San Francisco, 1995. THERAPEUTIC VACCINES Trials page, 169-170 PHYSICAL DESCRIPTION: Env 2,3 (recombinant gpl20) [Biocine] is a non-glycosylated, fully denatured recombinant polypeptide modeled on envelope glycoprotein gpl20. It is derived from the SF-2 strain of HIV-1 and propagated in yeast cells. Administered with a combination of adjuvant muramyl tripeptide (MTP-PE) and an emulsion (MF59). MF59 may also have some adjuvant properties. MN rgpl20/HIV-l: [Genentech] is a genetically engineered form of envelope glycoprotein gpl20 derived from HIV-1 strain MN. It is propagated in a mammalian cell line. The HIV-1 strain MN is highly representative of strains commonly found in North America. IIIs rgpl20/HIV [Genentech] is a genetically engineered form of envelope glycoprotein gpl20 derived from HIV-1 strain IIIB. It is propagated in mammalian cells. rgpl20 (CHO) [Biocine] is a recombinant form of envelope glycoprotein gpl20 derived from HIV-1 strain SF-2. The molecule is fully glycosylated, allowing it to closely simulate the three-dimensional structure of naturally-occurring gpl20. Expressed in Chinese hamster ovary cells. Administered with a combination of adjuvant muramyl tripeptide (MTP-PE) and an emulsion (MF59). MF59 may also have some adjuvant properties. MECHANISM OF ACTION: It is theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cellular immune responses. However, recent data from non-HIV infected people who received experimental vaccines indicate that antibodies induced by recombinant subunit vaccines are not effective at neutralizing primary (clinical) isolates of HIV (see Cohen, 1994). It is not clear what the implications of these data are for therapeutic vaccine trials. TRIAL RESULTS ENV 2,3 (recombinant gpl20): Eight HIV+ patients received three intramuscular injections of 30 ptg ENV 2,3. McElrath and co-workers report 58

Page  59 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 that some patients also received varying doses of MTP-PE in MF59. The vaccine with adjuvant was well-tolerated. Forty-five asymptomatic HIV+ patients with CD4 counts >400/mm3 have enrolled in a randomized, blinded, controlled trial of ENV 2,3. Patients received ENV 2,3 30 plg in MF59 with or without MTP-PE, or MF59 MTP-PE alone at months 0, 1, 4, 7, and 10. McElrath and Corey have reported preliminary data which show that lymphoproliferative and antibody responses to HIV envelope antigens are enhanced in patients who received ENV 2,3. No changes in CD4 counts or quantitative viral culture have been detected. MN rgpl20/HIV-I and IIIB rgpl20/HIV-l: Genentech Inc. has halted the development of gpl20 as a potential treatment for HIV+ individuals. Their gpl20 model, designed to slow the development of AIDS-related symptoms, has shown no clinical benefit. Results were collected from a fifteen-month phase II placebo-controlled trial involving 573 asymptomatic HIV+ individuals with CD4 counts greater than 600/mm3. A randomized, double-blind, placebo-controlled study evaluated MN rgpl20 in 57 persons seronegative for HIV. 36 volunteers received MN rgpl20 at doses of 100, 300, or 600 pig while 12 others received a combination of 300 pg MN rgpl20 and 300 ipg IIIB rgpl20. The control group included 9 participants who received alum adjuvant. The vaccines were safe and immunogenic. Three injections of vaccine induced antibodies that neutralized MN rgpl20 (46/48), SF-2 (45/48), or IIIB (30/48) strains of HIV-1. No plans have yet been made for a large, phase III clinical trial of MN rgpl20 as a preventative vaccine. rgpl20 (CHO): A five arm study (ACTG 240) of 128 HIV+ patients with CD4+ counts > 500 cells/mm3 has been completed. The rgpl20 (CHO) is one of the immunogens being studied. TOXICITY/SIDE EFFECTS: ENV 2,3 (recombinant gpl20): ENV 2,3 alone is well-tolerated. Dolin and co-workers have observed that 40% of patients who received ENV 2,3 with MTP-PE experienced "severe" local or systemic reactions including malaise, myalgia, headache and moderate fever. In addition, Dolin reports that 7-8% of those receiving vaccine without adjuvant experienced severe local or systemic reactions. Keefer et al. report that 12/30 HIV+ volunteers who received ENV 2,3 30 pig with 5 - 100 pig of MTP-PE experienced severe local or systemic reactions. 2/18 patients who received ENV 2,3 (30 or 100 pg) in MF59 alone experienced severe local reactions. MN rgpl20/HIV-1 and IIIB rgpl20/HIV-l: Allan et al. and Belshe et al. report that no clinically adverse events attributable to MN or IIIB rgpl20 HIV-1 occurred in the phase I study. rgpl20 (CHO): Mild myalgia, headache, low-grade fever have been observed. REFERENCES: Allan JD et al. Safety and immunogenicity of MN and IIIB rgp 120/HIV-1 vaccines in HIV-1 infected subjects with CD4 counts >>500 cells/mm3. Abstract PO-B27-2137, IX Intl Conf AIDS, Berlin, 1993. Belshe RB et al. Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gpl20 from the MN strain of HIV-1. JAMA, 272:475-480, 1994. Birx DL et al. Immunogenicity and safety of rgp120(lai) in early stage HIV positive patients. Abstract TuB 0564, VIllth Intl Conf AIDS, Amsterdam, 1992. Cohen J. Jitters jeopardize AIDS vaccine trials (news & comment). Science 262:980-1, 1994. Corey L et al. A phase I HIV-1 vaccine trial in asymptomatic HIV-infected individuals using ENV 2-3 in MF59 with or without MTP-PE. Abstract PO-B28-2152, IX Intl Conf AIDS, Berlin, 1993. Keefer M et al. Phase I trial of an HIV-1 vaccine candidate, ENV 2,3, in combination with MTP-PE/MF59. Abstract PO-A29-0708, IX Intl Conf AIDS, Berlin, 1993. McElrath J et al. A Phase II HIV vaccine trial in seronegative subjects: Safety, immunogenicity, and future directions. Abstract 317A, X Intl Conf AIDS, Yokohama, 1994. McElrath J et al. Evaluation of a nonglycosylated yeast-derived envelope vaccine on HIV-1 specific immunity in a randomized, blinded, controlled HIV-1 seropositive trial. Abstract PO-A28-0670, IX Intl Conf AIDS, Berlin, 1993. OTHER REPORTS: Kahn J et al. Phase I study of an HIV-1 gp120 vaccine combined with novel adjuvant emulsion MF59/MTP-PE in sero-negative adults. 32nd ICAAC, abstract #860, 1992. Steimer KS et al. Neutralization of divergent HIV-1 isolates by conformation-dependent human antibodies to gp120. Science 254:105-108, 1991. 59

Page  60 Immune-Based Therapies PHYSICAL DESCRIPTION: IIIB rgpl60 [Immuno U.S.]: A recombinant form of purified envelope glycoprotein gpl60 derived from either the IIIB or MN strain of HIV-1. It is fully glycosylated, with a three-dimensional shape approximately identical to gpl60. rgpl60 is formulated with alum and deoxycholate adjuvant and propagated in mammalian tissue culture cells. VaxSyn (recombinant gpl60) [MicroGeneSys]: a molecularly-cloned, denatured envelope glycoprotein derived from the LAV strain of HIV-1 which is propagated in insect cells and adsorbed to an alum adjuvant. The preparation is expressed in baculovirus. MECHANISM OF ACTION: It has been theorized that subunit vaccines consisting of HIV antigens may stimulate humoral and lymphoproliferative cellular immune responses. However, recent data from non-HIV infected people who received experimental vaccines indicate that antibodies induced by recombinant subunit vaccines are not effective at neutralizing primary (clinical) isolates of HIV (see Cohen, 1994). It is not clear what the implications of these data are for therapeutic vaccine trials. The conformational similarity of rgpl60 to the native gpl60 may have positive implications for its ability to block primary infection of diverse HIV-1 strains. Some investigators (Moore et al.) have hypothesized that since the VaxSyn molecule is substantially denatured, it may stimulate less relevant antibodies than recombinant vaccine products which mimic the three-dimensional structure of native viral particles. TRIAL RESULTS IlsB rgpl60 (Immuno U.S.): Fifty five HIV+ asymptomatic subjects with CD4+ counts above 600 cells/mm3 were enrolled in a study by Schwartz et al. Participants were randomized to receive either six injections of IIIB rgpl60 50 pg IM or placebo administered over five months, or four injections of either IIIB rgpl60 50 pg or a hepatitis-B vaccine administered over five months. Fresh peripheral blood mononuclear cells (PBMC) from seven rgpl60 recipients and seven placebo or hepatitis-B vaccine recipients were assessed for proliferative responses ex vivo to IIIB rgp 160 (Immuno U.S.) or VaxSyn gpl60 (MicroGeneSys). After 3 injections, cells from the vaccinees exhibited enhanced proliferative responses compared with baseline. No change was observed in the cells from the placebo and hepatitis-B vaccine recipients. Responses to tetanus toxoid and candida antigen were stable in all groups. An ongoing phase I/II double-blinded trial in Europe has enrolled 208 HIV+ asymptomatic patients. Individuals were divided into groups based on CD4+ count and randomized to receive either 6 courses of immunization over a one year period with boosters at 15, 18, and 21 months or placebo. T-cell memory was induced in half of the volunteers with CD4+ count above 500/mm3 and in approximately one-third of the subjects with CD4+ counts between 200 and 500/mm3. MN rgpl60 (Immuno AG): In an ongoing, double-blind, randomized, safety and immunogenicity clinical trial, 20 HIV+ patients received 200 Vtg of MN rgpl60 at 0.1 and 6 months (n = 11) or 0, 2 and 8 months (n = 9) and 4 patients received placebo (Gorse et al.). Local injection site pain was the most frequently reported side effect in 13/20 patients enrolled. Upon administration of the third and fourth doses, vaccine induced envelope-specific T-cell memory and HIV-I MN neutralizing antibodies were reported in the majority of patients treated. VaxSyn (recombinant gpl60): DeMaria et al. has reported preliminary safety and immunogenicity data from a phasel/II study in 141 HIV+ patients. Data in 105 patients indicate more frequent serologic response in patients with greater than 200 CD4+ cells/mm3 than in patients with fewer than 200 CD4+ cells/mm3. None of the 31 patients with entry CD4+ counts < 100 cells/mm3 had a serologic response at 6 months. To date, base-dissociated p24 Ag and plasma RNA PCR show no evidence of increased or decreased viral activity post-vaccination. There are no significant differences in CD4+ count changes among randomization groups. Birx et al. recently reported results from a phase II/I11 randomized, double-blind, placebo-controled study of recombinant gpl60 in 608 HIV+ patients with > 400 CD4+ cells/mm3 and no prior antiretroviral therapy. The primary endpoints of the study were disease progression and/or a 50% decline in mean CD4+ count over baseline. Approximately 17% of patients were lost to follow-up. Both arms combined, a total of 159 reached one of the primary endpoints; a total of 78 patients reached both endpoints. There were no differences between the placebo and the treatment group for either the primary endpoints or endpoints which assessed immunologic or virologic responses. The study was adequately powered to detect a clinically significant difference if it were present. TOXICITY/SIDE EFFECTS: VaxSyn (recombinant gpl60) has been well-tolerated when given intramuscularly. Local reactions are common including tenderness and induration at the injection site. Mild fever, myalgia or fatigue may accompany local reactions. Intradermal administration results in subcutaneous nodule formation, prolonged skin discoloration, occasional purulent drainage and local pruritis. Other side effects include headaches and nausea. 60

Page  61 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 07 REFERENCES: Belshe RB et al. Safety and immunogenicity of fully glycosylated rgpl60 IIIB vaccine in low risk volunteers. Abstract PoA 2432, VllIth Intl Conf AIDS, Amsterdam, 1992. Birx D et al. DoD/NIH rgpl60 phase II efficacy trial. CPCRA Group Meeting. May 2, 1996. Blick G et al. A phase 1I/I study of the toxicity, immunogenicity and efficacy of recombinant gp160 and p24 vaccines (VaxSyn) in HIV-infected individuals regardless of CD4+ cell count. Abstract TuB 0562, VIlllIth Intl Conf AIDS, Amsterdam, 1992. Bratt G et al. The one year results of vaccination with a gp 160 vaccine (VaxSyn HIV-1 MicroGeneSys) in asymptomatic HIV-carriers. Abstract PO-B27-2138, IX Intl Conf AIDS, Berlin, 1993. Coady W et al. Therapeutic gp160 vaccine (VaxSyn) in adults with CD4 counts <400/mm3. Abstract PB0307, X Intl Conf AIDS, Yokohama, 1994. Cohen J. Jitters jeopardize AIDS vaccine trials (news & comment). Science 262:980-1, 1994. Gorse GJ et al. Evaluation of HIV-1 MN recombinant gp160 candidate vaccine. Abstract 1147, 35th ICAAC, San Francisco, 1995. Moore J et al. Which gp160 vaccine? (letter) Nature 361:503, 1993. Orentas RJ et al. Induction of CD4+ human cytolytic T cells specific for HIV-infected cells by gp160 subunit vaccine. Science 248:1234-1237, 1990. Redfield RR et al. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. New Engl J Med 324(24) 1677-84, 1991. Schwartz D et al. Interim results of rgpl60 vaccine trial in HIV+ volunteers. Abstract PO-A28-0668, IX Intl Conf AIDS, Berlin, 1993. OTHER REPORTS: Sandstr6m E et al. A 12 month study with gp160 vaccine (VaxSyn HIV-1; MicroGeneSys) in asymptomatic HIV-carriers. Abstract 0-17.2, Illrd Euro Conf Clin Aspects and Treatment AIDS, Paris, 1992. Trials, page 169, 170 PHYSICAL DESCRIPTION: HIV-Immunogen is composed of gpl20 depleted HIV-1 propagated in HUT-78 cells and inactivated by P-propiolactone and yirradiation. It is derived from Zairian HIV-1 strain HZ-321. The inactivated material is emulsified with mineral oil (Incomplete Freund's Adjuvant) in the final formulation. MECHANISM OF ACTION: Administration of whole inactivated virus may stimulate new or existing humoral and lymphoproliferative cellular immune responses. These responses may slow the replication of HIV-I through increased immunologic control over infected cells or other as yet undetermined mechanisms. The use of whole inactivated virus could theoretically stimulate broader immune responses that are capable of suppressing more diverse strains of HIV than vaccines based on subunits of the virus. TRIAL RESULTS Twenty-three patients with persistent generalized lymphadenopathy (PGL) (Slade et al) received a median of 8 doses of HIV-immunogen 100g subcutaneously over a 3 year period in a phase I/II safety study. 21 patients evaluable for humoral response (as measured by p24 antibodies) were followed-up for four years. No differences from baseline were evident. Cell-mediated immunity was evaluated by delayed-type hypersensitivity testing (DTH); 12/23 subjects developed a DTH response. In a placebo-controlled immunogenicity study (Turner et al), 48 asymptomatic HIV positive patients with CD4+ cells >600/mm3 received HIV-Immunogen either 50, 100, 200, 400 pg or placebo. A significant increase in p24 antibody titers relative to adjuvant controls was noted at all dose levels greater.than 50 Gg. One hundred and three asymptomatic patients (mean CD4+ count = 656/mm3) enrolled in a one year double-blind placebo controlled phase II/III study (Trauger et al). Patients received subcutaneous injections of either HIV-Immunogen 100 mg or incomplete Freund's adjuvant (IFA) at 0, 3 and 6 months. Significant differences in cell-mediated immune responses to HIV-1 and p24 core antigen were observed between the control and the treated groups (P <.01). Control patients had a mean rise in HIV-DNA levels in peripheral blood of 56% versus a 14% rise in treated patients (P = 0.016). Control patients had a 5% decline in CD4+ percentage versus a decline of 0.2% in treated patients (P = 0.024). Positive effects were seen on other HIV-1 surrogate markers including HIV-1 RNA, p24 antibody titers and lymphocyte proliferation. According to the manufacturer (1995), in a two-year clinical follow-up of these same subjects, fewer first clincal events were observed in the treated group compared to the control group in the second year but not in the first year. During follow-up, patients treated with HIV-1 immunogen also experienced a slower decline in the percentage of CD4+ cells when compared to the IFA control group. A phase III clinical endpoint study is currently underway. The trial is a multicenter, double-blind, adjuvant-controlled study of the effect of 10 units of HIV-1 immunogen and IFA alone every three months on AIDS-free survival in subjects with HIV infection and CD4+ counts between 300 and 549 cells/mm3 regardless of concomitant HIV therapies. The target accrual number is 2850 patients. Similar phase III studies in patients with fewer than 300 and greater than 550 CD4+ cells/mm3 are also being developed. TOXICITY/SIDE EFFECTS: Fevers, aches, rash and local pain at the injection site have been reported. Reactions are typically transient and are resolved within 24 to 48 hours of manifestation. REFERENCES: Moss, RB et al. Inactivated HIV-1 immunogen: Impact on markers of disease progression. JAIDS 7(Suppl 1):S21-S27, 1994. Trauger, RJ et al. Effects on Immunization with Inactive gpl20-depleted Human Immunodeficiency Virus Type 1 (HIV-1) immunogen on HIV-1 immunity, viral DNA, and percentage of CD4 cells. JID 169:1256-64, 1994. Turner JL et al. HIV-1 immunogen induction of HIV-1-specific delayed-type hypersensitivity: results of a double-blind, adjuvant-controlled, dose-ranging trial. AIDS 8:1429-1435, 1994. OTHER REPORTS: Trauger, RJ et al. Cell-mediated immunity to HIV-1 in Walter Reed stages 1-6 individuals: correlation with virus burden. Immunology 78:611-615, 1993. 61

Page  62 Immune-Based Therapies OTHER IMMUNE-BASED THERAPIES Trials, page 171-172 PHYSICAL DESCRIPTION: Autologous CD8 infusion is a treatment in which CD8+ T-lymphocytes are isolated from an HIV+ person and stimulated to replicate in vitro outside the body by culture with cell-activating proteins. The expanded population of CD8+ T cells is then reinfused into the patient. MECHANISM OF ACTION: Walker et al. have reported that CD8+ lymphocytes are capable of suppressing the replication of HIV in autologous peripheral blood mononuclear cells of patients with AIDS. Walker et al. demonstrated that HIV-specific cytotoxic lymphocytes (CTL) were capable of killing HIV-infected autologous B cells in 8/8 seropositive individuals. Schnoll et al. reported that CD8+ cells from asymptomatic HIV+ donors suppress viral replication whether or not the cells had been PHA stimulated, although stimulated CD8+ cells resulted in a more powerful and less reversible suppression. According to one sponsor, CD8+ cells obtained from HIV+ donors are capable of suppressing HIV production in CD4+ T cells in vitro. TRIAL RESULTS Five HIV+ patients (entry CD4 range 46 - 817/mm3) completed a six month phase I dose-ranging study of autologous CD8+ infusion with IL-2 (ACTG 080). Ho et al. reported that participants received up to six infusions of 108 - 1010 cells every 2 - 3 weeks. 4/5 patients also received IL-2 (one million IU/m2/day by continuous infusion) for five days during and after the last infusion of CD8+ cells (one patient refused IL-2 due to concerns about toxicity). In vitro, the expanded cells had CTL activity against HIV gag, pol, and env peptides. 111 Indium-labeled cells were found to accumulate primarily in the lungs, as well as in the liver, spleen, and bone marrow. No clear effects on CD4+ and CD8+ counts were observed. Toxicities were those often associated with IL-2 therapy, including rapid heartbeat and flu-like symptoms. Twenty patients with CD4 counts between 100 - 400/mm3 were enrolled in an open-label, dose-escalating study of an autologous CD8+ infusion procedure (DATRI 006). The procedure used differed from the one used by Ho et al. in that the cell lines were selected for in vitro anti-HIV-1 activity, and concurrent IL-2 was not administered. Six patients received single infusions of 1 billion cells and three patients received single infusions of 5 billion cells; no toxicity was observed. Lieberman et al. report that transient CD4 increases were observed in several patients. Anti-HIV-CTL increased in most of the patients. A phase II study is under way to compare autologous CD8+ infusion in combination with IL-2 and a nucleoside analogue, IL-2 in combination with a nucleoside analogue, or a nucleoside analogue alone. Greenberg and co-workers at the Fred Hutchinson Cancer Center in Seattle have noted some antiviral activity in three treated volunteers using genetically altered CD8+ cells. CD8+ cells that specifically attack the HIV gag gene were selected out, cloned and reinfused into their patients. Because CD8+ cell infusion in animal models suggest the possibility of potentially fatal lung and brain inflammation, the cells were infused with a "suicide gene" before cloning. This cellular marking permits the ablation of the clones if an excessive inflammatory response persists. A total of 15 seropositive adults with CD4+ counts between 200 and 500/mm3 have been recruited. Other trials with CD8+ cells fitted with cytokine-receptor genes are under development. REFERENCES: Ho M et al. A phase I study of adoptive transfer of autologous CD4+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS. Blood 81:2093-101, 1993. Koenig S et al. Transfer of HIV-1 specific cytotoxic T lymphocytes to an AIDS patients leads to selection of mutant HIV variants and subsequent disease progression. Nature Medicine 1:330-6, 1995. Lieberman J et al. Immunotherapy with autologous expanded HIV-specific cytotoxic T cells in infected patients with CD4 counts between 100-400 mm3. Abstract and oral presentation, Keystone Symposium on the Prevention and Treatment of AIDS, 1994. Schnoll S et al. The ability of CD8 cells to suppress HIV replication is affected by their state of activation. Abstract 172, 2nd National Conference on Human Retroviruses, Washington, 1995. Walker BD et al. HIV specific cytotoxic T lymphocytes in seropositive individuals. Nature 328:345-8, 1987. Walker CM et al. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234:1563-6, 1988. 62

Page  63 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 PHYSICAL DESCRIPTION: F105 is a human monoclonal antibody derived from a patient with HIV; it is an IgGI K antibody produced by the fusion of Epstein-Barr-virus-transformed cells with a human myeloma analogue. MECHANISM OF ACTION: F105 binds to the CD4 binding region of gpl20 and neutralizes HIV strains MN, IIIB and SF2 at concentrations achievable clinically (0.150 -10 itg/mL). F105 has been reported to react with a conformationally defined epitope on HIV-l/gpl20 which is important for binding to the cell surface by the virion (Posner et al.). TRIAL RESULTS A phase I pharmacokinetic and safety study (ACTG 232) of intravenous F105 has been completed. In Phase A of this study eight subjects received a single intravenous dose of F105 (100 or 500 mg/m2). F105 was well tolerated at both dosing levels. TOXICITY/SIDE EFFECTS: No side effects attributed to F105 have been observed. REFERENCES: Posner MR et al. An ACTG phase la safety and pharmacokinetics trial of immunotherapy with the anti-CD4 binding site human monoclonal antibody F105. Abstract 515. 2nd National Conference on Human Retroviruses, Washington, 1995. Posner MR et al. An IgG k human monoclonal antibody that reacts with HIV-1/gpl20, inhibits virus binding to cells, and neutralizes infection. J Immunol 146(2). 4325-32, 1991. PHYSICAL DESCRIPTION: Recombinant human growth hormone (rHGH) is the genetically engineered version of pituitary-derived human growth hormone (GH). It is identical to the endogenous protein with an extra amino acid at the N-terminus of the molecule. RHGH is approved for the long-term treatment of children with short stature due to endogenous growth hormone deficiency. IGF-I is a growth-hormone dependent protein which mediates many of the effects of HGH. MECHANISM OF ACTION: The growth-inducing properties of GH have been studied extensively and are well-characterized. rHGH has been studied as a treatment for HIV-related wasting (see: Weight Loss in HIV Disease, page 137). A number of in vitro and in vivo studies also suggest the hormone plays an important role in the human immune system, possibly through an interaction between the pituitary and thymus glands. However, this role has not been clearly defined. LABORATORY RESULTS: Laurence et al. report that in vitro rHGH enhanced viral replication in acutely infected PBMC. The investigators, while noting that the clinical relevance of these in vitro results are not clear, suggested that rHGH should only be used in conjunction with antiretroviral treatment in HIV+ people. Kelley et al. reported that thymus glands were regenerated when growth-hormone-secreting pituitary cells were implanted into rats with thymic atrophy. T-cell proliferative responses were also enhanced compared with controls. The same group also showed that exogenous GH alone enhanced T- cell proliferative responses in aged rats. Since GH did not increase thymus-gland growth in this experiment, the investigators speculated that GH directly enhances T-cell proliferation by increasing the synthesis of growth factors or receptors involved in T-cell activation. Durum et al. used GH to treat mice with severe combined immunodeficiency (SCID), which lack CD4+ and CD8+ cells. After three days' treatment with GH, CD4/CD8+ cells were detected in the thymus. Treatment with IL-2 did not produce this effect. TRIAL RESULTS Many of the growth-promoting effects of HGH are mediated through the growth-hormone dependent protein insulin-like growth factor 1 (IGF-I). A phase I study of the combination of rHGH (Genentech) and rlGF-I in HIV+ patients with CD4 counts between 100 - 300/mm3 is under way at NCI. Patients receive rHGH (0.1 mg/kg daily) alone (6 patients), rlGF-I (200 plg daily) alone (5 patients), or the combination of rHGH (0.05 mg/kg daily) and rIGF-I (100 pg/kg daily)(5 patients). After 12 weeks of treatment, no consistent trend in changes in CD4 counts was observed (Nguyen et al.). After treatment, most patients' T cells exhibited increased IL-2 production in vitro in response to HIV-1 peptides as well as non-HIV antigens. CHILDREN: Hirschfeld et al. recently reported results from a pilot study conducted to determine the safety, tolerance, and efficacy of rHGH and rIGF-I in HIV infected children with growth failure. All patients were randomized to receive either rHGH at 40 jg/kg daily or IGF-1 at 90 jg/kg bid for 36 weeks in combination with AZT and ddl. Increases in CD4+ counts and linear growth rates were reported in both treatment groups. TOXICITY/SIDE EFFECTS: Nguyen et al. observed headache, edema, arthralgia, and myalgia to be the most common side effects. 63 I

Page  64 Immune-Based Therapies REFERENCES: Durum SK et al. CD4/CD8 differentiation of T cells in mice with severe combined immunodeficiency (SCID) without receptor rearrangement. Abstract #7567, Federation of American Societies for Experimental Biology, annual meeting, 1991. Hirschfeld S et al. Effects of recombinant human growth hormone and recombinant insulin-like growth factor-1 administration in children with human immunodeficiency virus infection and growth failure. Abstract #511, 2nd National Conference of Human Retroviruses, Washington DC, 1995. Kelley KW et al. GH3 pituitary adenoma cells can reverse thymic aging in rats. PNAS 83: 5663-7, 1986. Kelley KW et al. Growth hormone, lymphocytes and macrophages. Biochem Pharmacol 38(5): 705-13, 1989. Kelley KW et al. The role of growth hormone in modulation of the immune response. Ann NY Acad Sci 95-103, 1990. Laurence J et al. Effect of recombinant human growth hormone on acute and chronic human immunodeficiency virus infection in vitro. Blood 79: 1-6, 1992. Nguyen BY et al. A pilot study of recombinant human insulin-like growth factor (rhlFG-1) and recombinant human growth hormone (rhGH) in patients with HIV-1 infection. Abstract 110, 1st Natl Conf on Hum Retrovir, 1993. OTHER REPORTS: Bondy CA et al. Clinical uses of insulin-like growth factor I. Ann Int Med 120:593-601, 1994. Trial page, 172 PHYSICAL DESCRIPTION: Passive immunotherapy is a treatment in which plasma from healthy HIV+ donors is processed to inactivate HIV and then infused into HIV+ subjects. The plasma donors are selected for high levels of HIV neutralizing antibodies. MECHANISM OF ACTION: Although naturally developing anti-HIV antibodies may be inadequate to control disease progression, it is hypothesized that methods to boost or elicit high titer antibodies in AIDS patients may be beneficial in limiting viral spread or preventing new infection. Fultz et al. have found that, in macaques and mangabeys, the presence of neutralizing antibodies or antibodies that inhibit SIV reverse-transcriptase activity did not correlate with protection from clinical disease. To date, the clinical value of administering anti-p24 antibodies/HIV-neutralizing antibodies has not been established. A major difficulty with this treatment is the characterization and standardization of the product. TRIAL RESULTS Lefrere et al. randomized 82 patients with CD4 <200/mm3 to receive 300 ml of anti-HIV plasma or sero-negative plasma IV every two weeks for one year. Anti-HIV plasma was derived from HIV+ donors with CD4 >400/mm3, undetectable p24 antigen, and high p24 antibody titers (>1000). The plasma was heated at 560C to inactivate HIV. 42 patients received active treatment, and 40 received control plasma in a double-blind fashion. The time to AIDS was significantly longer in the treated group (>365 vs. 230 days, P = 0.009) and fewer new AIDS defining events occurred in the treated group (16 v. 27, P = 0.0008). No significant difference in the number of deaths was observed (7 in the treated group and 11 in the control group). Jacobson et al. conducted a randomized comparison of anti-HIV hyperimmune plasma and placebo in 63 patients with AIDS (mean CD4 count 38/mm3 and 40/mm3 in the treatment and control groups respectively). Subjects received 250 ml of anti-HIV plasma or antibody-negative plasma IV every 4 weeks. Anti-HIV plasma was derived from asymptomatic HIV+ donors with CD4 counts >400/mm3, high p24 antibody titers (>640), and no p24 antigenemia. No significant differences in survival, occurrence of new 01, change in CD4 count or HIV viremia were observed. Levy et al. enrolled 220 patients with HIV disease and CD4 counts <200/mm3 to receive 500 or 250 cc of anti-HIV plasma or placebo IV monthly. The anti-HIV plasma was derived from healthy HIV+ donors, pooled, and sterilized with p-propiolactone. At twelve months no overall differences in survival or CD4 counts were observed. In a sub-group analysis of 72 patients with CD4 counts between 50 - 200/mm3, treated patients had significantly increased CD4 counts compared with placebo recipients (32.7 cell/mm3 increase vs. 2.5 cell/mm3 decrease, P = 0.033). However, significantly better survival was not observed among these treated patients. A phase III double-blind placebo-controlled study of passive immunotherapy is under way in California. The process used is the same as that described by Levy et al. above (HemaCare Corp.). The enrollment target is 600 patients. TOXICITY/SIDE EFFECTS: Side effects included headaches, nausea, fevers, cold extremities, and transient rashes. REFERENCES: Fultz PN et al. Humoral response to SIV/SMM infection in macaque and mangabey monkeys. J AIDS 3: 319-23, 1990. Jacobson JM et al. Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection. JID 168:298-305, 1993. Lefrere JJ et al. Passive immunotherapy in AIDS: biological results of a double blind randomized phase II study. Abstract LB10, 2nd National Conference on Human Retroviruses, Washington DC, 1995. Levy J et al. Efficacy and safety of passive hyperimmune therapy (PHT) in HIV disease. Abstract PO-B28-2149, IX Intl Conf AIDS, Berlin, 1993. OTHER REPORTS: Karpas A et al. Passive immunization in patients with the acquired immunodeficiency syndrome-related complex and acquired immunodeficiency syndrome. PNAS 87:7613-7, 1990. Karpas A et al. Passive immunotherapy in treatment of advanced human immunodeficiency virus infection. JID 170:742, 1994. Vittecoq D et al. Passive immunotherapy in AIDS: a randomized trial of serial human immunodeficiency virus-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. JID 1165:364-368, 1992. 64

Page  65 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 PHYSICAL DESCRIPTION: THF is a natural peptide hormone isolated from calf thymus. MECHANISM OF ACTION: THF is reported to increase the number of Tlymphocytes and augment cell-mediated immunity. TRIAL RESULTS As a part of a double-blind, placebo-controlled clinical trial, Maggliolo et al. treated 12 patients with AZT (500 mg/day) and, for 6 months, with either THF 4g, THF 40g or placebo (2 times a week by injection). At the end of six months subjects were offered open-label THF at the highest dose (40g). The results of the double-blind study are still being analyzed. To evaluate the open-label period of this study, a case-control group design was used. The control group was matched to treated patients (1:2) as to sex, age, CDC classification, CD4+ cell count, prior opportunistic infections and AZT use. Patients in the THF group were followed for 23 (+/- 5) months; the control group was followed for 22 (+/-9) months. Two deaths were reported in the THF treated group, while 14 deaths (58.3%) were reported in the control group (P = 0.04). Kouttab et al. enrolled 14 HIV+ subjects with CD4 count between 100 - 500/mm3 in a phase I study of THF 5, 10 or 25 mg/kg/day administered intramuscularly daily on a two-weeks on/one week off cycle for 12 weeks. All subjects were receiving AZT. Overall, increases in mitogen responses, NK activity and DTH responses were observed. According to the manufacturer (1995), an interim analysis of a multi-center double-blind placebo controlled study comparing intramuscular THF and oral AZT to oral AZT alone in HIV+ asymptomatic subjects, demonstrated no significant difference between the two groups in terms of CD4+ count increases and decreases in viral RNA. Future development of THF has been discontinued in the United States. TOXICITY/SIDE EFFECTS: Mild fatigue and reduced mental acuity have been reported. REFERENCES: Kouttab N et al. Phase I trial of intramuscular (IM) thymic humoral factor (THF) in combination with zidovudine (ZDV) in HIV infected individuals. Abstract PoB3447, VIII Intl Conf AIDS, Amsterdam, 1992. Maggliolo F et al. AZT and THF therapy in HIV positive patients. Abstract #118, 34th ICAAC, Orlando, 1994. PHYSICAL DESCRIPTION: Thymopentin (TP-5) is a biologically active synthetic pentapeptidethat corresponds to the active site of the thymic hormone, thymopoietin. MECHANISM OF ACTION: In vitro, TP-5 regulates the function of peripheral T cells, acting via a cyclic GMP-linked cell surface receptor and enhances T-cell functions by increasing lymphokine production. The mechanism of action in HIV disease is. unclear. Hirsch et al. reported that thymopentin had no effect on HIV replication in vitro TRIAL RESULTS Conant et al. conducted two randomized phase II double-blind placebo-controlled studies of TP-5. A total of 91 HIV+ patients without AIDS were enrolled. Participants were stratified into symptomatic and asymptomatic groups and received thymopentin 50 mg SC or placebo three times weekly. Patients enrolled in the first study (n = 45) were treated for 24 weeks and patients in the second study (n = 46) were treated for 52 weeks. The studies were identical in other respects. 26/52 asymptomatic and 20/39 symptomatic subjects received TP-5. Among asymptomatic patients, trends toward higher percentages of CD4+ cells were observed in both studies. Based on the studies described above, a phase III randomized double-blind placebo-controlled trial of thymopentin was conducted. Participants were asymptomatic at entry with CD4+ counts between 200 - 500/mm3. Three hundred and fifty two asymptomatic subjects were randomized to receive, in addition to AZT, thymopentin 50 mg SC or placebo three times weekly. Subjects were stratified according to prior AZT use (< 6 mo., > 6 mo.). The primary endpoint of the study was the change in CD4 counts. After 48 weeks of treatment, there were no differences in CD4+ counts between patients receiving AZT/thymopentin and those receiving AZT/placebo. Overall, 4/173 (2.3%) receiving TP-5/AZT progressed to ARC, AIDS or death compared to 16/179 (8.9%) receiving AZT/placebo (P = 0.007, Goldstein et al.). Oral candidiasis and oral hairy leukoplakia comprised a substantial proportion of the endpoints (8/16 endpoints in the placebo group and 1/4 endpoints in the thymopentin group). Similar findings were reported after an 80 week observation period. Thymopentin delayed disease progression to both AIDS or death (P = 0.037) and to ARC, AIDS or death (P = 0.004). 65 I~

Page  66 Immune-Based Therapies I A multicenter phase III double-blind placebo-controlled trial of TP-5 is underway. 2,100 asymptomatic subjects with CD4+ counts between 200 - 400 cells/mm3 on antiretroviral therapy will be randomized to receive TP-5 (50 mg SC tiw) or placebo for one year. TOXICITY/SIDE EFFECTS: Respiratory congestion has been reported in subjects receiving TP-5. REFERENCES: Conant M et al. Maintenance of CD4+ cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebo-controlled study. AIDS 6: 1335-1339, 1992. Goldstein G et al. Thymopentin with zidovudine (AZT) reduces disease progression in asymptomatic HIV-infected patients. Abstract PO-B2-2144, IX Intl Conf AIDS, Berlin, 1993.Hirsch RL et al. Thymopentin effects on HIV transmission and expression in vitro. Abstract W.A. 1075, VII Intl Conf AIDS, Florence, 1991. Merigan TC et al. The prognostic significance of serum viral load, codon 215 reverse transcriptase mutation and CD4+ T cells of progression of HIV in a double-blind study of thymopentin. AIDS 10:159-65, 1996. OTHER REPORTS: Heaver GA et al. Peptide analogs of thymopentin distinguish distinct thymopoietin receptor specificities on two human T cell lines. Regulatory Peptides 27: 257-62, 1990. Thompson SE et al. Effects of thymopentin on disease progression and surrogate markers in HIV infection. VI Intl Conf AIDS San Francisco, 3:207(S.B.484), 1990. 66

Page  67 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 DESCRIPTIONS OF TREATMENTS FOR OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS ABV/ABVD ABV is a combination of intravenous anti-cancer drugs consisting of adriamycin (doxorubicin), bleomycin and vincristine. ABVD is ABV with the addition of dacarbazine. Under investigation for Kaposi's sarcoma and lymphoma. Acyclovir (Zovirax) An approved oral, intravenous, or topical antiviral drug indicated for the treatment of herpes simplex and varicella-zoster virus infections. It is active in vitro against herpesviruses, particularly HSV-1 and HSV-2. Recently, both acyclovir-resistant HSV and zoster infections in AIDS patients have been described. Oral administration is associated with little toxicity; intravenous administration rarely causes local phlebitis, rash, diaphoresis, nausea, hematuria, or hypotension. Concomitant probenecid use may increase blood levels of acyclovir, thus increasing the risk of side effects. A patient-assistance/reimbursement program is available, see page 210. Adriamycin, See: Doxorubicin Albendazole An oral antibiotic under investigation for microsporidiosis. Approved in the UK for the treatment of intestinal parasitic infections. Side effects include GI distress, headaches and dizziness. Less frequent reactions include rash, fever, elevated LFT and hair loss. Available through compassionate use protocol, see see page 210. All-trans retinoic acid (ATRA) An experimental derivative of vitamin A which regulates epithelial differentiation within many neoplastic cell systems. Under investigation for the oral treatment of Kaposi's sarcoma. No toxicity information is available. TretinoinLF, an intraveous liposomal formulation of ATRA, is undergoing clinical investigation. Another retinoid currently undergoing investigation is 9-cis-retinoic acid, which binds to different retinoid receptors than ATRA. Alpha Interferon (Roferon, Intron A, Alferon-N Injection). A recombinantly produced protein, administered by intramuscular injection, and approved for the treatment of Kaposi's sarcoma in certain AIDS patients. The most common side effects include flu-like symptoms such as fever, chills, muscle-aches, fatigue; neutropenia is also seen, as well as other, less common toxicities. Also approved for the treatment of genital warts. Alpha interferon has been shown to increase bone-marrow toxicity associated with AZT, fluytosine, ganciclovir, pentamidine, pyrimethamine, and chemotherapy for malignancies. A patientassistance/reimbursement program is available, see page 210. Amikacin sulfate An approved aminoglycoside antibiotic, administered IM or IV, indicated for the treatment of severe bacterial infections. In vitro and in vivo, amikacin exhibits bactericidal activity against MAC. Under investigation in combination therapy for MAC. Side effects include auditory, vestibular and renal dysfunction. Amphotericin B (with or without flucytosine [5-FC]) An approved intravenous macrolide antibiotic indicated for the treatment of progressive, disseminated fungal infections including cryptococcal meningitis, systemic candidiasis, coccidioidomycosis and aspergillosis. Serious toxicities are frequent and can include azotemia, fever, chills, muscle pain, venous phlebitis, nausea, vomiting, potassium deficiency, and anemia. Cancer chemotherapeutics, amikacin, pentamidine, cyclosporine, and foscarnet, when used concomitantly with amphotericin B, has been shown to increase the risk of kidney damage. Similarly, concomitant use with AZT, flucytosine, or ganciclovir, may increase the risk of bone-marrow toxicities. A liposome-encapsulated form of amphotericin B is under investigation. Liposome encapsulation might reduce toxicity and improve treatment response. An experimental, intravenously administered molecule containing two lipids (DMPC/DMPG) and amphotericin B is being investigated for cryptococcal meningitis, systemic candidiasis, coccidioidomycosis. ABLC has been associated with transient increases in transaminases, transient renal 67

Page  68 Description of Treatments for Opportunistic Infections I toxicity, fever and chills. An oral form of amphotericin B is being investigated in patients with fluconazole-resistant oral candidiasis. Both liposomal encapsulated and colloidal dispersion formulations of amphotericin B are available through compassionate use and expanded access protocols, see page 210. Anti-B4-blocked Ricin An experimental, intravenously administered monoclonal antibody linked to a blocked ricin (a plant toxin). Blocking the ricin prevents it from binding to most cells, while the anti-B4 antibody targets the molecule to malignant B cells. Under investigation for the treatment of non-Hodgkin's lymphoma in AIDS. No toxicity information is available. Ara-C (cytarabine, cytosine arabinoside) An approved intravenous anti-cancer drug used primarily in combination with other agents for the treatment of acute myelocytic leukemia. Under investigation for the treatment of PML. Frequent toxicities include myelosuppression, nausea, and vomiting; fever, anorexia, and oral ulceration may also occur. Atovaquone (Mepron) An approved oral antibiotic indicated for the treatment of mild-to-moderate PCP in patients intolerant to standard therapies. Clinical trials are under way for PCP, toxoplasmosis, and microsporidiosis. Side effects include maculopapular rash, nausea and fever. Due to the high lipophilicity and poor absorption rates associated with tablet formulation of atovaquone, a new oral suspension formula has been approved by the FDA; preliminary data indicate that it is more bio-available than the tablet formulation. Atovaquone should be taken with a fatty meal to enhance absorption. Furthermore, studies have shown that concomitant use with acetaminophen, acyclovir, benzodiazepines, cephalosporin antibiotics, laxatives, and rifampin many decrease levels of atovaquone in the blood. A patient assistance/reimbursement program is available, see page 210. Azithromycin (Zithromax) An approved oral macrolide antibiotic which achieves high intracellular drug concentrations, indicated for the treatment of Chlamydia. Is also approved for the treatment and prophylaxis of MAC. Under investigation for the treatment of MAC, toxoplasmosis and cryptosporidiosis. Toxicities are infrequent, but may include GI distress. Studies have reported decreased blood levels of azithromycin when used concomitantly with antacids containing aluminum or magnesium. Available through compassionate use protocol, see page 210. Bactrim, See: TMP/SMX Bleomycin (Blenoxane) An approved intravenous anti-cancer drug which appears to work by fragmenting DNA. It is active, alone or in combination, against a wide spectrum of tumors. Under investigation for Kaposi's sarcoma and lymphoma. The most serious potential side effect is pulmonary toxicity, which is associated with age greater than 70 and cumulative doses higher than 400 units. The most frequent side effects are fever and various mucocutaneous reactions. The risk of side effects are increased when bleomycin is administered with AZT, foscarnet, ganciclovir, or amphotericin B. A patient assistance/reimbursement program is available, see page 210. Capreomycin An approved, intramuscularly injected antibiotic, active against certain strains of TB. It is used concomitantly with other anti-TB agents. Toxicities can include hearing loss, tinnitus, proteinuria, cylindruria, and nitrogen retention. Capsaicin (Axsain, Zostrix) An approved topical cream indicated for the temporary relief of pain in cases ranging from peripheral neuropathy to herpes zoster. It is a naturally occurring substance obtained from the Solanaceae plant family; it interrupts mediators of pain impulses from the periphery to the brain. Side effects can include mild burning sensations during the first few days of use. Carbamazepine An approved oral anti-convulsant and specific analgesic for trigeminal neuralgia. It is related chemically to tricyclic antidepressants. Carbamazepine can be used to reduce pain associated with peripheral neuropathy. Adverse reactions include dizziness, nausea and vomiting. Acute intoxication with carbamazepine can result in aplastic anemia, neuromuscular disturbances, and respiratory and cardiovascular complications. Reduced blood levels of carbamazepine have been reported in patients receiving concomitant phenobarbital, phenytoin, and primidone. Erythromycin, clarithromycin, cimetidine, propxyphene, terfenadine, isoniazid, fluoxetine, and calcium channel blockers have been shown to increase blood levels of carbamazepine. Ceftriaxone (Rocephin) An approved intravenous or intramuscular antibiotic under investigation as an alternative to penicillin for the treatment of neurosyphilis. Side effects can include local reactions at the injection site, rash, and diarrhea. Probenecid has been shown to increase blood levels of ceftriaxone. A patient assistance/reimbursement program is available, see page 210. 68

Page  69 AIDS/HIV Treatment Directory, Vol 8, No. 3; January 199 P7 CHOP A four-drug chemotherapy regimen including cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine) and prednisone used in the treatment of several cancers including lymphoma. All four drugs are available through a patient assistance/reimbursement program, see page 210. Cidofovir (HPMPC, Vistide) An intravenous, intravitreal, or topical antiviral drug with broad-spectrum anti-herpesvirus activity in vivo. It is approved for the treatment of CMV retinitis. The topical treatment for herpes simplex virus and the intravitreal injections. Renal toxicitis have been the primary dose-limiting toxicity associated with intravenous HPMPC use. To prevent renal toxicities, concomitant probenicid is being used in ongoing clinical trials. Serum creatinine and proteinuria must be measured and evaluated within 48 hours prior to infusion ofcidofovir. Ciprofloxacin (Cipro) An approved oral antibiotic used for the treatment of several common bacterial infections; under investigation for combination therapy of MAC. Side effects include GI distress, headache, rash, and CNS symptoms. Antacids and the buffer found in ddl have been shown to decrease ciprofloxacin absorption rates. A patient assistance / reimbursement program is available, see page 210. Cisplatin An approved IV anti-cancer drug used in combination or as a single agent for the treatment of advanced-stage tumors including testicular, ovarian and bladder cancer. Renal toxicity is a major dose-limiting side effect; ototoxicity, anemia and nausea are also observed. Clarithromycin (Biaxin) An approved, oral macrolide antibiotic which achieves high intracellular concentrations. Approved for the treatment (in combination with other anti-mycobacterial drugs) of disseminated MAC. Clarithromycin has also been approved as prophylaxis against MAC in patients with advanced HIV infection. Under investigation alone and in combination therapy for toxoplasmosis. At high doses (>2 g bid), clarithromycin can cause severe abdominal pain. Clarithromycin and rifabutin exhibit a pharmacokinetic interaction; clarithromycin serum levels decrease if rifabutin is added after the initiation of clarithromycin. However, no interaction is seen if clarithromycin is added to the regimen after the initiation of rifabutin. Concomitant administration of astemizole or terfenadine in patients receiving clarithromycin has been reported to increase the risk of heart toxicity. Clarithromycin has also been shown to decrease AZT levels in the blood. A patientassistance/reimbursement program is available, see page 210. Clindamycin An approved oral or intravenous antibiotic that has been investigated as an alternative treatment for toxoplasmosis and PCP. Toxicities include pseudo-membranous colitis, diarrhea and rash. Usually used in combination with primaquine for PCP, in combination with pyrimethamine for toxoplasmosis. Erythromycin has been shown to reduce blood levels of clindamycin. Also, various treatments for pain management (codeine and oxycodone) may increase the risk of diarrhea associated with clindamycin. A patient assistance / reimbursement program is available, see page 210. Clofazimine (Lamprene) An approved oral anti-leprosy agent. Despite earlier studies suggesting that clofazamine has inhibitory activity against MAC, several recently-completed studies conclude that the drug should not be used for the treatment of MAC. A patient assistance / reimbursement program is available, see page 210. Clotrimazole (Mycelex) An approved antifungal drug supplied as a cream, tablet, or lozenge. The lozenge form is indicated for candidiasis. Side effects of the lozenge formulation can include GI distress and elevated liver function tests. A patient assistance / reimbursement program is available, see page 210. COMP An anti-cancer chemotherapeutic regimen consisting of cyclophosphamide, Oncovin (vincristine), methotrexate and prednisone. These drugs are available through a patient assistance/reimbursement program, see page 210. Co-trimoxazole, See: TMP/SMX Corticosteroids, adjunctive A group of approved, oral or intravenous drugs used as adjunctive therapy in the treatment of moderate to severe PCP. Complications may include immunosuppression (evidenced by a higher rate of oral thrush and herpes simplex infection in one study); additionally, abrupt discontinuation of steroids and antimicrobial therapy increases the risk of clinical relapse of PCP. Concomitant use of oral contraceptives may increase corticosteroid blood levels. Cyclobut-G (Lobucavir) An experimental, oral antiviral drug with in vitro activity against human herpesviruses and HIV. A safety and pharmacokinetics trial for CMV retinitis is underway. No toxicity information is available. 69 I

Page  70 Description of Treatments for Opportunistic Infections Cyclophosphamide An approved intravenous or oral anti-cancer drug with activity, alone or in combination, against a wide spectrum of tumors. Under investigation for lymphoma. The most prominent side effects are hair loss, nausea and vomiting; thrombocytopenia and hemorrhagic cystitis have also been observed. Phenobarbital has been shown to increase the effect of cyclophosphamide. Cyclophosphamide, when used with amphotericin B, foscarnet, or ganciclovir, has been shown to increase the risk of kidney toxicities. A patient- assistance/reimbursement program is available, see page 210. Cycloserine (Seromycin) An oral anti-mycobacterial drug approved for the treatment of tuberculosis. It may be useful as one element of a treatment regimen for multi-drug resistant tuberculosis (MDR-TB). Side effects can include mood disturbances, psychosis, and seizures. Dacarbazine An approved intravenous anti-cancer agent used frequently in combination with other drugs for the treatment of metastatic melanoma and Hodgkin's disease. Nausea and vomiting are frequently observed; hair loss, leukopenia and thrombocytopenia are also common side effects. Dapsone An approved, oral antibiotic of the sulfone class used for the treatment of leprosy, and for the treatment and prophylaxis of PCP and toxoplasmosis. Side effects of dapsone include dose-related hemolysis (especially in G6PD-deficient patients), methemoglobinemia, rash. Patients taking dapsone as prophylaxis for PCP should take it two hours before taking ddl, since the antacid buffer in ddl may inhibit the gastric absorption of dapsone, which requires acidity for dissolution. Daunorubicin, liposomal (DaunoXome) An approved intravenous formulation of the anti-cancer drug daunorubicin that has been encapsulated in targeted liposomes. It is approved as first-line therapy for Kaposi's sarcoma. Liposome encapsulation may increase the cellular uptake of daunorubicin and reduce systemic toxicities. A patient-assistance/reimbursement program is available, see page 210. Doxorubicin (Adriamycin) An approved intravenous anti-cancer drug thought to bind DNA and inhibit nucleic acid synthesis. It is active, alone or in combination, against a wide spectrum of tumors. Under investigation for the treatment of Kaposi's sarcoma. The primary dose-limiting toxicity is hematologic (typically leukopenia). Infrequently, cardiac toxicity may also occur (usually when the cumulative dose exceeds 550 mg/m2). Other common toxicities include hair loss, nausea, vomiting, and oral ulcers. Doxorubicin, liposomal (Doxil) An approved intravenous formulation of doxorubicin that has been encapsulated in liposomes for the treatment of Kaposi's sarcoma. Liposome encapsulation may increase the cellular uptake of doxorubicin and reduce systemic toxicities. It is currently approved for patients with refractory Kapsosi's sarcoma. Side effects can include stomatitis, hair loss, nausea, and hematological toxicity. One case of fatal hepatic failure in a patient with a history of symptom-free hepatitis B was attributed to liposomal doxorubicin. A patient- assistance/reimbursement program is available, see page 210. Dronabinol (Marinol) An approved, oral drug indicated for appetite stimulation and the prevention of weight loss in HIV-infected people and for nausea and vomiting associated with cancer chemotherapy. It is a synthetically manufactured version of 9-tetrahydrocannabinol (THC), the active substance in marijuana. The most frequent side effects are psychotropic (drowsiness, muddled thinking, and coordination impairment). Concomitant amphetamine or antidepressant use may increase the risk of rapid heart beat and high blood pressure. A patient assistance/reimbursement program is available, see page 210. Erythropoietin (EPO, Epoetin alfa, Epogen, Procrit) An approved, injectable hematopoietic growth factor used for the treatment of anemia in both AZT-treated HIV-infected subjects and chronic renal-failure patients. It is only indicated in patients with endogenous erythropoietin levels less than 500 mU/mL. No significant toxicities have been observed in patients with HIV/AIDS. A patient assistance/reimbursement program is available, see page 210. Ethambutol (Myambutol) An approved, oral anti-mycobacterial antibiotic used in combination regimens for tuberculosis. Under investigation in combination with other drugs for MAC. Side effects can include optic neuritis, decreased or distorted vision, rash and fever. Antacids containing aluminum may decrease the bioavailability of ethambutol. A patient-assistance/reimbursement program is available, see page 210. 70

Page  71 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Ethionamide (Trecator) An oral anti-mycobacterial drug approved for the treatment of tuberculosis. It may be used in a treatment regimen for multi-drug resistant tuberculosis (MDR-TB). Frequent side effects include weight loss, nausea and vomiting, and a metallic taste. Hepatitis can also occur. Etoposide (Vepesid or VP-16.) An approved, oral or IV anti-cancer drug used against a variety of tumors. It is under investigation for the treatment of Kaposi's sarcoma. Leukopenia is a dose-limiting side effect. The risk of leukopenia is increased when used concomitantly with other chemotherapeutic treatments for cancer. Nausea, vomiting, and oral ulcers occur especially frequently with oral administration, while hair loss occurs frequently with both IV and oral administration. A patient-assistance/reimbursement program is available, see page 210. Famciclovir (Famvir) An approved anti-viral drug for the treatment of varicella zoster virus. It is the well absorbed oral form of the anti-herpes agent penciclovir and is under investigation for HSV-2 infections. A patient-assistance/reimbursement program is available, see page 210. 5-ASA An oral formulation of mesalamine, a rectal suspension enema approved for the treatment of colitis, proctosigmoiditis, and proctitis. It is under investigation for symptomatic relief of inflammatory bowel syndrome. No side effects have been reported. 5-Fluorouracil (5-FU, Efudex) An approved anti-cancer drug supplied in intravenous and topical formulations. The topical form is indicated for the treatment of superficial basal cell carcinomas and pre-malignant keratoses. Side effects of topical 5-FU include burning, inflammation and hyperpigmentation of the skin. Used for the treatment of human papillomavirus virus neoplasms, and under investigation for the treatment of HIV-related cervical dysplasia. Fluconazole (Diflucan) An approved, oral or intravenous antifungal drug indicated for the treatment of cryptococcal meningitis and esophageal candidiasis. It is under investigation for the treatment of HIV-related pulmonary coccidioidomycosis, and for the prophylaxis of serious fungal infections in HIV-infected people. Side effects may include nausea, rash, abdominal pain, headache, and mild transient increases in liver function tests. Concomitant use with rifampin significantly reduces serum levels of fluconazole, whereas concomitant rifabutin and fluconazole increases levels of rifabutin. Available through a compassionate use protocol, see page TK. A patient-assistance/reimbursement program is available, see page 210. Flucytosine (5-FC, Ancobon) An approved, oral antifungal drug used as an adjunct to amphotericin B. Under investigation as an adjunct to fluconazole and itraconazole. Side effects include bone-marrow suppression, rash, nausea & vomiting, diarrhea, and enterocolitis. A patient- assistance/reimbursement program is available, see page 210. Fluoxymesterone (Halotestin) An oral, approved androgenic hormone used as a treatment for testosterone deficiencies and delayed puberty. Under investigation for the treatment of wasting syndrome in AIDS patients. Side effects in men can include enlargement of the breast, excessive erections and low sperm counts; in women, menstrual cessation and virilization (acquisition of male characteristics such as deepening of the voice). Foscarnet (trisodium phosphonoformate, PFA, Foscavir) An approved, intravenous antiviral drug indicated for the treatment of CMV retinitis and acyclovir-resistant herpes simplex virus infections. It is active against both human herpesviruses and HIV. It is under investigation for the treatment of CMV colitis and herpes zoster infections. Side effects include nephrotoxicity (elevated creatinine), electrolyte abnormalities (sodium, potassium, phosphorus, calcium, magnesium), anemia, and possibly central nervous system toxicity, muscle twitching, nausea, and penile ulcerations in uncircumcised men. Foscarnet may increase the risk of kidney toxicities when used with amikacin, streptomycin, erythromcin, amphotericin B, ddC, and intravenous pentamidine. Simultaneous hydration with saline solution has been reported to reduce nephrotoxicity. Available through a compassionate use protocol, see page 207. A patient-assistance/reimbursement program is available, see page 210. Gamma interferon (Actimmune) The recombinant version of a naturally occurring biological response modifier, administered subcutaneously and approved for the treatment of chronic granulomatous disease. It is under investigation for the treatment of Mycobacterium tuberculosis in HIV+ people. Flu-like symptoms are the most common side effects. 71

Page  72 Description of Treatments for Opportunistic Infections Ganciclovir (DHPG, Cytovene) An approved, intravenous antiviral drug indicated for the treatment of CMV retinitis. Intravenous (IV) ganciclovir is under investigation for the treatment of CMV colitis. Oral ganciclovir is approved for the maintenance treatment of CMV retinitis and has also been approved as prophylaxis against CMV disease. Neutropenia is the most common dose-limiting toxicity; it may preclude concomitant use of other myelotoxic drugs such as AZT, cancer chemotherapeutic drugs, amphotericin B, and foscarnet. Ganciclovir has been shown to significantly increase plasma levels of ddl, thus increasing the risk of pancreatitis. A patient-assistance / reimbursement program is available, see page 210. A compassioinate use protocol for oral ganciclovir is available, see page 207. Ganciclovir, intraocular (Vitrasert) An approved intraocular pellet, surgically administered into the eye. Intraocular ganciclovir is approved for the treatment of CMV retinitis. It is not effective in treating disseminated CMV disease. Occurrences of endophthalmitis, retinal detachment, and vitreous hemorrhage have been associated with the administration of intraocular ganciclovir. A patient-assistance/reimbursement program is available, see page 210. G-CSF (Filgrastim, Neupogen) An approved, subcutaneously injected hematopoietic growth factor, indicated for the treatment of decreased neutrophil counts associated with cancer chemotherapy. Under investigation as an adjunct to myleosuppressive therapy in AIDS patients. It is the recombinant version of granulocyte colony stimulating factor, a human cytokine which induces proliferation and differentiation of blood-cell precursors. Bone pain is the most frequent side effect. A patient-assistance/reimbursement program is available, see page 210. GM-CSF (Sargramostim, Leukine) An approved, subcutaneously injected hematopoietic growth factor, indicated for the acceleration of myeloid recovery in patients with hematologic tumors undergoing autologous bone-marrow transplant. Under investigation as an adjunct to myleosuppressive therapy in AIDS patients. It is the recombinant version of a human granulocyte-macrophage colony stimulating factor, which induces proliferation and differentiation of blood-cell precursors. Side effects can include fever, asthenia, headache, bone pain, chills, and myalgia. A patient-assistance/reimbursement program is available, see page 210. Guanfacine An approved, oral anti-hypertensive drug indicated for the management of hypertension. Under investigation for the treatment of HIV-related neurological complications. Side effects include drowsiness, dry mouth, weakness, and dizziness. A withdrawal syndrome has been observed in some patients who suddenly discontinue guanfacine and other drugs in its class. Human Chorionic Gonadotropin (hCG) An approved therapy for treating infertility in women and cryptochidism (failure of testicles to descend) in boys. It is under investigation for the treatment of Kaposi's sarcoma. Systemic and intralesional formulations are being invesitigated. HCG, a polypeptide produced by the human placenta during pregnancy, inhibits the mother's immune system from rejecting the fetus as foreign tissue. Pre-clinical studies in mice have demonstrated that KS malignant cells can be inhibited by this pregnancy hormone. Human growth hormone, recombinant (rHGH, Somatropin, Serostim) An approved, subcutaneously injected recombinant version of pituitary-derived human growth hormone. It is indicated for the treatment of AIDS-related wasting. It is also indicated for the long-term treatment of children with short stature due to endogenous growth hormone deficiency. Headache, edema and muscle pain have been observed in some HIV-infected patients receiving human growth hormone. Available through a treatment IND protocol, see 207. Interleukin-4 (IL-4) An experimental, subcutaneously administered recombinant version of a naturally occurring cytokine with a wide range of immuno-regulatory functions. In vitro, IL-4 down-regulates the production of TNF and IL-6. Recombinant IL-4, administered subcutaneously, is under investigation for the treatment of Kaposi's sarcoma. Side effects seen in phase I studies in patients with non-HIV related malignancies include headache, fever, and edema. 72

Page  73 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 Immune globulin, intravenous (IVIG, Gamimune N, WinRho SD, Gammagard, Polygam SD, Venoglobulin) An approved, injected sterile solution of concentrated IgG antibodies used for maintenance treatment of patients unable to produce sufficient IgG antibodies and patients with ITP. It may be administered IV or IM. It is effective for the prevention of bacterial infections in HIV-infected children with CD4 counts greater than 200/mm3. IVIG can prevent or modify certain infectious diseases in susceptible individuals. Side effects can include flushing of the face, tightness of the chest, and headache. It should not be administered concomitantly with immunizations or live, attenuated vaccines. A patient-assistance/reimbursement program is available, see page 210. Insulin-like growth factor, recombinant An experimental, recombinantly produced version of the hormone IGF-I, which mediates the effects of human growth hormone. Administered subcutaneously, it is under investigation for weight loss and HIV. Reported side effects of rhIGF-1 include hypoglycemia and jaw tenderness, primarily at higher doses. ISIS 2922 An antisense RNA compound that inhibits a protein that regulates production of new CMV virus particles by binding to a specific sequence of mRNA. It is under investigation for the intravitreal treatment of CMV retinitis in AIDS patients who have failed standard therapy. Localized toxicities at the sites of injections have been reported in patients receiving high range doses of ISIS 2922. All protocols have been modified to reflect these reportings. Isoniazid (INH) An approved oral and IV antibiotic which, in combination regimens, is standard for the treatment and prophylaxis of tuberculosis. Side effects can include rash, fever, jaundice, peripheral neuritis, pancreatis, and hepatitis. Concomitant alcohol use may increase the risk of liver toxicities. Furthermore, concomitant corticosteroid use may reduce the levels of isoniazid in the blood. Isotretinoin (Accutane) An approved oral drug indicated for the treatment of severe recalcitrant cystic acne. Chemically it is related to vitamin A. It is under investigation in combination with alpha interferon for the treatment of anal dysplasia. Side effects include cutaneous reactions, hair loss, headache, and hypertriglyceridemia. Contraindications prohibit use by pregnant women. Itraconazole (Sporanox) An approved, oral antifungal drug indicated for the treatment of blastomycosis and histoplasmosis. It is being investigated as a treatment for cryptococcal meningitis and aspergillosis. Absorption of the drug has been found to be reduced in AIDS patients by approximately 50% as compared to non-immunocompromised patients. It should be taken with food to enhance absorption. Taking itraconazole with a cola beverage has been shown to increase the activity of the compound. Concurrent antacids, anticonvulsants, terfenadine and rifampin significantly reduce serum levels of itraconazole. Side effects can include rash, nausea, and vomiting. A patient-assistance/reimbursement program is available, see page 210. A compassionate use protocol is available, see page 210. Ketoconazole (Nizoral) An approved oral or topical anti-fungal drug used for the treatment of systemic or topical fungal infections including candidiasis, candiduria, blastomycosis, coccidioidomycosis, and histoplasmosis. Ketoconazole is not effective for treatment of fungal meningitis. It has been associated with liver toxicity. Two drugs commonly given for MAC and tuberculosis, INH (isoniazid) and rifampin, can decrease ketoconazole blood levels. Concurrent antacid use can decrease absorption. Most frequent side effects with oral administration are nausea, vomiting and anorexia. A patient-assistance/ reimbursement program is available, see page 210. L-Carnitine (Carnitor) An approved, oral or intravenous formulation of a naturally occurring amino acid required for energy metabolism and found especially in muscle tissue. It is indicated for the treatment of patients with camitine deficiency. Under investigation for the treatment of AZT-related muscle wasting (myopathy). Drug delivery is oral (tablet or solution) and side effects include mild GI distress. Letrazuril An experimental oral antibiotic, related to diclazuril, and under investigation for the treatment of cryptosporidiosis. In preclinical studies, the drug is more readily absorbed than diclazuril. No toxicity information has been reported. Leucovorin An approved, oral derivative of folic acid indicated for use after high-dose methotrexate therapy. Sometimes used to reduce the toxicity of folic-acid antagonists such as pyrimethamine and trimetrexate. Leucovorin has been shown to increase the toxicity of the cancer chemotherapeutic drug flourouracil. A number of death from GI disturbances have been reported in patients receiving the two drugs concomitantly. 73

Page  74 Description of Treatments for Opportunistic Infections ~ Levofloxacin (L-Ofloxacin) An experimental antibiotic, it is the active isomer of the approved antibiotic ofloxacin (a racemic mixture). It is under investigation for multi-drug-resistant TB. Side effects include GI distress, nausea, insomnia and headaches. A phase I double-blind placebo-controlled safety and pharmacokinetics study in asymptomatic HIV+ men indicated that the drug is well tolerated in this population, with adverse reactions not differing significantly from those seen with placebo. Liquid nutritional supplements Liquid nutritional supplements may be indicated for individuals who eat but do not gain weight and for those who have difficulty eating solid food. There is no consensus about the time to begin such supplementation or the type of supplement that is most beneficial. Generally, however, a free amino acid elemental oral food supplement or an intact modular food supplement is used to augment a high calorie, high protein, low fat, lactose-free diet. Some products such as Advera have reported moderate weight gain increases in clinical trials involving HIV+ patients; weight gain reported, however, was mostly fat mass. Many formulations of these nutritional supplements are available; use of these supplements may be individualized according to personal taste. Lomustine (CCNU) An approved oral anti-cancer drug used in the treatment of Hodgkin's disease and other lymphomas. Dose-limiting side effects include bone-marrow suppression and thrombocytopenia. Nausea and vomiting are frequently observed. Liposomal Tretinoin (TretinoinLF), See: AII-trans-retinoic acid mBACOD A chemotherapy regimen consisting of methotrexate, bleomycin, adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), and the steroid dexamethasone. All of these drugs are available through patientassistance/reimburesment program, see page 210. Mechlorethamine An approved intravenous anti-cancer drug used primarily as part of the MOPP regimen in the treatment of Hodgkin's disease. It is an analog of mustard gas which inhibits rapidly proliferating cells. Side effects can include hematological suppression, severe nausea, vomiting and hair loss. Megestrol acetate (Megace) An approved oral drug indicated for the treatment of anorexia, cachexia, or unexplained, significant weight loss in patients with AIDS. It is administered in an oral suspension formulation. A tablet formulation of megestrol acetate is approved as a palliative treatment for advanced breast cancer. Side effects include diarrhea, rash, impotence, edema, flatulence, and weakness. Hypogonadism has been associated with megestrol acetate administration. Megestrol acetate is not recommended during the first four months of pregnancy. Furthermore, comcomitant rifampin administration has been reported to decrease the levels of megestrol in the blood. A patient assistance/reimbursement program is available, see page 210. Methotrexate An approved intravenous or oral anti-cancer drug which inhibits dihydrofolate reductase and thereby inhibits DNA synthesis. It is active against a wide range of tumors, and is also used to treat severe psoriasis. Side effects can include leukopenia, thrombocytopenia, oral ulcers, diarrhea, nausea and vomiting. A patient-assistance/reimbursement program is available, see page 210. Methylphenidate hydrochloride (Ritalin) An approved oral drug, related to amphetamine, and indicated for the treatment of attention deficit disorders in children. It is sometimes used to alleviate symptoms of AIDS dementia complex. Side effects include nervousness and insomnia. A patient-assistance/reimbursement program is available, see page 210. Metronidazole (Flagyl, Femazole, Metezol, Satric) An oral antibiotic approved for the treatment of giardiasis, under investigation for the treatment of microsporidiosis. Most common side effects are headache, nausea, dry mouth, a metallic taste and alcohol intolerance. Infrequent serious toxicities can include peripheral neuropathy, and seizures. Oral or vaginal candidiasis can occur during metronidazole therapy. Mexiletine An approved oral antiarrhythmic indicated for the treatment of ventricular arrhythmias; under investigation as a treatment for HIV-related neuropathy. Adverse reactions include GI distress and dizziness. A patient-assistance/reimbursement program is available, see page210. 74

Page  75 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 MGBG (methylglyoxal-bis-guanylhydrazone) An intraveous chemotherapeutic agent currently undergoing investigation for treatment of AIDS-related non-Hodgkin's lymphoma. It has been found to cause fewer bone-marrow toxicities than other chemotherapeutic drugs for cancer. Available through a compassionate use protocol, see page 207 Mitoxantrone Mitoxantrone is an intravenous anti-cancer drug approved for the treatment of leukemia. Side effects can include granulocytopenia, nausea and vomiting, and hair loss. Under investigation for the treatment of Kaposi's sarcoma and lymphoma. MSL-109 A human monocolonal antibody being studied in combination with approved therapies for the treatment of CMV retinitis. Information of potential adverse events is not yet available. Nandrolone (Deca-derabolin) An approved, injectable anabolic steroid under investigation for the treatment of hypogonadism associated with megestrol acetate administration in HIV+ women. Potential toxicities of anabolic steroids in general include masculinizing effects in women (facial hair growth, deepened voice), and feminizing effects in men (breast development). Edema, jaundice, and hepatic carcinoma have also been reported. Nimodipine (Nimotop) An approved calcium-channel blocking agent indicated for the improvement of neurological outcomes in patients with subarachnoid hemorrhages. It is under investigation for the treatment of AIDS dementia complex. The most frequent side effect of nimodipine administration is decreased blood pressure. 9-cis-retenoic acid (LGD 1057) A retinoid currently undergoing investigation for the topical treatment of Kaposi's sarcoma. It is an endogenous hormone capable of binding to all six known members of the Retinoid Acid Receptors (RAR) and Retinoid X Receptors (RXR) subfamilies. Induction of tumor cell differentiation, maturation and death has been shown in vitro. See also: All-trans-retinoic acid Nitazoxanide (NTZ) An experimental anti-parasitic drug under investigation for the treatment of cryptosporidiosis. The most common side effects are abdominal pain, nausea and diarrhea. A compassionate use protocol is availabe, see page TK; A patientassistance/reimburesment program is also available, see page 210. Nystatin An anti-fungal agent approved for the treatment of candidiasis. It is available as tablets, a swish and swallow preparation, and in creams and ointments. In HIV-infected subjects treatment failure and relapses are common. An IV lipid formulation of nystatin, AR-121, has shown anti-HIV activity in vitro and is currently under investigation for the treatment of HIV-infection. A patient-assistance/reimbursement program is available, see page 210. Octreotide acetate (Sandostatin) An approved, subcutaneously injected drug indicated to treat two rare forms of intestinal cancer. It is thought to inhibit intestinal secretion and enhance water and electrolyte absorption. It is a synthetic peptide that mimics the inhibitory action of the naturally occurring hormone somatostatin. Under investigation for the treatment of HIV-related diarrhea. A patient assistance / reimbursement program is available, see page 210. Ofloxacin (Floxin) An approved, oral or intravenous antibiotic indicated for the treatment of a variety of common bacterial infections. It may be useful as one element of a treatment regimen for multi-drug resistant tuberculosis (MDR-TB). Side effects can include GI distress, headache, anxiety, tremulousness, and thrush. OPC-8212 (Arkin-Z, Vesnarinone) A 2(1H)-quinolinone derivative used in Japan as a treatment for mild to moderate congestive heart failure and under investigation in the USA as a treatment for HIV and Kaposi's sarcoma. Oxandrolone (Oxandrin) An approved, oral anabolic steroid indicated for the treatment of weight loss attributed to chronic illnesses. Oxandrolone is currently being investigated for the treatment of AIDS-related wasting syndrome. Side effects reported include elevated liver enzymes, edema, and masculinazation in women. A patient-assistance/reimbursement program is available, see page 210. Paclitaxel (Taxol) An approved, intravenous anti-cancer drug indicated for the treatment of refractory ovarian cancer and under investigation for the treatment of AIDS-associated Kaposi's sarcoma. Side effects reported include sore throat and mouth, neutropenia, hair loss and numbness of the fingers and toes. No formal drug-interaction studies have been performed. A patient-assistance/reimbursement program is available, see page 210. 75

Page  76 Description of Treatments for Opportunistic Infections Paromomycin (Humatin) An approved, oral antibiotic, indicated and occasionally used as a treatment for intestinal amebiasis and giardiasis. It is currently being studied for cryptosporidiosis. The drug is not absorbed into the systemic circulation upon oral administration. Side effects can include GI upset and diarrhea. PAS (Para-aminosalicylic acid) An oral anti-mycobacterial drug sometimes used for multi-drug-resistant TB. Side effects can include GI distress and elevated liver enzymes. PAS can be obtained through the CDC; call (404) 639-2530 for information. Pentamidine (NebuPent, Pentacarinat) An approved anti-protozoal drug, used for the treatment and prevention of PCP. It can be delivered by intravenous or intramuscular injection, or inhaled as an aerosol. IV pentamidine is a standard treatment for PCP. Aerosolized pentamidine is indicated for the prophylaxis of PCP in HIV+ individuals with CD4 counts below 200/mm3 or for those with prior episodes of PCP. It is less effective than TMP/SMX for the secondary prevention of PCP. Aerosolized pentamidine has also been studied for the acute treatment of mild to moderate PCP. Side effects of IV or IM pentamidine include kidney damage, hypoglycemia, pancreatitis, and hematologic and cardiac arrhythmias. Side effects of aerosolized pentamidine are coughing and bronchospasm. May increase the risk of bone-marrow toxicity when administered concomitantly with AZT, alpha interferon, ganciclovir, or foscarnet. A patient assistance/reimbursement program is available, see page 210. Pentoxifylline (Trental) An approved, oral xanthine derivative indicated for the treatment of patients with intermittent claudication and chronic peripheral arterial disease. Pentoxifylline also inhibits the production of tumor necrosis factor, a cytokine which has been shown to have a direct stimulatory role on Kaposi's sarcoma. It is under investigation for the treatment of HIV infection and KS. A patient-assistance/reimbursement program is available, see page 210 Peptide T An experimental synthetic peptide composed of eight amino acids, injected subcutaneously or sprayed into the nose. The efficacy data of peptide T as a treatment for peripheral neuropathy remains inconclusive. It is currently being studied as a treatment for psoriasis. No side effects have been reported. Peridex (chlorhexidine gluconate) An approved mouth rinse containing 0.12% chlorhexidine gluconate, indicated for the treatment of gingivitis. In bone marrow transplant patients it has been shown to reduce the incidence of thrush, and is under investigation for the prevention of thrush in HIV-infected patients. Phenytoin (Dilantin) An approved oral or intravenous anti-convulsant drug indicated for the treatment of epilepsy. Phenytoin can be used to relieve pain associated with peripheral neuropathy. Side effects, which are usually dose-related, can include dizziness, headaches, decreased coordination, nausea, and gingival hyperplasia. Hirsutism may occur in young women. Phenytoin must be carefully administered when other drugs are being administered concomitantly; a large number of drug interactions have been reported. A patient-assistance/reimbursement program is available, see page 210. PIXY321 (GM-CSFIIL-3 fusion protein) An experimental, intravenous recombinant fusion molecule which includes the functional sequences and biological activities of both GM-CSF and IL-3. GM-CSF (granulocyte-macrophage colony stimulating factor) is a cytokine which induces proliferation and differentiation of blood-cell precursors. IL-3 is one of several colony-stimulating factors which regulate the proliferation and differentiation of hematopoietic and lymphoid cells; it acts at an earlier progenitor cell level than GM-CSF. In vitro, GM-CSF and IL-3 exhibit synergistic activity. PIXY 321 is under investigation for the treatment of HIV-related pancytopenia. Side effects might include those associated with GM-CSF (fever, asthenia, headache, bone pain, chills, and myalgia) or IL-3 (fever, headache, flushing, and local redness at the injection site) but have not been defined for the fusion molecule. Platelet Factor 4 (rPF4) An experimental, subcutaneously injected, synthetic version of a naturally occurring protein which inhibits angiogenesis (blood vessel formation). Under investigation for the subcutaneous treatment of Kaposi's sarcoma. No side effects have been reported. Primaquine An approved oral antibiotic effective against malaria. When used in combination with clindamycin, it is effective for acute PCP. GI upset is the most frequent toxicity in caucasians; blacks with G6PD deficiency are susceptible to anemia from intravascular hemolysis. 76

Page  77 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Procarbazine An approved oral anti-cancer drug used primarily as part of the MOPP regimen in the treatment of Hodgkin's disease. It inhibits DNA, RNA and protein synthesis. Side effects can include myelosuppression, nausea, and vomiting. PRO-MACE/MOPP A chemotherapy regimen consisting of courses of prednisone, methotrexate (with leucovorin rescue), Adriamycin (doxorubicin), cyclophosphamide, etoposide/mechlorethamine, Oncovin (vincristine), prednisone, and procarbazine. Frequently used for the treatment of non-Hodgkin's lymphoma. All drugs available through a patientassistance/reimbursement program, see page 210. Pyrazinamide An approved oral anti-tuberculosis drug used in combination regimens. Side effects include hepatitis, GI distress, rash, and gout. Patients should be evaluated for hepatic function before and during therapy, and the drug is contraindicated in patients with hepatic dysfunction. A patient-assistance/reimbursement program is available, see page 210. Pyrimethamine An approved oral antibiotic used in combination with a sulfonamide drug for the prophlyaxis of malaria and the treatment of toxplasmosis. Pyrimethamine in combination with sulfadiazine in the treatment of toxoplasmosis. It has also been tested in combination with dapsone as prophylaxis for PCP. Side effects include bone marrow suppression and skin rashes. A patient assistance/reimbursement program is available, see page 210. Rifabutin (Mycobutin) An approved oral anti-mycobacterial drug indicated for the prophylaxis of disseminated MAC in patients with CD4 counts under 200/mm3. Clinical trials are under way to evaluate rifabutin in combination with other drugs for the treatment and prophylaxis of MAC. Side effects include rash, fever, GI distress, leukopenia, hemolysis and arthralgia. Uveitis (eye pain, inflammation and vision loss) has been reported in some patients receiving rifabutin, particularly in patients receiving high doses (>300 mg/day) and in patients receiving concomitant fluconazole, which increases serum levels of rifabutin. If symptoms of uveitis develop in patients receiving rifabutin, the drug should be stopped immediately and an ophthalmologic examination should be performed. A patient-assistance/reimbursement program is available, see page 210. Rifampin An approved oral or intravenous anti-mycobacterial drug indicated for the treatment of TB. Under investigation in combination regimens as treatment for MAC and prophylaxis for TB. Side effects can include rash, fever, GI distress, and jaundice. Orange discoloration of body secretions also occurs. A number of drug interactions have been reported. Rifampin may decrease levels of itraconazole, ketoconazole, and dapsone. Ritalin, See: Methylphenidate hydrochloride. RMP-7 An experimental synthetic peptide which produces an increase in permeability of the blood-brain barrier to a number of small molecules. It is under investigation in combination with amphotericin B in patients with cryptococcal meningitis. Saccharomyces boulardii An experimental oral treatment comprised of non-pathogenic yeast. It is under investigation for the treatment of chronic diarrhea in HIV-infected people. The mechanism of action is unclear. According to the manufacturer, the product is not systemically absorbed and no toxicities have been observed to date. Septra, See: TMPISMX Sodium tetradecyl sulfate injection (Sotradecol) An intravenous anionic surfactant employed as a sclerosing agent, approved for the treatment of varicose veins. One report suggests it may be effective for the intralesional treatment of intraoral Kaposi's sarcoma lesions. The most significant side effect is local necrosis. Sorivudine (BV ara-U) An experimental, oral antiviral drug active in vitro against HSV-1 and varicella-zoster (VZV), with a pre-clinical toxicity profile which suggests that it may be as well tolerated as acyclovir. In studies in Japan, no apparent side effects were noted when HIV-negative subjects were given oral doses up to 600 mg/d for 5 days. Studies are under way comparing BV ara-U to acyclovir for the treatment of herpes zoster. SP-303T An experimental topical antiviral drug with activity against a broad range of viruses including respiratory syncytial virus (RSV), influenza A and B, parainfluenza (PIV) types I and 3, hepatitis A virus, and herpes simplex virus types I and 2. It is under investigation for the topical treatment of acyclovir-resistant herpes simplex virus infection. 77

Page  78 Description of Treatments for Opportunistic Infections I Streptomycin An approved aminoglycoside antibiotic which was the first effective drug used for TB. Injected intramuscularly, side effects include ototoxicity, renal toxicity, and pain at the injection site. While streptomycin is no longer a first-line treatment for TB, some strains of MDR-TB are susceptible to it. A patientassistance/reimbursement program is available, see page 210. Sulfadiazine An oral sulfonamide antibiotic which, in combination with pyrimethamine, is standard therapy for toxoplasmosis. Side effects include bone-marrow suppression, fever and rash. Adequate re-hydration and urine alkalization are recommended to prevent sulfadiazine-induced crystalluria. Suramin An approved intravenous trypanocidal drug sometimes used for the treatment of African sleeping sickness. It has anti-HIV activity in vitro but has not demonstrated any clinical benefit in HIV infection. Under investigation for the treatment of lymphoma. Side effects can include fatigue and nausea, and infrequently, vomiting, shock, and loss of consciousness. Hepatic dysfunction and adrenal insufficiency have been observed in AIDS patients receiving suramin. Taxol, See: paclitaxel Testosterone (Delatestryl, Depo-testosterone, Testoderm) Testosterone is approved in intramuscular and transdermal patch formulations to treat hypogonadism. An oral form is approved to treat inoperable breast cancer. Both the intramuscular and transdermal forms are under investigation for the treatment of decreased sex drive and wasting syndrome. While side effects in HIV+ patients have not yet been reported, possible adverse events include acne, jaundice, changes in sex drive, anxiety and depression. A patient-assistance/reimbursement program is available, see page 210. Thalidomide (Synovir) An oral sedative withdrawn from the drug market because of its teratogenic and neurotoxic side effects. Recently, it has been used for treating severe skin reactions in certain cases involving leprosy. Thalidomide is currently under investigation for the treatment of a variety of diseases with autoimmune characteristics, including aphthous ulcers of non-viral and non-fungal origin. It is also under investigation as a treatment for wasting syndrome. Side effects include birth defects, drowsiness, dry mouth and peripheral neuropathy. See also, Treatments for HIV Infection, page TK. It is available under both a compassionate use and emergency IND protocols, see page 210. 3TC (Lamivudine, Epivir) An approved antiretroviral agent for the treatment of HIV (in combination with AZT). It is currently being studied as a treatment for hepatitis B virus (-HBV). A patient-assistance/reimbursement program is available, see page 210. TLC G-65 (liposomal gentamicin) An experimental, intravenously administered, liposome-encapsulated version of the approved aminoglycoside gentamicin. It is under investigation for the combination treatment of MAC. One MAC patient on high-dose TLC G-65 in a phase I trial developed reversible renal failure; no other toxicity was observed. TMP/SMX (co-trimoxazole, Bactrim, Septra) An approved oral or IV antibiotic, for the treatment and prophylaxis of PCP. TMP/SMX may also protect against toxoplasmosis. Each double-strength tablet is composed of 160 mg of trimethoprim and 800 mg of sulfamethoxazole. Side effects can include nausea, decreases in white blood cell counts, and elevated liver-enzyme levels. HIV-infected patients have a high incidence of allergic reactions (especially skin rash) to TMP/SMX. Reversible hyperkalemia has been observed in patients receiving high doses intravenously for treatment of PCP. Concomitant use of dieretics may increase the risk of hemorrhaging. Concurrent use of AZT or ganciclovir, may decrease levies of red blood cells and neutrophils. A patient assistance / reimbursement program is available, see page 210. TNP-470 An experimental drug which is an analog of fumagillin (a naturally secreted antibiotic of Aspergillus fumigatus fresenius). It inhibits angiogenesis (blood-vessel formation). Under investigation for Kaposi's sarcoma as well as solid tumors. Total Parenteral Nutrition (TPN) A method of supplying nutritional supplementation by intravenous infusion. It is only used for individuals with severely compromised bowel function who are unable to meet their nutritional needs with oral consumption. The procedure involves infusing a liquid nutrient preparation directly into the bloodstream through a central venous line catheter. Trifluridine (TFT, Viroptic) An approved topical antiviral drug indicated for the topical treatment of epithelial keratitis and used experimentally for the treatment of acyclovir-resistant and foscarnet-resistant HZV infection. Side effects to topical treatment can include a mild burning sensation after application. 78

Page  79 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Trimethoprim (TMP) An approved oral antibiotic which is used most frequently in conjunction with sulfamethoxazole (SMX). TMP/SMX is a first-line therapy for the prevention and treatment of PCP; TMP in combination with dapsone is also used for PCP. A patient-assistance/reimbursement program is available, see page210. Trimetrexate (Neutrexin) An approved oral antibiotic indicated for the treatment of moderate-to-severe PCP in patients intolerant to TMP/SMX. It is also is active in vitro against Toxoplasma gondii. Trimetrexate is administered with leucovorin (folinic acid) to prevent toxicity. Side effects include hepatic, renal, hematological and GI toxicities. A patient-assistance/reimbursement program is available, see page 210. Valaciclovir An approved oral antiviral drug (a valine ester of acyclovir), which is rapidly metabolized in vivo to acyclovir. The bioavailability of oral valaciclovir is significantly greater and less variable than that of oral acyclovir. It is under investigation for HIV-related CMV and herpes simplex virus. A patient-assistance/reimbursement program is available, see page 210. Vidarabine (Ara-A, adenine arabinoside) An approved, intravenous or topical antiviral drug with activity against herpes simplex and varicella-zoster (VZV) viruses. It is used to treat HSV encephalitis; neonatal encephalitis, infections of the skin, eyes, and mouth, disseminated HSV & VZV infection with visceral involvement, and herpes zoster (shingles) due to reactivated VZV infections in immunosuppressed patients. Side effects can include rash, reactions at the injection site, weakness and hypokalemia. Vinblastine (Velban) An intravenous anti-cancer drug derived from the periwinkle plant. It is thought to interfere with certain amino-acid metabolic pathways. Under investigation for the treatment of Kaposi's sarcoma and lymphoma. Side effects include leukopenia and occasional hair loss. A patient-assistance/reimbursement program is available, see page 210. Vincristine (Oncovin) An intravenous anti-cancer drug derived from the periwinkle plant. It is thought to interfere with cell mitosis. Under investigation for the treatment of Kaposi's sarcoma and lymphoma. Side effects include neuromuscular impairment, constipation, and occasional hair loss. A patient-assistance/reimbursement program is available, see page 210. 79

Page  80 Opportunistic Infections and Related Disorders TREATMENT RESULTS OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS BACTERIAL/MYCOBACTERIAL INFECTIONS BACTERIAL INFECTIONS Trials, page 173 People with HIV are more susceptible to certain bacterial infections, including salmonellosis, that HIV-negative people. Pneumonias resulting from Streptococcus pneumoniae and Haemophilus influenzae, diarrheal infection caused by Shigella and Campylobacter are especially common. Infection of the sinuses (sinusitis) has been reported to occur frequently in HIV+ people (Godofsky et al. and Zurlo et al.). Sinusitis is often recurrent or persistent, and may be asymptomatic. Thompson et al. report that many HIV+ patients with sinusitis are infected with common bacteria (in particular staphyloccous epidermidis.) Most patients have at least a partial response to antibiotic treatment, although complete resolution of symptoms is often difficult to achieve. Increasingly, in AIDS patients with advanced disease, Pseudomonas aeruginosa is the cause of chronic sinusitis. Selwyn et al. report that in HIV+ injection drug users, pyogenic bacterial infections are both a substantial cause of pre-AIDS morbidity and mortality and a significant predictor of progression to AIDS. In this prospective study of a cohort of patients from a methadone clinic, 13/318 HIV+ patients without a diagnosis of AIDS died of bacterial infections, while 1/411 HIV-negative patients died of bacterial infections. The United States Public Health Service and the Infectious Disease Society of America (1995) have published guidelines for the prevention of respiratory and enteric bacterial infections. To prevent pneumococcal infections, the guidelines state that adults should receive a single dose of 23-valent polysaccharide pneumococcal vaccine (along with annual influenza vaccination) as soon as possible after HIV infection has been diagnosed. H. influenzae vaccination should also be considered. Steinhoff et al. H. influenzae type b polysaccharide (PRP) vaccine to polysaccharide-mutant diphtheria toxoid conjugate vaccine (PR-CRM). In asymptomatic and early symptomatic HIV+ men (and in HIV-negative men), the PRP-CRM vaccine caused a three-fold greater antibody response than the PRP vaccine. However, in men with AIDS, the PRP vaccine induced a greater response. Standard antimicrobial therapies are generally effective for established bacterial infections in HIV+ patients. Two species of R. henselae and R. quintana have been established as causes of cutaneous bacillary angiomatosis, peliosis hepatitis, and persistent fever and bacteremia in HIV+ individuals (Bignall). Susceptibility to these opportunistic pathogens result primarily from defects in cell-mediated immunity. Erythromycin is the most commonly prescribed treatment, although one case report describes successful treatment of one patient with azithromycin (Guerra et al.). TREATMENT RESULTS Clinical trials of intravenous immunoglobulin (IVIG) have reported conflicting results regarding the reduced incidence of serious bacterial infections (meningitis, bacteremia, osteomyelitis, septic arthritis, acute sinusitis, pneumonia, acute mastoiditis, or abscess of an internal organ) in HIV+ children with CD4+ count >200/mm3 associated with its use. Two hundred fifty-five children with symptomatic HIV infection were enrolled in a double-blind placebo-controlled study (ACTG 051) comparing the combination of AZT and monthly infusions of IVIG 400 mg/kg with AZT alone (Spector et al.). After a median follow-up of 30 months, no significant benefit beyond that provided by AZT and PCP prophylaxis with TMP/SMX was observed. On the contrary, the National Institute of Child Health and Development enrolled 372 symptomatic HIV+ children in a double-blind placebo-controlled study of IVIG 400 mg/kg once a month. Equal numbers of patients in each group also received AZT (39% overall) and PCP prophylaxis (48% overall). After a median follow-up of 17 months, an interim analysis showed that among the 317 children who entered the study with CD4+ cell counts >200/mm3, 12/162 (7%) IVIG recipients experienced a lab-proven serious bacterial infection, compared with 24/155 (15%) placebo recipients. For children with entry CD4+ counts <200/mm3, there was no difference in the rate of these infections. Mortality rates were equal (31 deaths in each group). 80 80

Page  81 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 ONGOING PROPHYLAXIS STUDIES: A Phase II/III randomized trial (ACTG 254) of atovaquone and azithromycin compared to TMP/SMX in the prevention of bacterial infections in HIV+ children between the ages of 2 and 8 years of age is currently underway. REFERENCES: Bignall J. Rochalimaeas from cat-scratch to Kaposi. Lancet 342: 359, 1993. Centers for Disease Control. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24, 1995. Godofsky EW et al. Sinusitis in HIV-infected patients: a clinical and radiographic review. Amer J Med 93: 163-70, 1992. Guerra LG et al. Rapid response of AIDS-related bacillary angiomatosis to azithromycin. Clin Inf Dis 17:264-6, 1993. Hardy WD et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N ENGL J MED 237:1824-8, 1992. Selwyn PA et al. Clinical manifestations and predictors of disease progression in drug users with human immunodeficiency virus infection. N ENGL J MED 327:1697-703, 1992. Spector SA, et al. A controlled trial of intravenous immune globulin for the prevention of serious bacterial infections in children receiving zidovudine for advanced human immunodeficiency virus infection. N ENGL J MED 331(18). 1181-7. Steinhoff MC et al. Antibody responses to Haemophilus influenzae type B vaccines in men with HIV infection. N ENGL J MED 325: 1837-42, 1991. Zurlo JJ et al. Sinusitis in HIV-1 infection. Amer J Med 93:157-62, 1992. OTHER REPORTS: Chaisson RE. Infections due to encapsulated bacteria, Salmonella, Shigella, and Campylobacter. Infect Dis Clin N Am 2(2): 475-84, 1988. Molina JM et al. Campylobacter infections in HIV-infected patients: clinical and bacteriological features. AIDS 9:881-885, 1995. Perkocha LA et al. Clinical and pathological features of bacillary peliosis hepatitis in association with human immunodeficiency virus infection. N ENGL J MED 323(23): 1581-86, 1990. Relman DA et al. The agent of bacillary angiomatosis - an approach to the identification of uncultured pathogens. N ENGL J MED 323(23) 1573-80, 1990. Schrager LK et al. Bacterial infections in AIDS patients. AIDS, 2(Supp.1): S183-9, 1990. Slater LN et al. A newly recognized fastidious gramnegative pathogen as a cause of fever and bacteremia. N ENGL J MED 323(23): 1587-92, 1990. Steinhart R et al. Invasive Haemophilus influenzae infections in men with HIV infection. JAMA 268:3350-2, 1992. MYCOBACTERIUMA VIUM COMPLEX (MAC) Trials, pages 173-175 PATHOGEN: MAC refers to a family of similar mycobacterial organisms, Mycobacterium avium and M. intracellulare. Disease-causing MAC organisms are ubiquitous; they can be found in water, soil, foods, and a variety of animal species. SITES OF INFECTION: When MAC occurs in non-immunocompromised people, it usually causes infection in the respiratory tract. In patients with AIDS, MAC is frequently disseminated (disseminated MAC or DMAC). Almost any organ system can be involved, especially those with many mononuclear phagocytes (e.g., the liver, spleen and bone marrow). In the United States, the reported incidence of disseminated MAC disease, which ranges from 18% to approximately 50% in patients with AIDS, has increased over the last five years. The risk of developing disseminated MAC disease increases with the degree of immunosuppression; the highest risk is associated with CD4+ counts < 75-100 cells/mm3 and a prior opportunistic infection. Nightingale et al. prospectively monitored 1,006 patients with AIDS for the development of MAC bacteremia (culture of MAC from blood; no symptoms of MAC disease). Among patients who survived for 2 years after an AIDS diagnosis, 43% developed MAC bacteremia. The risk of developing MAC bacteremia increased as the CD4+ count fell, and most cases occurred in patients with CD4+ counts below 100/mm3. SYMPTOMS: Signs and symptoms of DMAC are generally nonspecific, such as fever, night sweats, weight loss, weakness, and anorexia. Diarrhea, malabsorption, and abdominal pain may indicate gastrointestinal involvement; enlargement of the liver and spleen is common. Laboratory findings often include anemia, neutropenia, and elevated alkaline phosphatase levels. Respiratory symptoms (and pulmonary involvement) are uncommon in AIDS-related MAC. DIAGNOSIS: Blood and/or bone-marrow cultures are the most sensitive. Disseminated MAC may be diagnosed from one positive blood culture. A positive sputum or stool culture may precede the development of symptomatic disease but may also represent colonization rather than infection. Disseminated MAC is an uncommon presenting AIDS diagnosis; it usually occurs in late-stage AIDS in patients with histories of multiple opportunistic infections and CD4+ cell counts <50/mm3. 81

Page  82 Opportunistic Infections and Related Disorders TREATMENT RESULTS The U.S. Public Health Service and the Infectious Disease Society of America have published guidelines for the prevention and treatment of MAC (1995). No standard therapy has been established for disseminated MAC. However, the guidelines recommend a combination treatment regimen which includes at least two drugs, one of which should be either clarithromycin (500 mg bid) or azithromycin (500 mg qd). Ethambutol ( 15 mg/kg qd) may be considered as the second drug. Third-tier drugs that may be considered include rifabutin (300 to 450 mg qd), rifampin (100 mg/kg qd), amikacin (7.5 mg/kg - 15 mg/kg qd), and ciprofloxacin (500 to 750 mg bid). Clinical and microbiologic responses are usually evident within 4-6 weeks, after which treatment should be continued for life. In the case of relapsed MAC bacteremia, in vitro susceptibilities to azithromycin or clarithromycin should be assessed. While few data are available, the Public Health Service recommends that the guidelines outlined above also be applied to children with disseminated MAC. FIRST TIER COMPOUNDS CLARITHROMYCIN OR AZITHROMYCIN: Both clarithromycin and azithromycin are the two treatments studied and approved thus far that have demonstrated the most significant antimycobacterial against MAC organisms. Three studies comparing clarithromycin to placebo have demonstrated clarithromycin to be an effective treatment for MAC (Dautzenberg et al., Gupta et al., Chaisson et al. 1994). Azithromycin, compared to either placebo (Young et al.) or clarithromycin (Berry et al.), has been shown to be an effective treatment for MAC disease, with response rates comparable to clarithromycin. However, recent preliminary data reported by Wood et al. suggest that clarithromycin is more effective. To date, 61 patients have been enrolled in a Veteran's Administration HIV Consortium Study Group trial. Data are available on 29 evaluable patients from two unevenly randomized arms. Eighteen patients have received clarithromycin and ethambutol, eleven patients have received azithromycin and ethambutol At week 16, 92% of the patients in the clarithromycin were culture negative as compared with 45% of the azithromycin patients (P = 0.030). Likewise, the time to clearance of MAC bacteremia was shorter for the clarithromycin group (4.38 weeks) than the azithromycin group (16 weeks) (P = 0.0018). There was no significant difference between the two groups in the proportion of patients with negative blood cultures at week 12. The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) has recently concluded that HIV+ patients with MAC being treated with clarithromycin should not be treated with the higher-than-standard dose (> 500 mg bid). The NIAID recommendation is based on the results of CPCRA 027, an open-label randomized trial comparing the efficacy of four three-drug regimens for the treatment of DMAC. All patients received ethambutol (15 mg/kg qd) and were randomized to receive either standard-dose clarithromycin (500 mg bid) or high-dose clarithromycin (1000 mg bid), and either rifabutin (300 mg qd) or clofazimine (100 mg qd). After review of the first interim analysis (Feb. 1996), the Data and Safety Monitoring Board (DSMB) recommended termination of the clarithromycin dose comparison because of poor survival in patients randomized to receive high-dose clarithromycin. Through that date, 69 patients were randomized; 36 to receive 500 mg bid and 33 to receive 1000 mg bid of clarithromycin with a median follow-up of 3.3 months. At the time of the first interim analysis, seven deaths had occured in the standard dose group and 17 deaths in the high-dose group (P = 0.005). Different doses of clarithromycin have been compared previously, in ACTG 157 (Chaisson et al. 1994) and a trial conducted by the manufacturer. Both studies found a significantly poorer survival rate in the high-dose groups when compared to the standard-dose groups at earlier stages (12-16 weeks of patient follow-up). Despite initial clinical and bacteriologic improvement with clarithromycin monotherapy, relapses with cross-resistant strains to both clarithromycin and azithromycin are frequent (Chaisson, 1994; Heifets, 1993). Accordingly, multidrug regimens have been proposed to lower the rate of relapse. SECOND TIER COMPOUND ETHAMBUTOL: Ethambutol, compared to sparfloxacin and ciprofloxacin, demonstrated significant efficacy in a clinical trial (Young et al.). Ethambutol was also reported to be more efficacious than clofazamine and rifampin in a clinical trial reported by Kemper et al.. Poorer response rates are associated with ethambutol, when retrospectively compared to clinical trials of clarithromycin and azithromycin (Kemper et al.). The efficacy of ethambutol added to a clarithromycin-containing combination has been established. Chaisson et al. (1996) studied 106 HIV+ patients with DMAC to determine whether adding ethambutol to a combination of clarithromycin and clofazamine is more effective than the two drugs alone. Clinical and microbiological responses were similar in both groups (69% responded in both groups). There were 8 relapses in the two-drug group and 2 relapses in the three-drug group. The estimated risk of relapse at 26 weeks was 68% and 5%, respectively (P = 0.004). All MAC relapses reported were clarithromycin-resistant. 82

Page  83 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199i 7 THIRD TIER COMPOUNDS AMIKACIN, RIFAMPIN, RIFABUTIN, CIPROFLOXACIN: Several clinical trials examining these compounds in combination with either clarithromycin or azithromycin have been reported. Clofazamine (Lamprene), a drug commonly studied in combination with clarithromycin, has been associated with high mortality rates in various clinical trials. As a result, NIAID has concluded that clofazamine not be used as adjunctive therapy for HIV+ patients with DMAC. One particular trial, examining the efficacy of adding ethambutol to a combination of clarithromycin and clofazamine (discussed above) reported that 38% of patients in the two-drug combination and 61% of patients in the three-drug combination died during follow-up (P = 0.03), and time to death was shorter in patients treated with three drugs (P = 0.01) (Chaisson et al., 1996). Interim results from an open, randomized study of 2 clarithromycin combination treatments for MAC bacteremia have been reported (May et al.). Data were available in 123/132 patients enrolled. Patients were randomized to receive either clarithromycin (2000 mg qd for 2 months, then 1000 mg qd) and clofazamine (200 mg qd, then 100 mg qd) or clarithromycin (2000 mg qd for 2 months, then 1000 mg qd), rifabutin (450 mg qd), and ethambutol (1200 mg qd). The median CD4+ count was 14 cells/mm3. At 2 months, the success rate (defined as alive with decreased fever and negative blood cultures) was 36/49 (73%) for patients in the clarithromycin and clofazamine group and 32/46 (70%) in the triple combination group (P = 0.51). At 6 months, the success rate was 7/25 (28%) and 12/26 (46%), respectively (P = 0.51). Eighteen patients experienced relapse (postive for MAC bacteremia) between months 2 and 6 in the clarithromycin/ethambutol drug combination group (14 with resistance to clarithromycin) versus 6 relapses in the triple combination group (2 resistant to clarithromycin) (P < 0.01). There was no difference in survival distribution between the two groups. Shafran et al. recently published the final results of a 16-week open-label trial conducted by the Canadian MAC Study Group. Two hundred twenty nine HIV+ patients with MAC bacteremia were randomized to receive either ciprofloxacin 750 mg twice daily, ethambutol 15 mg/kg/day, rifampin 600 mg/day and clofazimine 100 mg/day or clarithromycin 1000 mg twice daily, rifabutin 600 mg/qd and ethambutol 15 mg/kg/day. The rifabutin dose was halved to 300 mg/day after 125 patients were randomized, due to the development of uveitis at the 600 mg dose. Data were evaluated in 187/229 patients. Proportions of MAC bacteremia clearance at 15 weeks were 67/97 (69%) on the three-drug arm and 26/90 (29%) on the four-drug arm (P < 0.001 ). The proportion clearing was higher in the three-drug than four-drug arm at the higher dose of rifabutin (79% vs 22%, P < 0.001) and at the lower dose (58% vs 36%, P < 0.05). The median survival times were 8.6 months in the three-drug arm and 5.2 months in the four-drug arm (P < 0.001). The authors concluded that the three-drug combination was superior in terms of clearing bacteremia and survival. The higher dose of rifabutin was more effective than the lower but caused more uveitis. Parenti et al. treated 79 symptomatic HIV patients with disseminated MAC in a randomized study of rifampin 600 mg/day, ciprofloxacin 500 mg bid, clofazimine 100 mg/day and ethambutol 15 mg/kg/day with or without amikacin 10 mg/kg/day. After a 1-2 week observation period, 37 patients were randomized to receive amikacin and 37 patients to matching placebo. The mean CD4+ counts at entry were 10 cells/mm3. Median duration of treatment was 12 weeks with a median follow-up of 23 weeks. Patients were classified as complete or partial responders on the basis of decreases in clinical symptoms of fever, diarrhea and antipyretic use after 4, 8, and 12 weeks of treatment. At 4 weeks, 33% of patients randomized to amikacin had a complete or partial response, versus 35% in the placebo group; at 8 weeks reported responses were 62% and 65%, respectively. Quantitative cultures showed no significant difference between the two groups in the decrease of mean CFUs relative to baseline at any visit. There was no statistical difference between the two groups in survival distribution. Dautzenberg et al. reported results from a twelve week, double-blind placebo-controlled trial of rifabutin in combination with ethambutol, clofazimine and isoniazid. Two hundred patients with disseminated MAC and a median CD4+ count of 10 cells/mm3 were randomized to ethambutol, clofazimine and isoniazid with either placebo or rifabutin (600 mg daily). In the intent-to-treat analysis, MAC bacteremia declined in 46/100 (46%) patients in the rifabutin combination group and in 30/100 (30%) patients in the placebo group. Nightingale et al. enrolled 21 patients with AIDS and disseminated MAC (median entry CD4+ count = 6/mm3) in a phase I/11 dose-ranging trial of TLC G-65 (liposome-encapsulated gentamycin). Patients received TLC G-65 (1.7, 3.4 or 5.1 mg/kg) IV twice weekly for 4 weeks. One patient at the highest dose developed reversible renal failure; no other toxicities were observed. All doses of TLC G-65 gave serum levels above the in vitro inhibitory concentration. A one-log reduction in MAC colony-forming units in the blood was observed after treatment, and 4/6 evaluable patients on the highest dose reported reduction in symptoms and in night sweats. A phase II study of TLC G-65 in combination with clarithromycin and ethambutol is underway. ONGOING TREATMENT STUDIES: A study comparing clarithromycin and ethambutol vs. clarithromycin and rifabutin vs. clarithromycin, ethambutol, and rifabutin (ACTG 223) is underway. A second study is comparing clarithromycin and ethambutol to clarithromycin, ethambutol and ranging doses of rifabutin. 83

Page  84 Opportunistic Infections and Related Disorders I~ PROPHYLAXIS RESULTS The U.S. Public Health Service (PHS) and the Infectious Disease Society of America (IDSA) have established guidelines for the prevention of MAC (CDC, 1995). The guidelines state that HIV+ persons with CD4+ counts < 75/mm3 should receive prophylaxis with rifabutin 300 mg/day. A review article (Gordin and Masur, 1994) observed that some clinicians might decide to forego prophylaxis while closely monitoring the patient for signs of disseminated MAC. Moreover, both clarithromycin and azithromycin have both shown to be more effective as MAC prophylaxis than rifabutin; both drugs were approved after the guidelines were drafted and approved. This option was considered reasonable given the expense, potential toxicity, and incomplete efficacy of currently available prophylactic therapy. However, this is the strategy tested in placebo-controlled trials of prophylaxis and these studies have shown a survival benefit of MAC prophylaxis. Rifabutin (300 mg PO daily), clarithromycin (500 mg PO bid), and azithromycin (1200 mg qw) have been approved as prophylaxis for MAC in HIV+ patients with CD4+ counts below 200/mm3. Two studies found that rifabutin effectively delays or prevents MAC bacteremia compared to placebo in AIDS patients with CD4+ counts under 200/mm3 (Nightingale et al.). The first study enrolled 590 patients. The mean baseline CD4+ count was 66 in the rifabutin group and 56 in the placebo group. 24/292 (8%) of rifabutin recipients and 51/298 (17%) of placebo recipients developed MAC bacteremia (P <0.001). The second study enrolled 556 patients. The mean baseline CD4+ count was 61 in the rifabutin group and 55 in the placebo group. 24/274 (9%) of rifabutin recipients and 51/282 (18%) of placebo recipients developed MAC bacteremia (P <0.002). There was no survival difference between the MAC and placebo groups in either study. The frequency of adverse reactions was similar in the rifabutin and placebo groups, with discolored urine occurring more frequently in the rifabutin group. Uveitis (eye pain, inflammation and vision loss) has been reported in some patients receiving rifabutin (Frank et al., Fuller et al. and Havlir et al.), particularly in patients receiving high doses (>300 mg/day) and in patients receiving concomitant fluconazole, which increases serum levels of rifabutin. If symptoms of uveitis develop in patients receiving rifabutin, the drug should be stopped immediately and an ophthalmologic examination should be performed. Chaisson et al. has conducted Cox proportional hazards analyses for survival from the two prophylaxis clinical trials of rifabutin originally reported in 1993 (Nightingale et al., 1993). Data from 1145 patients with CD4+ counts < 200 cells/mm3 were assessed. The risk of death at 12 and 18 months was evaluated. At 12 months, the relative risk of death in patients receiving rifabutin was 20%, compared to 28% in those not receiving rifabutin. At 18 months the risk of death in the two treatment groups was 28% and 45%, respectively. Pierce et al. have reported results of a double-blind, multicenter trial of daily prophylaxis treatment with either clarithromycin (500 mg bid) or placebo in HIV+ people with CD4+ cell counts of 100 cells/mm3 or less. Six hundred eighty two patients (341 clarithromycin, 341 placebo) were enrolled and followed for a median of 10.2 months. MAC bacteremia developed in 19/341 (5.7%) of the clarithromycin group and 53/341 (15.9%) of the placebo group (P < 0.001). In those who developed MAC bacteremia, clarithromycin-resistant isolates were recovered from 11 out of 19 patients in the clarithromycin group. 106 patients in the clarithromycin group died compared to 136 patients in the placebo group. Median survival was 700 days for those who received clarithromycin versus 573 days in the placebo group. Placebo recipients who developed MAC culture positivity had an increased relative risk of death of 2.6 compared to those who were MAC negative (P < 0.001). Discontinuation due to adverse events was 4% and 6%, respectively. A randomized, double-blind study (ACTG 196/CPCRA 009) has been completed comparing rifabutin to clarithromycin to the combination of both for the prevention of MAC bacteremia or disease in 1178 patients (Benson et al.). The median CD4+ count upon entry was 28 cells/mm3. During the median follow-up of 589 days, 35/398 (9%) developed MAC in the clarithromycin group, 59/339 (15%) developed MAC in the rifabutin group, and 26/389 (7%) developed MAC in the combination group (P = 0.001). A preliminary analysis of 75% of the break-through patients indicated a similar frequency of resistance in the clarithromycin group (29%) and the combination groups (25%). No clarithromycin resistant isolates (MIC > 32 pg/ml) were seen in the rifabutin group. Survival time did not differ among the three treatment groups (515 deaths total). Two studies of azithromycin as MAC prophylaxis have been completed. Oldfield et al. compared azithromycin (1200 mg once weekly) to placebo in 182 HIV+ patients with a mean CD4+ count of 44 cells/mm3. Mean duration of time on treatment was 400 days in the azithromycin group and 340 days in the placebo group. MAC bacteremia developed in 7/85 (10.6%) patients receiving azithromycin and 20/86 (24.7%) patients receiving placebo (P = 0.002). There was no statistical difference in the time to death 84

Page  85 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 or number of deaths in either the treatment or control groups (11 and 10 deaths, respectively). The major type of toxicity was gastrointestinal (83.3% in the romycin group and 44% in the placebo group). The investigators conclude that azithromycin is effective in preventing MAC bacteremia. In another reported study, Havlir et al. randomized 693 HIV+ patients with fewer than 100 CD4+ cells/mm3 who received either azithromycin (1200 mg once weekly) or rifabutin (300 mg daily) or a combination of both. In the final analysis, which included endpoints occurring up to one year (mean time on study drug was 318 days), the incidence of DMAC infection was 15.3% with rifabutin, 7.6% with azithromycin, and 2.8% with both drugs. The risk of infection in the azithromycin group was half that in the rifabutin group (P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (P < 0.001) or azithromycin alone (P = 0.03). A significantly higher proportion of patients had adverse events in the combination therapy group than in the monotherapy groups (P < 0.001 for both comparisons). Survival time did not differ significantly between the three treatment groups. Of 44 breakthrough isolates of MAC tested, only 2 (both in the azithromycin monotherapy arm) were resistant to azithromycin and clarithromycin. The investigators conclude that weekly azithromycin is an effective alternative to daily rifabutin and combination treatment is more effective than either drug alone. REFERENCES: Benson CA et al. A phase III prospective, randomized, double-blind study of the safety and efficacy of clarithromycin vs. rifabutin vs. clarithromycin/rifabutin for the prevention of MAC disease in HIV+ patients with CD4+ counts < 100 cells/mm3. Abstract #205, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Centers for Diseases Control. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24, 1995. Chaisson RE et al. Survival analysis of two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex in AIDS. 35th ICAAC, Abstract 1204, San Francisco, 1995. Chaisson RE et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. Ann Int Med 121: 905-911, 1994. Chaisson RE et al. Controlled trial of clarithromycin/ethambutol with or without clofazimine for MAC bacteremia in AIDS. Abstract #LB17, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Frank MO et al. Rifabutin and uveitis. N ENGL J MED 330:868, 1994. Fuller JD et al. Rifabutin prophylaxis and uveitis. N ENGL J MED 330:1315-6, 1994. Dautzenberg et al. Rifabutin vs placebo in combination therapy for the treatment of disseminated MAC in HIV+ patients. Abstract #A/1, 34th ICAAC, Orlando, 1994. Dube M et al. Prevention of relapse of MAC bacteremia in AIDS: A randomized study of clarithromycin, plus clofazimine, with or without ethambutol. Abstract #206. 3rd Conference on Retroviruses and Opportunistic Infections, Washington DC, 1996. Gordin F and Masur H. Prophylaxis of Mycobacterium avium complex bacteremia in patients with AIDS. Clin Inf Dis 18:S223-6, 1994. Havlir D et al. Uveitis associated with rifabutin prophylaxis. Ann Intern Med 121: 510-512, 1994. Havlir DV et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N ENGL J MED 335:392-8, 1996. Heifets L et al. Mycobacterium avium strains resistant to clarithromycin and azithromycin. Antimicrob Agents Chemother 37:2364-70, 1993. Horsburgh CR et al. Clinical presentation of disseminated M. avium complex (MAC) disease: A case-controlled analysis. 35th ICAAC, Abstract 192, San Francisco, 1995. Jacobson et al. Randomized, placebo-controlled trial of rifampin, ethambutol, and ciprofloxacin for AIDS patients with disseminated Mycobacterium avium complex infection. J INFECT DIS 168:112-9, 1993. Kemper CA et al. The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS. J Infect Dis 170: 157-164, 1994. May T et al. A French randomized open trial of 2 clarithromycin combination therapies for MAC bacteremia: First results. 35th ICAAC, Abstract LB-19, San Francisco, 1995. Morrissey AM et al. Changes in quantitative blood cultures, colonial morphology and susceptibility of Mycobacterium avium during therapy. Abstract 1124, 33rd ICAAC, New Orleans, 1993. Nightingale SD et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients. J INFECT DIS 1165: 1082-5, 1992. Nightingale S et al. Phase 1/Il study of TLC-G-65 (liposome-encapsulated gentamicin) for treatment of Mycobacterium avium complex disease. 32nd ICAAC, abstract 898, Anaheim, 1992. Nightingale SD et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N ENGL J MED 329:828-33, 1993. Oldfield EC et al. Once weekly azithromycin for the prevention of MAC infection in AIDS patients. Abstract #203, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Parenti D et al. A Phase II/111 trial of rifampin, ciprofloxacin, clofazimine, ethambutol with or without amikacin in the treatment of disseminated MAC. 2nd Natl Conf Human Retroviruses and Rel Infect, Abstract 6, Washington, DC, 1995. Phillips P et al. The Canadian randomized open-label trial of combination therapy for MAC bacteremia: blood culture results. Abstract #555B, X Intl Conf AIDS, Yokohama, 1994. Pierce M et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced acquired immunodeficiency syndrome. N ENGL J MED 335:384-91, 1996. Shafran SD et al. Comparison of two regimens for Mycobacterium avium complex bactermia in AIDS. N ENGL J MED 335:377-83, 1996. Sullam PM et al. Efficacy of rifabutin in the treatment of disseminated infection due to Mycobacterium avium complex. CID 19.84-6, 1993. Von Reyn CF et al. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. Lancet 343:1137-41, 1994. OTHER REPORTS: Benson C et al. Treatment of disseminated disease due to the Mycobacterium avium complex in patients with AIDS. Clin Inf Dis 18:S237-42, 1994. Dautzenberg B et al. Activity of clarithromycin against Mycobacterium-avium infection in patients with AIDS. Am Rev Respir Dis 144: 564-9, 1991. 85

Page  86 Opportunistic Infections and Related Disorders Dautzenberg B et al. Clarithromycin and other antimicrobial agents in the treatment of disseminated Mycobacterium avium infections in patients with Acquired Immunodeficiency Syndrome. Arch Intern Med 153: 368-72, 1993. Hewitt RG et al. Prevention of M. avium complex (MAC) bacteremia in patients with CD4 <200 by rifabutin, clarithromycin or dapsone. Abstract PO-B07-1184, IX Intl Conf AIDS, Berlin, 1993. Horsburgh CR et al. Mycobacterium avium complex infection in the acquired immunodeficiency syndrome. N ENGL J MED 324: 1332-8, 1991. Horsburgh CR et al. Environmental risk factors for acquisition of Mycobacterium avium complex in persons with human immunodeficiency virus infection. J Infect Dis 170: 362-367, 1994. Inderlied CB et al. in vitro and in vivo activity of azithromycin (CP 62,993) against the Mycobacterium avium complex. J Infect Dis 159(5): 994-7, 1989. Ives DV et al. Impact of clarithromycin and azithromycin in patterns of treatment and survival among AIDS patients with disseminated Mycobacterium avium complex. AIDS 9:261-266, 1995. Kallenius et al. Human immunodeficiency virus type 1 enhances intracellular growth of Mycobacterium avium in human macrophages. Infect and Immun: 2453-8, 1992. Kerlikowske KM et al. Antimycobacterial therapy for disseminated Mycobacterium avium complex infection in patients with acquired immunodeficiency syndrome. Arch Intern Med 152: 813-7, 1992. Kolonoski PT et al. Therapeutic efficacy of WIN 57273 (WIN) and sparfloxacin (SPA) for disseminated Mycobacterium avium complex (MAC) infection in beige mice. Abstract 1247, 30th ICAAC, 1990. Newman GW et al. Interleukin-12 enhances antigen-specific proliferation of peripheral blood mononuclear cells from HIV-positive and negative donors in response to Mycobacterium avium. AIDS: 1413-1419, 1994. Onyeji CO et al. Activities of clarithromycin, azithromycin, and ofloxacin in combination with liposomal or unencapsulated granulocyte-macrophage colony-stimulated factor against intramacrophage Mycobacterium avium - Mycobacterium intracellulare. J INFECT DIS 172:810-6, 1995. Opravil M et al. Dapsone-pyrimethamine might prevent mycobacterial disease in HIV infection. 33rd ICAAC, abstract #1080, 1993. Pentoxifylline aggravates impairment in tumor necrosis factor-secretion and increases mycobacterial load in macrophages from AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. J Infect Dis 170: 484-487, 1994. Rastogi N et al. Potential drug targets for Mycobacterium avium defined by radiometric drug-inhibitor combination techniques. Antimicrob Agents Chemother 38: 2287-2295, 1994. Yajko CA et al. Intracellular activity of sparfloxacin (Cl-978, AT-4140) versus ciprofloxacin against AIDS-derived strains of Mycobacterium avium complex. Abstract 24, 30th ICAAC, 1990. Young LS and Inderlied CB. Mycobacterium avium complex infections. A comprehensive overview of diagnosis and treatment. AIDS Patient Care 4(5): 10-8, 1990. SALMONELLOSIS PATHOGEN: Salmonellae are non-spore-forming, gram-negative rods of the family Enterobacteriaceae. S. typhosa causes typhoid fever; other Salmonellae cause diarrhea and bacteremia. SITES OF INFECTION: Infection is usually by the oral route and results from ingestion of contaminated food or water. The bacteria multiply after entering the small intestine. Salmonellae infections are usually systemic and disseminated in HIV+ patients. While salmonellosis is an infrequent 01 in AIDS, the incidence of salmonellosis in AIDS patients is about 20 times higher than in immunocompetent people. Recurrent Salmonella septicemia in HIV+ adults establishes an AIDS diagnosis. SYMPTOMS: Most patients present with non-specific symptoms such as fever, chills, sweats, weight loss, diarrhea, and anorexia. Although enterocolitis is common in AIDS, it is usually not caused bySalmonella. DIAGNOSIS: Bacterial culture of stool or blood. TREATMENT Treatment for immune-competent people is normally supportive; hovever, in AIDS patients antibiotic therapy is indicated. Ciprofloxacin, ampicillin, chloramphenicol, and TMP/SMX are effective. Relapse is frequent and maintenance therapy with ciprofloxacin may be indicated. 86

Page  87 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199i 7 SYPHILIS/NEUROSYPHILIS PATHOGEN: Treponema pallidum, a spirochetal bacterium. SITES OF INFECTION: Soon after initial infection, the organism enters the lymphatic system and/or blood stream and disseminates throughout the body. Nearly all organs can be invaded, including the central nervous system. SYMPTOMS: Primary syphilis is characterized by a painless chancre (a sore or lesion) at the site of inoculation in the genital tract. This chancre does not always develop, however, and multiple chancres are also possible which heal within 3-6 weeks. Lymphadenopathy accompanies the chancre. The principal manifestation of secondary syphilis, which typically begins to occur as the primary canchre is starting to heal, is a diffuse rash, condyloma lata, lymphadenopathy, and various constitutional symptoms such as fever. It should be noted that neurosyphilis can occur at any stage of syphilis; syphilitic meningitis and meningovascular syphilis occur early (months to a few years after infection) and general paresis and tabes dorsalis occur later (5-30 years after infection). In addition to neurosyphilis, late syphilis can affect almost any organ through gummatous lesions and cardiovascular involvement. Johns et al. hypothesize that co-incident HIV infection accelerates the course of syphilis, and Flood et al. report that symptomatic early neurosyphilis may be more common in HIV+ people. DIAGNOSIS: In early syphilis, darkfield examination of exudate from lesions and direct fluorescent antibody tests on lesions or tissue are definitive. Non-specific serologic tests are useful for syphilis screening and for monitoring response to treatment. Specific serologic tests are used for establishing the diagnosis. They usually remain positive for life and therefore cannot be used to monitor response to treatment. CSF examination is necessary for diagnosis of neurosyphilis. In HIV+ individuals, false-positive serological tests despite adequate therapy are possible due to polyclonal B-cell activation or auto-immune processes. Conversely, but extremely rarely, false-negative serological tests have been reported. Extraordinary means (such as direct examination of lesion material) may be necessary to establish the diagnosis in these unusual cases. Gordon et al. have concluded that cerebrospinal fluid (CSF) PCR is not a sensitive test for neurospyphilis in HIV+ patients. Despite clinical improvements reported in a trial of intravenous penicillin G, CSF VDRL levels measured by PCR remained high in all patients examined. TREATMENT RESULTS Standard treatment for early syphilis is parenteral penicillin (benzathine penicillin G). However, prospective studies to establish the most effective drugs and dosages in HIV+ patients have not been conducted. The CDC recommends a single dose of 2.4 million units of benzathine penicillin G administered intramuscularly for both HIV-negative and HIV+ patients. Musher et al. propose higher doses (three 2.4 million unit doses at weekly intervals) in order to prevent possible relapse to neurosyphilis. While ceftriaxone (500 mg or 1 g IM qd for 10 days) may be an effective alternative regimen, it has not been adequately evaluated. In the penicillin-allergic HIV+ patient with early syphilis, some clinicians use doxycycline as an alternative to desensitization or ceftriaxone. CDC guidelines recommend 7.2 million units of benzathine penicillin given in three weekly doses IM for late latent syphilis of more than one year's duration with no CSF evidence of neurosyphilis. CDC guidelines for neurosyphilis recommend aqueous crystalline penicillin G potassium 2 to 4 million units IV every four hours for 10 to 14 days (total dose 12 - 24 million units). Alternative regimens include procaine penicillin 2 to 4 million units IM daily plus probenecid 500 mg IM four times daily for 10 to 14 days. A study of 11 HIV+ patients with symptomatic neurosyphilis receiving aqueous crystalline penicillin G potassium (18 - 24 million units daily for 10 days) concluded that HIV infection may affect both the natural course of syphilis and the response to treatment (Gordon et al.). At 24 weeks after treatment, serum titers on rapid plasma reagin (RPR) of four patients decreased by at least two doubling dilutions, and four patients had reductions in the cerebrospinal fluid titers. In two patients, there was no normalization or improvement in serum titers, and one patient relapsed with meningovascular syphilis six months after therapy. Gourevitch et al. studied a cohort study of 50 intravenous drug users with syphilis. Thirty one were HIV+ and 19 were HIV-negative. HIV infection did not appear to affect the response to treatment. Most patients had late latent syphilis at presentation (15/31 and 13/19 patients in the HIV+ and HIV-negative groups, respectively). Follow-up was adequate to assess treatment outcomes in 43 patients (26 HIV+ and 17 HIV-negative). A variety of treatment regimens were used. Among the evaluable HIV+ patients, 12 received the standard CDC-recommended regimen of penicillin and 14 received other therapy (either high doses of penicillin or non-penicillin regimens). All responded adequately to therapy. Among the HIV-negative subjects, 9 received standard therapy and 8 received other therapy. One patient (who received two weeks of tetracycline) did not respond adequately. 87

Page  88 Opportunistic Infections and Related Disorders Dowell et al. retrospectively compared ceftriaxone (1-2 g/day for 10-14 days) and benzathine penicillin (2.4 million units weekly for three weeks) for late latent syphilis or asymptomatic neurosyphilis in HIV+ patients. 28/44 ceftriaxone recipients and 8/13 benzathine-penicillin recipients responded to treatment. The investigators concluded that ceftriaxone and benzathine penicillin appear equivalent for patients with normal CSF. Trials are underway comparing IV ceftriaxone and IV penicillin G for neurosyphilis, and alternate penicillin regimens for syphilis. REFERENCES: Centers for Disease Control and Prevention. Primary and secondary syphilis among HIVinfected patients. MMWR, 42:RR-14, 27-44, 1993. Dowell ME et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Amer J Med 93:481-8, 1992. Flood JM et al. Neurosyphilis in San Francisco during the AIDS epidemic, 19851989. 31st ICAAC, abstract 334, 1991. Gordon SM et al. The response of symptomatic neurosyphilis to highdose intravenous penicillin G in patients with human immunodeficiency virus infection. N ENGL J MED 331:14691473, 1994. Gourevitch MN et al. Effects of HIV infection on the serologic manifestations and response to treatment of syphilis in intravenous drug users. Ann Int Med 118:3505, 1993. Johns DR et al. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N ENGL J MED 316: 156972, 1987. Musher DM et al. Effect of HIV infection on the course of syphilis and on the response to treatment. Ann Int Med 113: 872-881, 1990. OTHER REPORTS: Hook EW and Marr CM. Acquired syphilis in adults (review). N ENGL J MED 326: 10609, 1992. Johnson PDR et al. Specific syphilis serological tests may become negative in HIV infection. AIDS 5: 41423, 1991. Matlow AG et al. Syphilis serology in HIV-infected patients with symptomatic neurosyphilis: case report and review. Rev Infect Dis 12: 703-7, 1990. Musher DM et al. Neurosyphilis in HIVinfected persons. N ENGL J MED 331:1516-1517, 1994. Pope V et al. Effect of syphilis and HIV coinfection on expression of peripheral blood lymphocyte immunophenotypes. Abstract #L8, 34th ICAAC, Orlando, 1994. TUBERCULOSIS Trials, page 175-176 PATHOGEN: HIV+ people are particularly susceptible to infection with Mycobacterium tuberculosis, and the course of the disease is accelerated. Nosocomial outbreaks of tuberculosis have occurred in health care settings. One report (Di-Perri et al.) described a tuberculosis outbreak among 18 HIV+ patients on an inpatient ward in an Italian hospital. 8/18 patients exposed to a patient with active tuberculosis developed TB. Another report (Daley et al.) described an outbreak of tuberculosis among residents of a group housing facility; active tuberculosis developed within four months in 11/30 (37%) and newly positive skin tests developed in 4/30 (13%). SITES OF INFECTION: Initially, the alveoli of the lungs. Extrapulmonary tuberculosis is unusual in non-HIV+ patients but frequently occurs in HIV+ people, especially in those with lower CD4+ counts (Jones et al.). While most patients with AIDS-associated tuberculosis have pulmonary involvement, in at least half of these cases the disease is not confined to the lungs. The lymphatic system is frequently involved. Berenguer et al. report that while tuberculous meningitis occurs more frequently in HIV+ people, clinical outcomes are similar to those in non-HIV+ people. SYMPTOMS: The classic symptoms of tuberculosis (cough, weight loss, fever, night sweats, fatigue) are often present but not necessarily indicative of TB in people with AIDS. DIAGNOSIS: The sensitivity of tuberculin skin tests is reduced in most cases of TB with severe immune suppression, however, PPD testing should be done (a positive PPD indicates exposure but not necessarily active disease). Diagnosis of TB requires isolation of M. tuberculosis by culture. TREATMENT RESULTS The CDC has released guidelines for the treatment of TB (Centers for Disease Control and Prevention, 1994). These guidelines address the growing prevalence of multi-drug resistant TB (MDR-TB). All HIV+ patients with M. tuberculosis should have drug-susceptibility testing performed on their first isolate; the results of testing should provide the basis for clinical therapeutic decisions. Initial treatment of susceptible organisms should include four drugs; during the first two months the regimen should include isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin. If the organisms are susceptible, they should be continued on therapy with isoniazid and rifampin. Since data are not available to determine if a 88 I_

Page  89 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 six-month regimen is sufficient for HIV+ patients, they should be treated for a total of nine months, and for at least 6 months after sputum conversion. CDC also recommends that directly observed therapy (DOT) be considered for all patients, since the biggest reason for failure of treatment is inadequate compliance El-Sadr et al. have reported that the addition of levofloxacin to a four drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol does not improve culture responses in HIV+ patients with M. tuberculosis. CPCRA 019/ACTG 222 enrolled 227 patients from both isoniazid-resistant and sensitive geographic locations (geographic areas with resistance rates of greater or less than 10%, respectively). Pulmonary TB was confirmed by culture in 145 patients, 111/174 (64%) patients enrolled from resistant areas and 34/53 (64%) patients from sensitive areas; patients enrolled in resistant areas were evenly randomized to receive either the addition of levofloxacin or placebo (87 patients in each arm). The primary endpoint was negative sputum culture at eight weeks or at least two negative follow-up sputum cultures with no intervening or subsequent positive cultures and a completed eight week visit. In the resistant areas, 36/37 in the four drug group and 46/48 patients in the five drug group responded to treatment. In the sensitive areas, 28/29 patients responded to treatment. The second half of this study, which will attempt to determine the optimal duration of maintenance therapy, is still underway. Malabsorption of anti-mycobacterial drugs occurs relatively frequently in AIDS patients with TB (Bering et al., Gordon et al., Peloquin et al.). To prevent treatment failure, screening for drug malabsorption may be indicated in situations where patients do not respond to correct therapy given under direct observation. There is currently one trial underway for patients with either drug sensitive or multiple-drug-resistant tuberculosis. ACTG 222/CPCRA 019 will provide patients with lovoflaxin, isoniazid, rifampin, a pyrazinamide for variable lengths of time. MULTI-DRUG RESISTANT TUBERCULOSIS:: Several outbreaks of multi-drug resistant tuberculosis (MDR-TB) among HIV+ people in hospitals and prisons have been reported. Mortality among these patients is very high (approximately 80%) and the disease progression is extremely rapid. Edlin et al. and Fischl et al. studied outbreaks of MDR-TB in hospitals. They report that nosocomial transmission of MDR-TB bacilli among HIV+ patients can occur. They caution that acid-fast-bacilli isolation procedures must be strictly enforced in hospitals. Additional data (Small et al. 1992) indicate that multi-drug resistance in HIV+ people can result from re-infection with resistant strains of M. tuberculosis. This re-infection can occur during or after therapy for drugsensitive tuberculosis. Inadequate treatment is the primary cause of the development of MDR-TB (Mahmoudi and Iseman, 1993). Multiple levels of resistance are especially likely to accrete when single drugs are added to a failing regimen. When initiating treatment in patients with confirmed MDR-TB, both the treatment history and the in vitro susceptibilities of the patient's strain should be evaluated (Iseman, 1993). The patient should be hospitalized, and the selected regimen should include between four and seven drugs. Drugs with potential utility in a re-treatment regimen include pyrazinamide, ethambutol, streptomycin, ofloxacin, ciprofloxacin, ethionamide, cycloserine, capreomycin and PAS. In cases where chemotherapy is unsuccessful, adjunctive treatment with resectional surgery may be considered. ONGOING TREATMENT STUDIES: A clinical trial (ACTG 238/CPCRA 026) is underway and closed to enrollment to identify risk factors for the development of MDR-TB and to evaluate the efficacy of multiple-drug regimens including levofloxacin. PROPHYLAXIS RESULTS The CDC has recommended that HIV+ patients with latent l. tuberculosis infection (as determined by a tuberculin skin test reaction greater than 5mm, or prior history of positive skin test not followed by treatment) receive 12 months of preventive isoniazid therapy (CDC, 1995). Isoniazid prophylaxis may also be indicated for some anergic HIV+ patients at high-risk for TB (such as those from areas with a high incidence of TB). Since HIV+ patients are at risk for peripheral neuropathy, those receiving isoniazid should also receive pyridoxine. A retrospective chart review (Moreno et al.) illustrated both the high risk of re-activation of latent infection and the rapid progression of newly acquired infection in HIV+ people. The study population included 374 HIV+ people in Spain. The risk for active tuberculosis in patients not receiving isoniazid prophylaxis was 10.4 cases/100 person-years in patients with a positive PPD; 12.4 cases/100 person-years in anergic patients, and 5.4/cases/100 person-years in patients with a negative PPD. Further, Markowitz et al. have shown that the prevalence of PPD reactivity decreases and the prevalence of anergy increases as CD4+ counts decline in HIV+ people. The investigators concluded that since responses to delayed-type hypersensitivity tests depend on immune status, such tests should be conducted early in the course of disease. Because of recent nosocomial outbreaks of MDR-TB and the lack of data on effective prophylaxis for contacts to MDR-TB cases, BCG vaccination has been considered. BCG vaccine is used extensively outside the U.S. for the prevention of TB. It is generally given at birth. A recent meta-analysis (Colditz et al.) suggested 89

Page  90 Opportunistic Infections and Related Disorders that the average effectiveness may be about 50% (although the efficacy reported in individual studies ranged from less than 0% to 80% protective efficacy). However, disseminated disease from BCG vaccine has occurred in HIV+ persons, and it is contra-indicated in seropositive adults One study (Halsey et al.) has found that isoniazid prophylaxis decreases the incidence of tuberculosis in HIV+ asymptomatic patients compared to rifampin and pyrazinamide. Seven hundred eight-four HIV+ people in Haiti were randomized to receive a six-month course of isoniazid or a combination of rifampin and pyrazinamide. The risk of TB during the first 10 months after randomization was 3.5% for the rifampin/pyrazinamide group and 0.8% for the isoniazid group (P =.01). No significant differences in the rates of TB were observed 10 months after treatment had stopped. No TB was detected in either group during the first three months after randomization. The optimal duration of prophylaxis has not been determined. An effective prophylaxis regimen for people exposed to MDR-TB has not been established. One report (Horn et al.) described the use of ofloxacin 800 mg/day with pyrazinamide 1500 mg/day in 16 health-care workers exposed to MDR-TB. The health-care workers were not HIV+. 14/16 discontinued prophylaxis before the completion of six months of therapy because of side effects (arthralgia, GI distress, and others). ONGOING PROPHYLAXIS STUDIES: A clinical trial (ACTG 177/CPCRA 004) in 1600 HIV+ patients with confirmed latent tuberculous infection is currently underway. Isoniazid for 12 months is being compared to 2 months of rifampin and pyrazinamide. A second study is comparing isoniazid to rifabutin in patients with a positive PPD test in the absence of active disease. Both studies are closed to enrollment. REFERENCES: Berning SE et al. Malabsorption of antituberculous medications by a patient with AIDS. N ENGL J MED 327:1817-8, 1992. Berenguer J et al. Tuberculous meningitis in patients infected with the human immunodeficiency virus. N ENGL J MED 326:668-72, 1992. Centers for Disease Control. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24, 1995. Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the advisory council for the elimination of tuberculosis. Amer J Resp Crit Care Med 139:1359-1374, 1994. Colditz GA et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 271:698-702, 1994. Daley CI et al. An outbreak of tuberculosis with accelerated progression among persons infected with HIV. N ENGL J MED 326: 231-5, 1992. Di-Perri G et al. Nosocomial epidemic of active tuberculosis among HIV-infected patients. Lancet 2:1502-4, 1989. Edlin BR et al. An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome. N ENGL J MED 326: 1514-21, 1992. Fischl MA et al. An outbreak of tuberculosis caused by multiple-drug resistant tubercle bacilli among patients with HIV infection. Ann Int Med 117: 177-83, 1992. Gordon S et al. Impaired absorption of oral regimen in treatment of disseminated M. avium complex. 32nd ICAAC, abstract #896, 1992. Halsey NA et al. Twice weekly INH for TB prophylaxis. Abstract #PB0681, X Intl Conf AIDS, Yokohama, 1994. Holt E et al. Efficacy of supervised, intermittent, short course therapy of tuberculosis in HIV infection. Abstract WS-B09-4, IX Intl Conf AIDS, 1993. Horn DL et al. Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis (correspondence). N ENGL J MED 330:1241, 1994. Iseman MD. Treatment of multidrug-resistant tuberculosis. N ENGL J MED 329:784-91, 1993. Jacobs WR et al. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 260:819-22, 1993. Jones B et al. Relationship of the manifestations of tuberculosis to CD4+ cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148:1292-7, 1993. Mahmoudi A and Iseman D. Pitfalls in the care of patients with tuberculosis; Common errors and their association with the acquisition of drug resistance. JAMA 270: 65-8, 1993. Markowitz N et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Ann Int Med 119:185-93, 1993. Moreno S et al. Risk for developing tuberculosis among anergic patients infected with HIV. Ann Int Med 119:194-8, 1993. Peloquin CA et al. Malabsorption of antimycobacterial medications. N ENGL J MED 329:1122-3, 1993. Small PM et al. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N ENGL J MED 328:1137-44, 1993. OTHER REPORTS: Banerjee A et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263:227-30, 1994. Barnes PF et al. Tuberculosis in patients with HIV infection. N ENGL J MED 324: 1644-50, 1991. Davidson PT and Le HQ. Drug treatment of tuberculosis - 1992. Drugs 43(5): 651-72, 1992. Driver CR et al. Transmission of Mycobacterium tuberculosis associated with air travel. JAMA 272: 1031-1035, 1994. Goble M et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N ENGL J MED 328: 527-32, 1993. Shafer RW et al. Predictors of survival in HIV-infected tuberculosis patients. AIDS 10:269-272. 90 I

Page  91 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 FUNGAL INFECTIONS ASPERGILLOSIS PATHOGEN: Aspergillus, a fungal genus that includes several ubiquitous disease-causing species. They are frequently found in decaying vegetation and soil. Aspergillosis is relatively common among neutropenic cancer chemotherapy patients and those receiving immunosuppressive therapy for organ transplants. While it is still considered a rare infection in HIV+ patients, it is becomming increasingly common as a late-stage manifestation of AIDS. SITES OF INFECTION: Lungs and sinuses, with possible extrapulmonary dissemination. SYMPTOMS: Cough, chest pain, difficulty breathing, fever, and night sweats, sinus pain and facial swelling. Predisposing factors include neutropenia, long-term steroid use, marijuana use, previous lung disease, and CMV disease. DIAGNOSIS: Aspiration of lung or sinus, broncho-alveolar lavage, microscopy and culture of sputum. TREATMENT RESULTS Intravenous amphotericin B (AMB) remains the standard of care for invasive aspergillosis. Oral itraconazole has also been approved by the FDA for the treatment of mild to moderate aspergillosis. Oral itraconazole has been studied as an alternative to intravenous amphotericin B for the treatment of invasive aspergillosis. The Mycoses Study Group (Denning et al.) treated 76 patients with oral itraconazole. The overall response rate was 39%, however the failure rate was higher in patients with AIDS. Denning et al. reported variable results treating patients with amphotericin B, itraconazole or both. 10/13 patients died a median of three months after the diagnosis of aspergillosis. A multi-center study comparing itraconazole to amphotericin B for invasive aspergillosis in HIV-negative and HIV+ patients (MSG 21) has been closed prematurely due to poor accrual. REFERENCES: Denning D et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N ENGL J MED 324.654-62, 1991. OTHER REPORTS: Geissmann F et al. Aspergillus brain abscesses: Therapeutic effect of G-CSF and liposomal amphotericin B. Abstract #PB0602, X Intl Conf AIDS, Yokohama, 1994. Hawkins D et al. Pulmonary aspergillosis in 4 patients with advanced AIDS. Abstract PO-B09-1363, IX Intl Conf AIDS, Berlin, 1993. Just-Nuebling G et al. Aspergillus infection in AIDS. VI Intl Conf AIDS San Francisco, 1:237 (Th.B.463), 1990. Minamoto et al. Invasive aspergillosis in patients with AIDS. Clin Infect Dis 14: 66-74, 1992. Pursell et al. Aspergillus species colonization and invasive disease in patients with AIDS. Clin Infect Dis 14: 141-148, 1992. Walsh TJ et al. Amphotericin B Lipid Complex in the treatment of 228 cases of invasive mycosis. Abstract #M69, 34th ICAAC, Orlando, 1994 CANDIDIASIS Trials, page 177-178 PATHOGEN: Candida albicans is the most common fungus infecting AIDS patients and accounts for the vast majority of all cases of oropharyngeal candidiasis. Other species such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei may also cause symptomatic oral candidiasis in HIV+ individuals. SITES OF INFECTION: Mucous membranes of the mouth, vagina, esophagus, GI tract, and skin. DIAGNOSIS: By visual examination, culture, or smear. SIGNS AND SYMPTOMS: White elevated plaques of curdled appearance on mucosal epithelium. Dry mouth, altered sense of taste, oral ulcers, and difficulty swallowing. TREATMENT RESULTS OROPHARYNEAL CANDIDIASIS (THRUSH): Fluconazole and clotrimazole are the most commonly prescribed treatments for oral candidiasis. Other approved therapies include ketoconazole and nystatin. Three-hundred-thirty-four patients with oropharyngeal candidiasis were randomized to receive fluconazole 100 mg PO daily or clotrimazole 10 mg PO five times daily for 14 days. Clinical response was statistically equivalent in both groups (98% of fluconazole recipients were cured or improved vs. 94% of clotrimazole recipients). Fluconazole was more effective in eliminating C. albicans 91

Page  92 Opportunistic Infections and Related Disorders from the oral flora (65% vs. 48%) and maintaining an asymptomatic state through two weeks of follow up (82.3% vs. 50%). In a recent report, fluconazole oral suspension was found to be superior to nystatin oral suspension for the treatment of oral candidiasis in HIV+ patients (Pons et al.). 166 patients were randomized to receive fourteen days of therapy with fluconazole 100 mg PO daily or nystatin 5 ml five times daily. 59/68 (87%) patients receiving fluconazole reported a complete clinical response, compared to 33/68 (49%) receiving nystatin (P <0.05). Clinical trials have demonstrated itraconazole oral solution to be an effective alternative to fluconazole and clotrimazole in treating oral candidiasis. Darouiche et al. recently reported results from two clinical trials. The first trial compared itraconazole oral solution (200 mg qd) to clotrimazole (10 mg 5 times daily). The second study compared two doses of itraconazole oral solution (200 mg qd for either 7 or 14 days) to fluconazole (100 mg qd). In the first study, 134 HIV+ patients with oral candidiasis were enrolled; a total of 123 patients were evaluated. At fourteen days of therapy, a clinical response (defined as either complete or partial symptom reduction) was reported in 77% of patients receiving itraconazole oral solution and in 66% of patients receiving clotrimazole (P = NS). Mycological improvements (< 20 CFU/mL mouthwashings) were reported in 66% of patients receiving itraconazole oral solution and 47% of patients receiving clotrimazole (P = 0.04). In study two, 179/190 patients enrolled were evaluable. There were significant differences between the three treatment groups in regards to clinical or mycological responses at day 14. However, the investigators conclude that itraconazole oral solution was at least as effective as fluconazole in treating oral candidiasis. Graybill et al. treated 179 patients with itraconazole oral solution (200 mg/daily for seven days or 200 mg/daily for 14 days) or fluconazole (100 mg/daily for seven days). In the itraconazole groups, clinical cures were reported in 50/60 (83%) patients in the seven-day treatment arm and 57/59 (97%) in the fourteen-day treatment arm. Frechette et al. have reported the results of a randomized study comparing fluconazole (100 mg PO daily) with two doses of oral solution itraconazole (100 mg PO bid for seven days or 100 mg/daily for 14 days) in 244 HIV+ patients. By treatment end, 62/68 (91%) in the itraconazole groups and 71/78 (91%) in the fluconazole group were cured or markedly improved (P <0.05). Single dose fluconazole (150 mg) may be as effective as seven days of fluconazole 50 mg for the treatment of thrush. De Wit et al. randomly treated 51 patients with either regimen and evaluated for clinical and microbiologic efficacy, tolerability and rate of relapse during a 2 week follow-up. Clinical cure was observed at day 7 in 21/24 (85%) patients treated with a single-dose of fluconazole and 26/27 (96%) treated for 7 days (difference not significant). ESOPHAGEAL CANDIDIASIS: Laine et al. conducted a randomized, double-blind study of fluconazole(100 mg PO daily) and ketoconazole(200 mg PO daily) in 169 HIV+ patients with esophageal candidiasis. Treatment continued for two weeks after the resolution of symptoms or for a maximum of eight weeks. Clinical and endoscopic responses showed that 53/55 (96%) fluconazole-treated patients with a clinical cure also had an endoscopic cure compared to 25/44 (57%) ketoconazole-treated subjects. Side effects were minimal and comparable in the two groups. Results from one clinical trial suggest that itraconazole oral solution is an effective alternative to fluconazole in HIV+ patients with esophageal candidiasis. Moskovitz et al. randomized 110 patients with endoscopy-confirmed esophageal candidiasis to receive either itraconazole oral solution (100-200 mg qd) or fluconazole (100-200 mg qd). Treatment continued for 2 weeks beyond resolution of symptoms. In the itraconazole oral solution arm, 48/53 (91%) were clinically cured; 49/57 (86%) were clinically cured in the fluconazole arm. Mycological eradication occured in 45/49 (92%) patients receiving itraconazole oral solution and 40/51 (78%) patients receiving fluconazole. There were no statistically significant differences between the two treatment groups, suggesting that itraconazole oral solution is at least as effective as fluconazole in treating esophageal candidiasis. FLUCONAZOLE-RESISTANT CANDIDIASIS: Although candidiasis is usually amenable to therapy with local or systemic antifungal drugs, failures of fluconazole therapy for mucocutaneous infections due to C. albicans have been reported. Fluconazole-refractory candidiasis occurs in 5%-10% of HIV+ patients with low CD4+ counts who have received chronic treatment with fluconazole. Strains isolated during relapses are probably mutants of previously present, susceptible strains of C. albicans (Millon et al.). A multi-center open study of itraconazole solution (100 mg bid) for the treatment of fluconazole resistant oral candidiasis has been completed. Cartledge et al. reported a response to itraconazole solution in 16/25 patients who previously failed fluconazole. The manufacturer of itraconazole has submitted a Supplemental New Drug Application (1995) for the treatment of fluconazole-resistant oropharyngeal and esophogeal candiadisis. A compassionate use program is currently underway. Newman SL et al. reported eight cases of severe mucosal candidiasis in patients with AIDS (mean CD4+ cells counts of 15/mm3) who were taking fluconazole 400 to 800 92

Page  93 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 mg per day. In both reports, intravenous amphotericin B was effective in treating fluconazole-resistant and azole cross-resistant candidiasis. A phase II dose ranging clinical trial of oral amphotericin B 500 mg qid for 2-4 weeks for fluconazole-resistant oral candidiasis is active, fully enrolled. (ACTG 295). VAGINAL CANDIDIASIS: The most commonly recommended treatments for vaginal candidiasis are over the counter (OTC) antifungal therapies. Treatment with topical clotrimazole or miconazole for seven days has been reported to be effective in HIV+ women (anecodotal reports). For recurrent or persistant vaginal candidiasis, oral doses of fluconazole (200 mg qd) or ketoconazole (400 mg qd) for 14 days is commonly prescribed. PROPHYLAXIS RESULTS ORAL AND ESOPHAGEAL CANDIDIASIS: Powderly et al. have reported the results of a nested study (ACTG 981) in patients previously enrolled in a larger randomized trial of primary prophylaxis for Pneumocystiscarinii pneumonia. ACTG 981 was a prospective, randomized trial comparing fluconazole 200 mg PO daily to clotrimazole troches 10 mg PO five times daily for primary prophylaxis against various invasive fungal infections. A total of 428 HIV+ patients were enrolled for a mean follow-up time of 35 months. The median CD4+ counts were 90 cells/mm3 in the fluconazole group and 114 cells/mm3 in the clotrimazole group. A total of 20 confirmed cases of esophageal candidiasis were reported; 3/217 of those receiving fluconazole and 17/211 of those receiving clotrimazole (P = 0.004). There was no statistical difference in survival between the two groups. Eighty-four subjects were enrolled into a double-blind, placebo-controlled study (Marriott et al.) of fluconazole as secondary prophylaxis for oral candidiasis. After two to four weeks of therapy with fluconazole, the patients were randomized to receive fluconazole 150 mg weekly or placebo. Of the 73 evaluable subjects, the median time to relapse was >168 days for the fluconazole group and 37 days for the placebo group. Just-Nubling et al. conducted a randomized, open-label study of fluconazole as prophylaxis for recurrent oral candidiasis in HIV+ subjects with CD4+ count <100/mm3. Fifty-eight evaluable patients received fluconazole either 50 or 100 mg daily (observation time 137 - 215 days). Compared to untreated controls, fluconazole prophylaxis significantly reduced the frequency of relapse. The two fluconazole doses appeared equally effective. Other studies (Esposito et al., Stevens et al.) have shown that fluconazole (50 - 100 mg daily) appears to be effective in preventing recurrence of oral candidiasis in the short term (3 - 6 months). Grhnewald et al. treated 69 HIV+ individuals with CD4+ <200 cells/mm3 (median = 27 cells/mm3) who had at least two prior episodes of oral or esophageal candidiasis with biweekly oral fluconazole (100 mg). After a median follow-up of 9 months, 14 of 69 subjects had developed candidiasis (7 developed oral, 5 developed esophageal and 2 developed both). Fungal cultures were performed on 30/69 patients. C. albicans was isolated from 7 of the 30 subjects Whether prophylaxis for thrush and esophagitis is appropriate remains to be determined, however chronic fluconazole therapy may predispose to development of resistance and fluconazole-refractory disease. ACTG 323 open later this year to determine if chronic suppressive therapy is superior to observation and treatment of episodes as they occur. VAGINAL CANDIDIASIS: A randomized trial (CPCRA 010) fluconazole with placebo for prophylaxis of mucosal candidiasis in HIV+ women has been reported (Schuman et al.). A total of 323 women with a median CD4+ count of 180 cells/mm3 were randomized to receive fluconazole (200 mg/wk) or placebo. Open-label fluconazole was offered to any patient who reported an incidence of mucosal candidiasis. The time on drug was 16.4 months in patients randomized to receive placebo and 9.9 months in patients randomized to receive placebo (P = 0.0003). 33/162 (20.4%) fluconazole recipients and 44/161 (27.3%) reported a breakthrough of vaginal candidiasis (P = 0.04). Oropharyngeal candidiasis was reported in 42 (25.9%) fluconazole recipients and 68 (42.2%) placebo recipients (P = 0.0005). Breakthroughs of esophageal candidiasis were similar in the two groups (18 vs. 20, respectively, P = 0.74). No significant difference in the number of fluconazole-resistant candida isolates were reported; A total of 32 resistant isolates were reported in patients receiving fluconazole and 24 patients receiving placebo. A study by Fiore et al., conducted by AmFAR's CBCT Network, demonstrated that fluconazole is effective in preventing mucosal candidiasis in HIV+ women. Fifty women with CD4+ counts below 500/mm3 were enrolled in a randomized cross-over study to receive either fluconazole 50 mg three times weekly or no treatment with intensive monitoring for candidal infections. Mucosal candidiasis developed in 48% of women who did not receive treatment and in 16% of the women receiving fluconazole (P <0.04). Multiple recurrences of candidiasis occurred in 35% who did not receive treatment and 6% in the fluconazole group (P <0.04). Results of a study by Hilton et al. in HIV-negative women with recurrent candidal vaginitis suggests that ingestion of yogurt containing Lactobacillus acidophilus cultures decreases both candidal colonization and infection. 93

Page  94 Opportunistic Infections and Related Disorders REFERENCES: Baily G et al. Fluconazole-resistant candidiasis in an HIV cohort. AIDS 8: 787-792, 1994. Cartledge JD et al. Itraconazole cyclodextrin solution-effective treatment for HIV-related candidiasis unresponsive to other azole therapy. J Anitmicrob Chemother 38:1071-1073, 1994. Darouiche RO et al. Itraconazole oral solution for the treatment of oropharyngeal candidiasis: results of two randomized, blinded studies. Abstract Mo.B. 117, XI International Conference on AIDS, Vancouver, 1996. de Repentigny L et al. Itraconazole vs ketoconazole in HIV-positive patients with oropharyngeal and/or esophageal candidiasis. 32nd ICAAC, abstract 1117, 1992. De Wit S et al. Single-dose versus 7 days of fluconazole treatment for oral candidiasis in human immunodeficiency virus-infected patients: a prospective, randomized pilot study. J INFECT DIS 168: 1332-3, 1993. De Wit S et al. Comparison of fluconazole and ketoconazole for oropharyngeal candidiasis in AIDS. Lancet 1(8641): 746-8, 1989. Esposito R et al. Maintenance therapy of oropharyngeal candidiasis in HIV-infected patients with fluconazole. AIDS 4: 1033-1034, 1990. Fiore TC et al. Fluconazole for prophylaxis of candidal infections in women. Abstract PO-B09-1369, IX Intl Conf AIDS, Berlin, 1993. Frechette G et al. Effects of itraconazole in the treatment of oral candidiasis in HIV patients, a double-blind, double-dummy, randomized comparison with fluconazole. 35th ICAAC, Abstract 1219, San Francisco, 1995. Graybill JR et al. Itraconazole oral solution versus fluconazole treatment of oropharyngeal candidiasis. 35th ICAAC, Abstract 1220, San Francisco, 1995. Grinewald TH et al. Prevention of symptomatic candidiasis with biweekly fluconazole in HIV-infected patients. 32nd ICAAC, abstract 1116: 297, 1992. Hilton E et al. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Int Med 116: 353-357, 1992. Just-Nubling et al. Fluconazole prophylaxis of recurrent oral candidiasis in HIV-positive patients. Eur Jour Clin Microbiol Infect Dis 10(11): 917-921, 1991. Laine L et al. Fluconazole compared to ketoconazole for the treatment of candida esophagitis in AIDS. Ann Int Med 117: 655-660, 1992. Marriott D et al. Fluconazole once a week as a secondary prophylaxis against oropharyngeal candidiasis in HIV-infected patients. Med Jrnl Australia 158: 312-316, 1993. Millon L et al. Fluconazole-resistant recurrent oral candidiasis in human immunodefiency virus-positive patients: persistence of Candidia albicans strains with the same genotype. Jrnl of Clin Micro 32(4): 1115-1118, 1994. Moskovitz BL et al. Itraconazole oral solution compared with fluconazole for treatment of esophageal candidiasis. Abstract Mo.B.116, XI International Conference on AIDS, Vancouver, 1996. Newman SL et al. Fluconazole resistant mucosal candidiasis. Clin Infect Dis, in print, 1994. Pons V et al. Comparative clinical study of oral suspension fluconazole versus topical liquid nystatin in the treatment of oropharyngeal candidiasis in AIDS. 35th ICAAC, Abstract 1221A, San Francisco, 1995. Pons V et al. Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, prospective multicenter study of oral fluconazole versus clotrimazole troches. JAIDS 6:1311-6, 1993. Powderly WG et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N ENGL J MED 332:700-5, 1995. Schuman P et al. A randomized trial comparing fluconazole with placebo for prophylaxis of mucosal candidiasis in women with human immunodeficiency birus infection. Abstract Tu.B.411, XI International Conference on AIDS, Vancouver, 1996. Smith DE et al. Itraconazole versus ketoconazole in the treatment of oral and oesophageal candidiasis in patients infected with HIV. AIDS 5: 1367-1371, 1991. Stevens DA et al. Thrush can be prevented in patients with acquired immune deficiency syndrome and acquired immune deficiency syndrome-related complex. Randomized, double-blind, placebo-controlled study of 100 mg oral fluconazole daily. Arch Intern Med 151: 2458-2464, 1991. Vecchiarelli A et al. Beneficial effect of recombinant human granulocyte colony-stimulating factor on fungicidal activity of polymorphonuclear leukocytes from patients with AIDS. Journ Infect Dis 171:448-54, 1995. OTHER REPORTS: Anaissie EJ et al. Correlation between in vitro and in vivo activity of antifungal agents against Candida species. J Infect Dis 170: 384-389, 1994. Bailey GG et al. Fluconazole resistant candidiasis in an HIV cohort. Abstract PO-B09-1375, IX Intl Conf AIDS, Berlin, 1993. Berthold P et al. Candida organisms in dental plaque from AIDS patients. J Infect Dis 170: 1052-1054, 1994. Dismukes W et al. A randomized, double-blind trial of nystatin therapy for the candidiasis hypersensitivity syndrome. N ENGL J MED 323(25): 1718-23, 1990. Horn CA et al. Azole-resistant oropharyngeal and esophageal candidiasis in patients with AIDS. AIDS 9:533-4, 1995. Puccetti P et al. Cure of murine candidiasis by recombinant soluble interleukin-4 receptor. J Infect Dis 169: 1325-1331, 1994. Redding S et al. Resistant of Candida albicans to fluconazole during treatment of oropharyngeal candidiasis in a patient with AIDS: documentation by in vitro susceptibility testing and DNA subtype analysis. Clin Infect Dis 18: 240-242, 1994. Wingard JR et al. Increase in Candida krusei infection among patients receiving bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N ENGL J MED 325 (18): 1274-1277, 1991. Quart A et al. Evaluation of fluconazole in refractory oropharyngeal candidiasis in patients with AIDS. Abstract PuB7456, VIII Intl Conf AIDS, Amsterdam, 1992. 94

Page  95 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 COCCIDIOIDOMYCOSIS Trials, page 179 PATHOGEN: Coccidioides immitis a fungus that resides in the soil and is endemic to the southwestern U.S., Mexico, and Central and South America. Infection is caused by inhalation of airborne, infective arthroconidia, one stage in the organism's life cycle. SITES OF INFECTION: Most commonly the lungs. Advanced disease may involve the kidneys, spleen, lymph nodes, brain, and thyroid gland. SYMPTOMS: Non-specific, including malaise, weight loss, fatigue and cough. Approximately 45% of people with coccidioidomycosis present with reticulo-nodular pulmonary infection, 35% with focal pulmonary disease, 15% with extrapulmonary involvement, and usually CD4+ count <100 cells/mm3. DIAGNOSIS: By examination of sputum or culture of bronchoscopically obtained specimen. Serologic tests for antibodies to C Immitis can be useful for diagnosis. According to recent guidelines published by the Centers for Disease Control (CDC, 1995), routine skin testing with coccidioidin (spherulin) in coccidioidomycosis-endemic areas is not predictive of disease and should not be performed. TREATMENT RESULTS Intravenous amphotericin B (0.5 - Imgkg qd) is the standard treatment for coccidioidomycosis. Oral fluconazole (400 mg qd) is being used frequently to treat C. immitis. Despite treatment, the mortality rate from coccidioidomycosis remains high. Meningitis is the most serious complication of infection with C. Immitis and is nearly always fatal if untreated. Galgiani et al. treated 47 patients with coccidioidal meningitis with fluconazole (400 mg PO qd). Nine of these patients were HIV positive, none of them responded to treatment at this dose. 6/9 received fluconazole 800 mg qd; 4/6 responded. Galgiani et al. treated 71 patients with chronic non-meningeal C. Immitis infection with fluconazole (200 - 400 mg PO daily) and 38 patients with coccidioidal meningitis with fluconazole (400 mg PO daily). 61% of non-meningeal subjects improved clinically by the eighth month of treatment; 1/38 patients with meningeal disease failed to respond and 4 subjects died. No significant toxicities were observed. Itraconazole has been used successfully in non-HIV-infected patients; comparative trials with fluconazole are in progress. PROPHYLAXIS RESULTS A multi-center phase II/III placebo-controlled study of fluconazole (200 mg daily) for the prevention of coccidioidomycosis has been discontinued due to poor accrual. REFERENCES: Galgiani JN et al. Fluconazole therapy for coccidioidomycosis. 30th ICAAC, abstract #574, 1990. Galgiani JN et al. Fluconazole therapy for coccidioidal meningitis. Ann Int Med 119(1): 28-35, 1993. OTHER REPORTS: Bronnimann DA et al. Coccidioidomycosis in the acquired immunodeficiency syndrome. Ann Int Med 106(3): 372-9, 1987. Centers for Disease Control. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24, 1995. Fish DG et al. Coccidioidomycosis during human immunodeficiency virus infection. Medicine 69(6): 384-91, 1990. Galgiani JN et al. Coccidioidomycosis in human immunodeficiency virus-infected patients. J Infect Dis 162(5): 1165-1169, 1990. Hostetler JS et al. Coccidioidal iifections with amphotericin B colloidal dispersion (Amphocil or ABCD). 32nd ICAAC, abstract 628: 215, 1992. CRYPTOCOCCAL MENINGITIS Trials, page 179-180 PATHOGEN: Cryptococcus neoformans, a yeast-like fungus found worldwide, particularly in soil contaminated with bird excrement. SITES OF INFECTION: Most commonly the brain; also the lungs. Advanced disease can involve almost any organ system. SYMPTOMS: Fatigue, fever, headache, nausea, seizure, and neurological changes; of pulmonary infection: lobar or interstitial pneumonitis and pleural effusion; infection may be asymptomatic. DIAGNOSIS: By CSF smear, antigen detection or culture. For patients with cryptococcal meningitis the most significant pre-treatment factor predicting early death is abnormal mental status (coma, lethargy, confusion). Other pre-treatment factors that predict treatment failure in AIDS patients with cryptococcal meningitis include a positive India ink stain, visual abnormalities, age less than 35 years and absence of antiretroviral therapy. 95

Page  96 Opportunistic Infections and Related Disorders TREATMENT RESULTS The preferred treatment for cryptococcal meningitis includes two weeks induction treatment with amphotericin B (0.7mg/kg/d IV) and flucytosine (25 mg/kg qid) followed by fluconazole (200-400 mg PO qd). All three drugs are approved for the treatment of cryptococcal meningitis. This treatment strategy is based on the results of two studies conducted by the Mycoses Study Group. Results from ACTG 159/MSG 017 have been reported by Van Der Horst and Saag et al. The study compared amphotericin B (0.7 mg/kg IV daily for 14 days) with or without flucytosine (5-FC) (25 mg/kg PO qid for 14 days) followed by a comparison of fluconazole to itraconazole as consolidation therapy in 408 patients with first-time cryptococcal meningitis. Van Der Horst et al. reported data in 381/408 eligible patients. After 14 days of induction therapy, 60% of those receiving amphotericin B and flucytosine remained CSF culture positive, compared to 51% in those receiving amphotericin B alone (P <0.05). CSF culture negative responses at 14 days were 23% and 30% of patients, respectively. These data were not statistically significant. There was no significant differences in clinical benefit or death between the two groups. In patients with greater than 250 ml (if associated with symptoms of high pressure) and 350 ml (irrespective of symptoms) of intracranial pressure (ICP), pressure reduction was administered through lumbar puncture drainage (25-30 ccs daily) and concurrent use of acetazolamide. Consolidation therapy preliminary results from the continuation of this clinical trial (ACTG 159/MSG 017) have been reported. Saag et al. reported data in 306/381 patients who completed maintenance therapy with either fluconazole (400 mg/daily) or itraconazole (200 mg bid). At ten weeks, 72% of those in the fluconazole group remained culture negative compared to 60% in the itraconazole group (P = 0.04). However, symptom reduction was similar in the two groups (68% versus 70%). There was no significant difference in death between the two groups. The benefit of concurrent use of flucytosine with amphotericin B for induction therapy was demonstrated in MSG 025, which showed lower relapse in those who received flucytosine. MSG 025 trial results are reported below. Complete responses in patients receiving initial or salvage treatment with high-dose fluconazole (800 mg/day) have been reported (Berry et al. and Haubrich et al.). The combination of fluconazole and flucytosine may be more effective than fluconazole alone (Milefchik et al.). Thirty-six patients with cryptococcal meningitis were randomized to receive fluconazole (800, 1,200 or 1,600 mg/day) alone or in combination with flucytosine (150 mg/kg daily for 4 weeks). Of the patients receiving only fluconazole, 7/24 (29%) survived and became CSF culture negative, compared with 9/12 (75%) receiving the combination. A phase II safety and efficacy trial of fluconazole (800 mg qd) in combination with flucytosine (5FC) (100 mg/kg qd) is currently underway. Twenty-three patients with cryptococcosis were treated with liposomal amphotericin B (Ambisome) in an open-label study (Coker et al.). All patients received 1 mg/kg on the first day, 2 mg/kg on the second day and 3 mg/kg IV every day thereafter until cultures were negative for 2 successive weeks. Of the 23 evaluable subjects, 14/23 had complete and 4/23 had partial responses. Sterilization of CSF was achieved in 12/18 responders, with cultures becoming negative after a median of 11 days. Adverse effects included elevated LFT, creatinine, fever, rigor and chills. Similar results using liposomal amphotericin B in similar study populations have been reported by other investigators (Lazar et al. and Schurmann et al.). Thirty patients with cryptococcal meningitis were randomized to receive either amphotericin B lipid complex (ABLC) or amphotericin B (Sharkey et al.). Patients received total ABLC doses of either 1.2 - 5.0 mg/kg/day IV; or amphotericin B 0.7 - 1.2 mg/kg/day IV. Of the 21 evaluable subjects receiving 12 doses of ABLC at the highest dose studied (5.0 mg/kg/day), 18/21 (86%) improved clinically; 8/21 (42%) reported negative CSF cultures. Less favorable responses were reported in patients receiving lower doses of ABLC. Transfusion requirements, mean decreases in hemoglobin level, and mean increases in creatinine level were significantly greater with amphotericin B than with ABLC. However, no significant differences in efficacy or adverse events were reported between the treatments being compared. ONGOING TREATMENT TRIALS: A phase III randomized trial comparing liposomal amphotericin B and amphotericin B, followed by fluconazole, is currently underway. MAINTENANCE RESULTS Long-term maintenance therapy is required to delay relapse. Fluconazole is superior to amphotericin B and to itraconazole for preventing relapse of cryptococcal meningitis. Saag et al. recently reported the results from a clinical trial comparing fluconazole (200 mg PO daily) to itraconazole (200 mg PO daily) in 107 patients who had been successfully treated for cryptoccocal meningitis (MSG 025). Patients were randomized to receive fluconazole (n = 52) or itraconazole (n = 55) and followed for documented CSF-culture positive relapses. Median follow up time was nine months. Recurrence of cryptococcal meningitis was reported in 2/52 (3.8%) patients receiving fluconazole and 13/55 (23.6%) patients receiving itraconazole 96

Page  97 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 (P = 0.003), prompting premature closure of the study. No deaths were attributed to crytoccocal meningitis in either of the two groups. Powderly et al. randomized 189 patients who had recovered from cryptococcal meningitis to receive fluconazole (200 mg PO qd) or amphotericin B (1 mg/kg qw) for 12 months. After a median follow-up of 286 days, 2/111 (2%) receiving fluconazole and 14/78 (18%) receiving amphotericin B had relapses of symptomatic cryptococcal disease (P <0.001) (14 patients had meningitis, one had lymphadenitis, and one had hepatic disease). The probability of death, relapse, or drug toxicity one year after the start of the study was 39% in the fluconazole group and 56% in the amphotericin B group. The probability of remaining relapse-free at one year was 97% for the fluconazole group and 78% for the amphotericin B group (P <0.001). Toxicity requiring withdrawal of treatment was more frequent in the amphotericin B group. PROPHYLAXIS RESULTS The United States Public Health Service has published guidelines for the prevention of crytococcal meningitis (CDC, 1995). The guidelines state that physicians may wish to consider chemoprophylaxis with fluconazole for adult and adolescent patients with CD4+ counts less than 50 cells/mm3. However, such prophylaxis should not be offered routinely because of the relative infrequency of crytococcal disease, the possibility of drug interactions, the potential development of resistance, and the cost of prophylaxis. Fluconazole is more effective than clotrimazole oral suspension in the prevention of invasive and serious systemic fungal infections (Powderly et al., 1995). 428 patients with CD4+ counts <200 cells/mm3 with no history of systemic fungal infections were randomized to receive fluconazole 200 mg/day or clotrimazole 10 mg five times daily (ACTG 981). After a mean follow-up of 35 months, 11 fluconazole recipients and 38 clotrimazole recipients developed serious fungal infections (including cryptococcosis, histoplasmosis, coccidioidomycosis, and aspergillosis) (P <.0001). Cryptococcal meningitis represented 2/11 infections in fluconazole recipients vs. 15/38 in the clotrimazole recipients (P = 0.0009). No survival benefit to fluconazole was observed: 98 subjects on fluconazole died vs. 89 on clotrimazole (P = 0.26). REFERENCES: BerryAJ et al. Use of high-dose fluconazoleas salvage therapy for cryptococcal meningitis in patients with AIDS. AntimicrobAgnts Chemo 36(3): 690-692,1992. CDC. USPHS/IDSAGuidelinesfor the Prevention of Opportunisticlnfections in Persons Infected with Human ImmunodeficiencyVirus. MMWR 44:1-24, 1995. Coker R et al. treatmentof cryptococcosiswith liposomal amphotericin B (Ambisome)in 23 patients with AIDS. AIDS 7: 829-835,1993. de Gans J et al. Itraconazolecompared with amphotericinB plus flucytosinein AIDS patients with cryptococcal meningitis.AIDS6: 185-190,1992. Graybill JR et al. Amphotericin Blipid complex in treatmentof cryptococcal meningitis in patients with AIDS. 31st ICAAC, abstract289: 147, 1991. Jones BE et al. A phase II trial of fluconazole plus flucytosinefor cryptococcal meningitis. VII Intl ConfAIDS, Florence. Vol 2: 266(W. B.2337), 1991. Haubrich RH et al. High-dose fluconazolefor treatment of cryptoccocaldisease in patients with human immunodeficiencyvirus infection. J Infect Dis 170: 238-242, 1994. Lazar JT et al. Efficacy and safety of AmBisome (LiposomalAmphotericin B) in primary episodes of cryptococcosisin patients with HIV infection. VII Intl Conf AIDS, Florence. Vol 2: 226(W. B.2177), 1991. Milefchik E et al. High dose fluconazolewith and without flucytosinefor AIDS associated cryptococcal meningitis. AbstractWVS-B12-5, IX Intl Conf AIDS, Berlin, 1993. Pettoello-Mantovani M et al. Enhancementof HIV-1 infection by the capsular polysaccharideof Cryptococcus neoformans Lancet 339: 21-23, 1992. PowderlyM et al. A randomized trial comparing fluconazolewith clotrimazoletroches for the prevention of fungal infectionsin patientswith advanced human immunodeficiencyvirus infection. N ENGL J MED 332:700-5, 1995. Powderly M et al. A controlled trial of fluconazole or amphotericin B to prevent relapse cryptococcal meningitis in patients with the acquired immune deficiency syndrome. N ENGL J MED 326(12): 793-798, 1992. Schurmann D et al. Safety and efficacyof liposomal amphotericin B in treating AIDS-associateddisseminated cryptococcosis.J INFECT DIS 164: 620-622,1991. Saag M et al. Comparison of fluconazole versus itraconazoleas maintenance therapy of AIDS-associated cryptococcal meningitis. 35th ICAAC, Abstract 1218, San Francisco, 1995. Saag M et al. Part II: Amphotericin B alone or with Flucytosine(5FC) for the treatmentof AIDS-related acute crytococcal meningitis. 35th ICAAC, Abstract 1216, San Francisco, 1995. Sharkey PK et al. Amphotericin B lipid comples compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 22:315-21, 1996. Van Der Horst et al. Part I: Amphotericin B alone or with Flucytosine (5FC) for the treatment of AIDS-related acute crytococcal meningitis. 35th ICAAC, Abstract 1216, San Francisco, 1995. OTHER REPORTS: Cameron ML et al. Manifestationsof pulmonarycryptococcosisin patients with acquired immune deficiencysyndrome. Rev Inf Dis 13:64-67,1991. Cameron ML et al. Human immunodeficiencyvirus (HIV)-infected human blood monocytes and peritoneal macrophages have reduced anticryptococcalactivity whereas H IV-infected alveolar macrophages retain normal activity. J Infect Dis 170. 60-67, 1994. NightingaleS et al. Primary prophylaxiswith fluconazoleagainst systemic fungal infections in HIV-positive patients. AIDS 6: 191-194,1992. QuagliarelloVJ et al. Primary prevention of crytococcal meningitis by fluconazole in H IV-infected patients. Lancet 345:548-552,1995. Viviani MA et al. Experiencewith itraconazolein cryptococcosisand aspergillosis.J Infect Dis 18(2): 151-65, 1989.H 97

Page  98 Opportunistic Infections and Related Disorders HISTOPLASMOSIS Trial, page 180 PATHOGEN: Histoplasma capsulatum, a fungus endemic to the south-central U.S. and South America, and found in soil contaminated by bird droppings or other organic material. After inhalation, the spores germinate into the yeast form. Patients with compromised immune systems, e.g. AIDS with CD4+ counts < 100 cells/mm3, are particularly susceptible in endemic areas. SITES OF INFECTION: Wide-spread dissemination occurs in most patients, most frequently in the lungs and less frequently in the skin and G.I. system. SYMPTOMS: Fever, weight loss, nodular or ulcerative skin lesions, respiratory complaints, anemia, and enlargement of the liver, spleen, and lymph nodes. DIAGNOSIS: By blood or bone marrow culture, biopsy of involved tissue, or detection of H. capsulatum antigen detection in urine, serum, bronchioalveolar lavage, or CSF. Antigen levels can be followed to monitor therapy and diagnose relapse. Antigen levels are obtained at the Histoplasmosis Reference Laboratory in Indianapolis, Indiana (call 1-800-HISTO-DG). TREATMENT RESULTS Intravenous amphotericin B and oral itraconazole are approved for the treatment of histoplasmosis. Long-term maintenance therapy is required to prevent relapse of disseminated histoplasmosis following initial induction treatment in patients with AIDS. Due to the absorption variability of itraconazole it is recommended that blood levels be monitored 2-4 hours after dosing during the second week of treatment and every 3 months thereafter. Ideally, itraconazole blood levels of 2 pg/ml should be achieved for induction and 1 ig/ml for maintenance. Wheat et al. enrolled 59 patients in a study (ACTG 120) of open-label itraconazole for the treatment and prevention of relapse of acute histoplasmosis. All subjects received 300 mg PO twice daily for 3 days followed by a 12 week course (200 mg twice daily). Fifty of 59 (85%) patients responded to treatment (clearance of fungemia) and were continued on itraconazole maintenance treatment (200 to 400 mg PO daily) for at least one year. Of the nine non-responders, six failed treatment, two experienced toxicity, one was lost to followup. Fluconazole has been reported to be less effective than either amphotericin B or itraconazole for the treatment of histoplasmosis (Wheat, personal communication). In ACTG 174, patients were randomized originally to receive fluconazole 1200 mg qd on the first day of therapy, followed by 600 mg qd for an additional 8 weeks. Interim analysis revealed a high failure rate (in the maintenance phase), prompting the investigators to increase the fluconazole dose to 1600 mg qd on the first day of therapy, followed by 800 mg qd for an additional 12 weeks. At the time of the original study's interim analysis, 16/20 (80%) patients responded to treatment. 36/49 (74%) patients who entered into the revised study responded to induction therapy. Six (12.2%) patients failed with progressive infection, one (2.0%) withdrew for toxicity, and five (10.2%) discontinued therapy before 12 weeks and were classified as non-responders. MAINTENANCE RESULTS Itraconazole is the maintenance treatment most commonly prescribed for histoplasmosis. Forty-two AIDS patients with disseminated histoplasmosis were treated with open-label itraconazole (ACTG 084) for the prevention of relapse of acute histoplasmosis (Wheat et al.). All subjects initially received induction therapy with amphotericin B followed by itraconazole 200 mg PO twice daily. The median duration of follow-up was 109 weeks (range, 4 to 134 weeks), and the median survival time was 98 weeks (range, 4 to 134 weeks). 39/42 patients responded to treatment (no clinical relapses) at the 200 mg/day dose. One patient withdrew from the study due to toxicity (hypokalemia). Histoplasma blood and urine antigen levels decreased in all patients except one. Results from the maintenance phase of ACTG 120 are available (Wheat, personal communication). A total of 46 patients who were succesfully treated in the induction phase of this study continued on fluconazole 200 mg/day as maintenance therapy for at least one year. 2/46 patients reported a relapse of histoplasmosis during a mean follow-up period of 87 weeks. Both patients reporting relapses were non-compliant with the protocol dosing schedule. The investigators conclude that 200 mg/day maintenance therapy is equally as effective as fluconazole 200 mg bid (as determined in ACTG 084) in preventing recurrence of histoplasmosis. Norris et al. found fluconazole 100-400 mg to be moderately effective and a reasonable choice in patients who were given induction therapy with amphotericin B and who could not take itraconazole because of drug interactions, malabsorption or side effects. Results from the maintenance therapy phase of ACTG 174 (described above) are consistent with moderate efficacy of fluconazole as maintenance therapy for HIV+ patients with histoplasmosis. The original maintenance phase of ACTG 174 was to study fluconazole 200 mg qd for at least one year in patients who responded to induction therapy. However, at the time of the interim analysis, 6/14 responders in the induction phase relapsed during maintenance therapy. Of 36 patients who 98

Page  99 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 entered the maintenance phase of the revised study, in which patients received fluconazole 400 mg qd, 15/36 (42%) responded and 11/36 (31%) failed with relapse of histoplasmosis or death (one patient). McKinsey et al. concluded that long-term, twice weekly maintenance therapy with amphotericin B (50 mg IV every two weeks) was well tolerated and effective in preventing relapse of histoplasmosis in HIV+ subjects. PROPHYLAXIS RESULTS A double-blind randomized study (MSG 28) comparing itraconazole (200 mg daily) with placebo for the prophylaxis of histoplasmosis in HIV positive people with CD4+ counts below 150/mm3 found itraconazole to reduce the incidence of histoplasmosis and cryptococcal meningitis (McKinsey et al.) REFERENCES: Hecht F et al. Itraconazole maintenance treatment for histoplasmosis in AIDS: prospective multi-center trial. 35th ICAAC, Abstract #1200, San Francisco, 1995. McKinsey DS et al. Histoplasmosis in patients with AIDS: efficacy of maintenance amphotericin B therapy. Amer Jrnl Med 92: 225-227, 1992. McKinsey DS et al. Histoplasmosis in AIDS: Incidence and risk factors. Abstract #PB0604, Intl Conf AIDS, Yokohama, 1994. Norris et al. Prevention of relapse of histoplasmosis with fluconazole in patients with the acquired immunodeficiency syndrome. Amer Jrnl Med 96: June, 1994. Wheat et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Amer Jrnl Med 98:55-9, 1995. Wheat et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. Ann Int Med 118(8): 610-6, 1993. OTHER REPORTS: Smith D et al. The pharmacokinetics of oral itraconazole in AIDS patients. VII Intl Conf AIDS, Florence. Vol 2: 225(W.B.2174), 1991. MALIGNANCIES KAPOSI'S SARCOMA Trials, page 181-186 PATHOGENESIS: Kaposi's sarcoma (KS) remains the most commonly diagnosed malignancy in HIV+ people. Although the incidence of KS as an AIDS-defining illness among gay and bisexual men has declined, an increasing proportion of AIDS deaths are now due to KS. Most often initially involving the skin, KS lesions usually present as red to purple nodules or plaques, that can appear in several parts of the body simultaneously, sometimes with associated edema. The etiology of KS remains unknown, but evidence suggests that a viral pathogen may be involved. In several published studies, herpesvirus-like DNA sequences, dubbed human herpesvirus 8 (HHV-8 or KSHV, have been identified in KS lesions from patients. In the first study, Chang et al., used representational difference analysis, which compares repeated PCR amplifications of short DNA fragments of diseased and nondiseased tissue. Herpesvirus-like DNA sequences were identified in from 90% of KS tissues. These sequences were not present in tissue DNA from HIV-negative patients, but were present in 15% of DNA samples from non-KS tissue of HIV+ patients. In another study (Moore et al.) herpesvirus-like DNA sequences were identified in 10 of 11 tissue samples from HIV+ patients with KS, in all 6 samples from patients with classic KS, and in all 4 samples from HIV-negative men with KS. There is increasing evidence that circulating growth factors play a key role in the pathogenesis of HIV-related KS. A number of cytokines and viral products produced by retrovirus-infected cells (or by the KS cells themselves) are potent growth factors for KS cells in vitro. These include the HIV-1 Tat protein, basic fibroblast growth factor (bFGF), the cytokines IL-I, TNF, and IL-6, and others. Some evidence suggests that KS may not in fact be a true malignancy, but rather an angiogenic disorder (a disorder in the formation of blood vessels) with widespread cellular proliferation occurring in response to circulating growth factors. Trials are underway of TNP-470 which inhibits angiogenesis in vitro and trials of other angiogenesis inhibitors are planned. 99 I

Page  100 Opportunistic Infections and Related Disorders SITES OF DISEASE: KS most commonly involves the skin, although involvement of the lymph nodes, the oral cavity, and gastrointestinal tract are often seen at presentation. Lesions are found in the GI tract in 40% of cases at diagnosis, up to 80% at autopsy, and are frequently asymptomatic. Pulmonary involvement, often occurring late in the disease, may cause severe respiratory symptoms and is associated with a poor prognosis. DIAGNOSIS: Biopsy confirmation establishes histological diagnosis. Suspected pulmonary lesions may be detected by bronchoscopy, but are generally not biopsied due to low yield and risk of hemorrhage. Chest x-rays and pulmonary gallium scans can also be used for evaluation. The concurrent presence of pulmonary infiltrates and nodular densities on chest x-ray, the lack of uptake of gallium in the pulmonary parenchyma and the presence of blood streaked sputum is virtually diagnostic for pulmonary KS when infectious causes have been ruled out. KS involving the gastrointestinal tract is best diagnosed visually on endoscopy (biopsies are frequently negative because the lesions are sub-mucosal). PROGNOSIS: There is no curative therapy; the natural course of the disease may be quite variable and many therapeutic approaches have side effects (e.g., myelosuppression). Thus, many factors must be considered in developing a treatment strategy: the extent and location of lesions, the presence of tumor-associated symptoms (e.g. pain, edema, GI bleeding), symptoms of HIV infection, and the status of the patient's immune system. Generally, KS patients with CD4+ cells >200/mm3, with no previous opportunistic infections, and few constitutional symptoms have a better prognosis. The primary indication for treatment may be cosmetic or emotional. Minimally myelosuppressive treatment may be more appropriate for patients receiving other myelosuppressive agents (e.g., ganciclovir) for an opportunistic infection, and although more aggressive chemotherapy might be more effective in controlling the tumors, it must be balanced against the need for other treatments with similar myelosuppressive toxicity. For rapidly progressive and/or disseminated mucocutaneous disease, or when tumor compromises the function of vital organs, systemic chemotherapy may effect rapid tumor regression and may be life saving. Among the drugs reported to be effective as single agents or, in some cases, as part of a combination regimen, are liposomal doxorubicin, liposomal daunorubicin, bleomycin, doxorubicin, etoposide, vinblastine and vincristine. Hemopoietic growth factors such as G-CSF and GM-CSF should be administered, when indicated, to control bone marrow toxicity (neutropenia) while maintaining therapy. TREATMENT RESULTS SYSTEMIC TREATMENT: Liposomal daunorubicin (DaunoXome) has been approved by the Food and Drug Administration as first line therapy in people with advanced HIV-associated Kaposi's sarcoma. Ross et al. have reported the results of a clinical trial comparing every two week administration of liposomal daunorubicin (40 mg/m2) versus adriamycin (10 mg/m2), bleomycin (15 mg) and vincristine (1 mg) for the treatment of KS. A total of 227 patients with greater than or equal to 25 mucocutaneous lesions or symptomatic visceral involvement were treated with Daunoxome (n = 116) or ABV (n = 111). Complete responses were reported in 3/116 (2.6%) patients receiving liposomal daunorubicin and 1/111 (0.9%) patients receiving ABV. Partial responses reported were 26/116 (22.4%) in the liposomal daunorubicin group and 30/111 (27.0%) in the ABV group. Stable disease rates were 72/116 (62.1%) and 64/111 (57.6%), respectively. Adverse events (fatigue, neuropathy, and hair loss) were significantly less frequent in the liposomal daunorubicin group, but there were no significant differences in response rates, survival, or neutropenia. Under the Food and Drug Administration's (FDA) accelerated approval mechanism, liposomal doxorubicin (DOXIL) has been approved for the treatment of KS in patients who have failed conventional treatment. Several phase II clinical trials have been performed to study the efficacy and safety of liposomal doxorubicin. In one trial (Stewart et al) of 247 patients with moderate to severe KS, response data after six cycles of liposomal doxorubicin therapy were available in 133 patients. Of these, 3 (2.3%) achieved a complete response, and 81 (60.9%) had a partial response. 38 (28.6%) had stable disease after six cycles of liposomal doxorubicin therapy, and 11 patients (8.3%) had progression in their KS. The manufacturer has submitted an application for full approval of DOXIL as first line therapy for HIV+ patients with KS. The application is based on data from two randomized controlled trials of liposomal doxorubicin in patients with progressive mucocutaneous and/or visceral KS; results from one trial have been presented and results from the second trial are still being evaluated. Results from a phase III randomized clinical trial comparing liposomal doxorubicin 20 mg/m2 to adriamycin 20 mg/m2, bleomycin 10 mg/m2, and vincristine 1 mg (ABV) in patients with extensive, progressive mucocutaneous and/or visceral KS were recently reported (Northfelt et al.). Patients were treated every two weeks for up to 6 cycles. The median CD4+ count at entry was 13.5 cells/mm3 in the liposomal doxorubicin group and 14.0 cells/mm3 in the ABV group. 51/118 (43.2%) randomized to receive liposomal doxorubicin achieved 100

Page  101 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 07 partial response versus 27/110 (24.5%) in the ABV group (P = 0.005). The median duration of partial response was 107 day and 92 days, respectively. Fewer toxicties (fever, nausea, neuropathy, hair loss and leukopenia) were reported in the liposomal doxorubicin group. Stewart et al. recently reported results form a randomized clinical trial comparing liposomal doxorubicin 20 mg/m2 to the combination of bleomycin 15 mg/m2 and vincristine 2 mg (BV) for the first-line treatment of KS. Conducted in Europe and in some United States clinical trial sites, this study enrolled 241 patients with 102 evaluable patients in the BV group and 116 evaluable in the liposomal doxorubicin group. Concomitant G-CSF was not permitted. Complete responses were reported by 7/116 (5.8%) in the liposomal doxorubicin group and by 1/102 (0.8%) in the BV group (P < 0.001). Partial responses were reported by 64/116 (52.9%) in the liposomal doxorubicin group and by 27/102 (22.5%) in the BV group (P < 0.001). Drug-induced bone marrow suppression (ANC < 1,500) was more common in liposmal doxorubicin-treated patients; 76.1% versus 52.5% in the BV group. Parasthesias were more common in patients receiving BV. These data were statistically significant. An open-label randomized safety and efficacy trial (ACTG 286) comparing liposomal doxorubicin monotherapy to liposomal doxorubicin in combination with bleomycin and vincristine as first-line chemotherapy for KS has recently completed enrollment. This trial is trying to determine if lipisomal doxorubicin will be more effective as part of a combination regimen. An interim analysis has shown higher toxicity for liposomal doxorubicin in combination with bleomycin and vincristine without clear evidence of superior therapeutic effects over liposomal doxorubicin (Krown, personal communication). Recombinant human alpha interferon has been approved for the treatment of KS in a subset of AIDS patients with CD4+ cell count greater than 200/mm3. Tumor regression is generally seen after 2 to 3 months of treatment in patients who lack systemic "B" symptoms (fever, weight loss, night sweats), have no history of prior opportunistic infections and have a CD4+ cell count > 200/mm3 at the start of treatment. Major side effects observed in approximately 80% of patients include flu-like syndrome (requiring dose reduction in 25% of subjects) and neutropenia. Although recombinant human alpha interferon was approved for use at high doses as monotherapy, the results of more recent studies suggest that it may be effective at much lower doses when combined with nucleoside analogues. In one of these studies, Beaulieu et al. randomized 118 patients to receive either a moderate dose of interferon (8 MU SC/day) or a low dose of interferon (1 MU SC/day) added to AZT (500 mg/day). While the overall response rate was higher in the moderate group (P =.07), only 10 patients completed 4 months of interferon (8 MU/day) without requiring dose reduction. Responses were also seen in the low dose interferon group when used in combination with AZT. Alpha Interferon is currently being studied in combination with ddl (ACTG 206). Patients are randomized to receive ddl with low dose (1 MU) or moderate dose (10 MU) alpha interferon. Krown and co-workers report that significant responses have been seen in some patients receiving low dose (1 MU SC/day) interferon in combination with ddl (200 mg/day bid), as well as those receiving moderate dose interferon. A study of paclitaxel (Taxol) was recently completed by Yarchoan et al. Twenty-nine patients with advanced KS were treated with paclitaxel 135 mg/m' IV every 21 days with escalation as tolerated to a maximum dose of 175 mg/m2. Fourteen patients (41%) had received prior chemotherapy. The objective response rate in 28 evaluable patients was 71%; 1 complete response and 19 partial responses. Five of 6 patients with pulmonary KS had a partial response of their lung disease. Median progression-free survival among responders was greater than 8 months. Paclitaxel was well tolerated, with neutropenia being dose-limiting. A trial (ACTG 269) is currently underway to evaluate low-dose oral etoposide for the treatment of relapsed or progressed KS after systemic chemotherapy. TOPICAL/INTRALESIONAL: Lesions of the face or other exposed parts of the body may be treated with local therapy. Preliminary analysis of a dose finding study has shown that intralesional recombinant platelet factor-4 (rPF4) administration led to an antitumor response in KS treatment (Staddon et al.). Results of the trial were based on data from seven patients with KS. When rPF4 was administered via intralesional injection, there were 2 complete responses, 2 partial responses, 2 with stable disease and 1 with progressive disease. No complete responses and only one partial response was reported in the non-injected, proximal and distant control lesions. Results from two clinical trials of human chorionic gonadotropin (hCG) have been published (Gill et al.). After in vitro evaluation of four commercially available hCG preparations, the most active product was evaluated in 12 patients with AIDS-related KS. Twenty-four patients received intralesional injections of hCG three times a week for two weeks at doses of 250, 500, 1000, or 2000 IU (6 patients each). In each patient three nodular lesions were injected, two with the drug and one with diluent alone (placebo). Treatment was tolerated at all doses. In the cohorts given 250, 500, 1000, and 2000 IU, 1,5, 5, and 10 of the 12 injected lesions responded, respectively (P = 0.03). Complete tumor regression was observed in one lesion each at 250 IU and 500 IU dose levels, in two lesions given the 1000 IU doses, and in five lesions given the 2000 IU dose. 101

Page  102 Opportunistic Infections and Related Disorders Results from a placebo-controlled study of hCG has also been reported (Gill et al.). In the double-blind study, none of the 12 lesions in the six paitents injected with diluent had responses, as compared with 10 of 12 lesions in the six patients injected with hCG (P = 0.015). Evidence of apoptosis was observed only in hCG-treated lesions. Other localized treatments under investigation for cutaneous KS include cryotherapy (topical liquid nitrogen), photodynamic therapy in combination with polyporphyrin, and 9-cis-retinoic acid. Radiation therapy (RT) can be used for intraoral or pharyngeal KS; localized, cosmetically problematic KS (e.g., the nose or ears); painful or bulky localized cutaneous KS; and lymphedema of the face and extremities. Radiation therapy can be an effective method of reducing facial edema and treating lymphedema due to KS. Substantial regression in oral KS has been reported; however side effects such as mucositis (mucous membrane inflammation) are common, can be severe, and may be life-threatening. Late effects of radiation therapy may include fibrosis with skin ulceration. Lesions may recur within radiated areas. REFERENCES: Boent P et al. Local peri-lesional therapy with rGM-CSF for Kaposi's sarcoma. Lancet 341: 1154,1993. Bonhomme L et al. Topical treatment of epidemic Kaposi's sarcoma with all-trans-retinoic acid. Ann Oncol 2: 234-235, 1991. Bonhomme L et al. Systemic treatment of AIDS-associated Kaposi's sarcoma (KS) with all-trans-retinoic acid (ATRA). Abstract PO-B12-1562, IX Intl Conf AIDS, Berlin, 1993. Chak L et al. Radiation therapy for acquired immunodeficiency syndrome-related Kaposi's sarcoma. J Clin Oncol 6: 863-7, 1988. Chang Y et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266:1865-9, 1994. Dennis et al. A phase II study of oral etoposide (VP-16) in AIDS-related Kaposi's Sarcoma. PB #0118, X Intl Conf AIDS, Yokohama, 1994. Ensoli B et al. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's Sarcoma. Nature 271:674-680, 1994. Gill PS et al. The effects of preparations of human chorionic gonadotropin on AIDS-related Kaposi's sarcoma. N ENGL J MED 335:1261-9, 1996. Krown SE et al. Interferon-alpha, zidovudine, and granulocyte-macrophage colony-stimulating factor: a phase I AIDS Clinical Trials Group study in patients with Kaposi's sarcoma associated with AIDS. J Clin Oncol 10: 1344-51, 1992. Huang L et al. Presentation of pulmonary Kaposi's Sarcoma. Abstract #PB0110, X Intl Conf AIDS, Yokohama, 1994. Milliken ST et al. A phase II study of stealth liposomal doxorubicin HCL (S-DXR) in HIV- associated Kaposi's sarcoma (KS). Abstract PO-B12-1570, IX Intl Conf AIDS, Berlin, 1993. Moore PS and Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N ENGL J MED 332:1181-5, 1995. Nair BC et al. Identification of a major growth factor for AIDS-Kaposi's sarcoma cells as Oncostatin M. Science 255: 1430-2, 1992. Northfelt DW et al. Randomized comparative trial of Doxil vs. adriamycin, bleomycin, and vincristine (ABV) in the treatment of severe AIDS-related Kaposi's sarcoma. American Society of Hematology, 1995. Ross M et al. Personal testimony to the Food and Drug Administration's Oncology Drug Advisory Committee. June 8, 1995. Simpson JK et al. Liposomal doxorubicin: initial experience in a major London centre. Abstract PO-B12-1603, IX Intl Conf AIDS, Berlin, 1993. Staddon et al. A randomized dose finding study of recombinant platelet factor 4 (rPF4) in cutaneous AIDS-related Kaposi's Sarcoma (KS). Proc Am Soc Clin Onco 13:50, 1994. Stewart S et al. Efficacy and safety of stealth liposomal doxorubicin (DOX-SL) in AIDS-related Kaposi's Sarcoma. Abtsract #PB0123, X Intl Conf AIDS, Yokohama, 1994. Stewart S et al. Randomized comparative trial of Doxil versus bleomycin and vincristine in the treatment of AIDS-related KS. Abstract LB.B.6026, XI International Conference on AIDS, Vancouver, 1996. Von Roenn J et al. All-trans retinoic acid (TRA) in the treatment of AIDS-associated Kaposi's sarcoma. Abstract PO-B12-1571, IX Intl Conf AIDS, Berlin, 1993. Yarchoan R et al. Activity of paclitaxel for the treatment of HIV-associated Kaposi's sarcoma. 1995 Meeting of the Laboratory of Tumor Cell Biology. Abstract #52, Bethesda, 1995. OTHER REPORTS: Huang YQ et al. HPV-16-related DNA sequences in Kaposi's sarcoma. Lancet 339: 515-518, 1992. 102

Page  103 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 LYMPHOMA Trials, page 187-190 DESCRIPTION: Lymphomas are malignancies characterized by abnormal, uncontrolled growth of lymphocytes, a type of white blood cell vital to proper immmune function. As people with AIDS are surviving longer, more and more cases of AIDS-related lymphoma are being diagnosed. Unlike other AIDS-associated neoplasms like Kaposi's sarcoma, which appears predominantly in homosexual men, lymphomas develop in every population group at risk for AIDS. Within this group three types of lymphomas are generally observed. These include systemic NHL (intermediate or high-grade non-Hodgkin's lymphoma), primary CNS lymphomas (high-grade NHL lymphomas confined to the central nervous system) and Hodgkin's disease. Usually, patients present with advanced stage disease and rapid progression. Extra nodal involvement is frequently seen. Large cell histology, higher CD4+ counts upon diagnosis, lack of extranodal disease, good performance status and an absence of opportunistic infections are associated with better prognosis after treatment. SYSTEMIC NON-HODGKIN'S LYMPHOMA (NHL) PATHOGENESIS: AIDS NHL is primarily of B-cell origin and occurs in 5% to 10% of individuals with HIV infection. AIDS NHL is much more likely to be of high-grade histology and more widely disseminated at presentation than NIHL in the general (non-HIV+) population. Several mechanisms are likely to be involved in the etiology of AIDS NHL though the cause still remains unknown. NHL is frequently associated with Epstein-Barr virus (EBV), a herpesvirus that infects B lymphocytes and stimulates their proliferation. EBV genomes can be detected in about 50% of AIDS related lymphomas. Some cytokines such as interleukin 6 (IL-6), IL-10 and tumor necrosis factor (TNF), which enhance HIV replication and are elevated during HIV infection, are known to influence B-cell differentiation and may also be factors in the development of NHL. Cesarman et al. recently identified herpesvirus-like DNA (HHV8) in tissue samples from eight HIV+ patients with an unusual form of NHL, so-called body-cavity-based B-cell lymphomas. The herpesvirus-like DNA was identical to that recently found in KS lesions; however they were 40 to 80 times more abundant in B-cell lymphomas. Shiramizu B et al. have identified 4 unusual cases of non-B cell NHL in which HIV was inserted near a known oncogene indicating a potential pathway for this rare type of HIV-induced lymphoma. SITES OF DISEASE: Common extranodal sites of AIDS NHL include the central nervous system, bone marrow, gastrointestinal tract, meninges, and liver. Less common sites include the mouth, rectum, heart and pericardium, and common bile duct. SYMPTOMS: NHL should be considered in patients presenting with a mass lesion at any site. Symptoms include enlarged spleen, hepatic obstruction, rectal pain, cardiac arrhythmia, unexplained gastrointestinal symptoms or GI bleeding. Constitutional symptoms include elevated fever, unexplained weight loss, and night sweats. DIAGNOSIS: Diagnosis of NHL is made by biopsy or examination of bone marrow, spinal fluid or other body fluids. X-rays, whole-body gallium scanning, computerized tomography (CAT) scans, magnetic resonance imaging (MRI) and bone marrow biopsies are used to stage NHL Lymph node biopsy is often performed in patients with asymmetrical lymphadenopathy and rapidly enlarging or bulky nodes. Elevated uric acid and lactate dehydrogenase may indicate the need for further evaluation. TREATMENT RESULTS Initial treatment of AIDS NHL generally involves cytotoxic chemotherapy. Combinations include mBACOD, COMP, CHOP, NHL-7 and PRO-MACE/MOPP, and an oral combination regimen. For individuals with poor immune function, evidence indicates that less aggressive regimens in combination with antiretroviral therapy may improve survival. The addition of growth factors such as G-CSF and GM-CSF may facilitate the administration of chemotherapy by reducing blood cell toxicity. Sparano et al. have reported success using a combination of cyclophosphamide, doxorubicin, and etoposide (CDE) for the treatment of NHL. CDE was administered at a continuous rate over 96 hours every 28 days to 21 patients. Nineteen patients (90%) had extranodal disease and the mean CD4+ count of all patients was 87 cells/mm3. Patients were followed for a median of 21 months. 13 (62%) achieved a complete response and 5 (24%) achieved a partial response. Grade IV neutropenia was reported in 38% of the cycles; fevers were associated with 21% of the cycles. The median survival was 18 months. 103

Page  104 Opportunistic Infections and Related Disorders II~ The Eastern Cooperative Oncology Group of the National Cancer Institute is conducting a phase II trial ofCDE in HIV+ patients with NHL. Investigational treatment approaches that are generally being tried in patients who are not responding to chemotherapy include monoclonal antibodies, clones of a single immune cell which can either destroy cancer cells themselves or carry toxins directly to the target site. Trials involving OKB-7, a monoclonal antibody attached to radioactive iodine, immunotoxin therapy, anti-CDI9, anti-CD22, and anti-B4 attached to a potent immunotoxin, ricin, are underway. Cytokines such as interleukin 2 (IL-2) and IL-4, which inhibit tumor growth in vitro are currently under evaluation in several clinical trials. Clinical trials are also underway for refractory AIDS-associated NHL using MGBG (methylglyoxal(bis)guanylhydrazone). The activity of this compound is believed to result from the inhibition of polyamine synthesis. Results from a trial in 31 patients with relapsed or refractory NHL have been reported (Levine et al.). Of 25 evaluable patients, 2 complete responses were reported; 5 partial responses were reported and one patient had stable disease at 10 months of treatment. Clinical benefit was observed in terms of weight gain (43% of patients) and improved performance status (33% of patients). A clinical trial of topotecan, a topoisomerase 1 inhibitor, is currently underway. Topotecan has been reported to be an effective anti-tumor treatment in a number of non-AIDS related neoplastic diseases. Intrathecal prophylaxis against meningeal lymphoma with ara-C (cytosine arabinoside) or methotrexate is used in patients with systemic NHL to prevent relapse of disease within the meninges. It is also used as treatment when the lymphoma cells are present in the spinal fluid (lymphomatous meningitis). -------- --- - - - - -- - - - - - - - - - -........ ------------------ - - - - - - - - - -I~~ Ll PRIMARY CNS LYMPHOMA PATHOGENESIS: Primary CNS lymphoma often occurs as a late complication of AIDS. Untreated, the survival rate of patients with AIDS-related primary CNS lymphoma is less than 2 months. With high doses of radiation, response rates have improved modestly (Baumgartner et al.), with reported median survival times of 2 to 5 months. Patients usually die from opportunistic infections. EBV sequences are consistently found in primary CNS lymphomas. This suggests that EBV might have a role as a marker in its diagnosis. SYMPTOMS: So et al. report focal neurologic signs such as hemiparesis (partial paralysis affecting one side of the body) or aphasia (loss of ability to speak or understand language) in 35%, seizures in 15%, and cranial nerve palsies in 10% of people with CNS lymphoma. Confusion, memory loss, and lethargy were reported in 60%. Gill et al. report changes in personality, apathy and confusion. Sometimes the only manifestation is a headache. Cranial nerve palsies, other than facial nerve paralysis, should be regarded as lymphomatous in origin until proven otherwise. Symptoms are not unlike those of toxoplasmic encephalitis adding further complications in making a confirmed diagnosis. DIAGNOSIS: Definitive diagnosis is usually only possible by brain biopsy. Biopsies are often not performed, however, for a variety of reasons including the overall status of the patient and the reluctance of some neurosurgeons to perform the procedure. Primarily, magnetic resonance imaging (MRI) and computed axial tomography (CAT) scans are used to make a presumptive diagnosis. Lumbar punctures with cytologic examination of the spinal fluid may permit a diagnosis in some cases. CNS lymphoma may present as single or multiple lesions which are sometimes indistinguishable from toxoplasmic encephalitis. If a biopsy cannot be performed and the patient has negative serology tests for toxoplasmosis, therapy for CNS lymphoma should be considered. Patients unresponsive to radiation should be further evaluated. Patients with positive toxoplasma serology who do not respond to a brief course of treatment (1-2 weeks) for toxoplamosis should be formally evaluated for CNS lymphoma. TREATMENT RESULTS Large dose whole-brain radiation is the standard method of treatment in patients with AIDS-related primary CNS lymphoma. Corticosteroids such as dexamethasone may be introduced to the treatment plan producing further shrinkage of edema and tumor. Although radiation often results in complete remission (20-50%), relapse is likely and the overall prognosis is poor. The aim of radiotherapy may not be towards greater survival time but rather an improvement in the quality of life. The role of chemotherapy (both systemic and intrathecal) prior to and following whole-brain radiation therapy is under investigation; this approach has produced improved results in patients with primary CNS lymphoma unrelated to HIV infection. 104

Page  105 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 A clinical trial combining CHOD, G-CSF, radiotherapy, and cytarabine (ACTG 252) is currently underway for the treatment of CNS lymphoma. A second trial combining etoposide and cisplatin is also enrolling. HODGKIN'S DISEASE PATHOGENESIS: Hodgkin's disease arises in the lymph nodes and usually spreads stepwise from one group of nodes to contiguous groups. Hessol et al. have observed an excess number of cases of Hodgkin's disease in a cohort of HIV+ homosexual men, and suggest that it may be an HIV-related malignancy. Others, however, have not confirmed an excess number of cases. The clinical behavior of Hodgkin's disease in AIDS patients is rather unpredictable and presentation usually involves late clinical stages (III and IV) with mixed cellularity as the predominant histological type. The etiology of Hodgkin's disease remains unknown. Case clustering (multiple cases in a single household) may suggest a viral origin. EBV has also been implicated. SYMPTOMS: Most non-HIV+ patients present with cervical or mediastinal adenopathy. In HIV, presentations are often atypical; possible systemic symptoms include itching, high fever, night sweats and weight loss. Bone involvement may produce pain in the diseased area. DIAGNOSIS: The diagnosis of Hodgkin's disease rests on the identification of Reed-Sternberg cells or morphological variants through lymph node biopsy. Because of bone marrow involvement in Hodgkin's disease, bone marrow biopsies are commonly recommended. TREATMENT RESULTS Disease staging is the principal factor in selecting appropriate treatment. For advanced stage disease (III and IV) combination chemotherapy is the choice treatment. MOPP and ABVD are both effective four-drug regimens. MOPP alternating with ABVD has shown similar benefit. Oral combination drug programs are also being evaluated. As in AIDS-associated NHL, the complete response rate to chemotherapy in AIDS-associated Hodgkin's disease is much lower than in Hodgkin's disease in non-HIV+ individuals. The addition of colony-stimulating factors may reduce the rate of primary failure and risk of long term complications. Early stage (I and II) Hodgkin's disease is most frequently treated with radiation therapy. A combination of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with G-CSF is currently being studied by the AIDS Clinical Trials Group (ACTG 149) for the treatment of AIDS-related Hodgkin's disease. REFERENCES: Baumgartner J et al. Primary central nervous system lymphomas: Natural history and response to radiation therapy in 55 patents with acquired immunodeficiency syndrome. J Neurosurg 73:206-211, 1990. Cesarman E et al. Kaposi's sarcomal-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N ENGL J MED 332:1 181-5, 1995. Gill PS et al. HIV-related malignant lymphoma: clinical aspects, treatment, and pathogenesis. Canc Invest 6: 413-6, 1988. Hessol NA et al. Increased incidence of Hodgkin disease in homosexual men with HIV infection. Ann Int Med 117:309-11, 1992. Hernier BG at al. Pathogenesis of AIDS lymphomas. AIDS 8: 1025-1049, 1994. MacMahon EME et al. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969-73, 1991. Schiramizu B et al. Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas. Cancer Res 54:2069-72, 1994. So Y et al. Primary central nervous system lymphoma in AIDS: a clinical and pathological study. Ann Neurol 20: 566-72, 1986. OTHER REPORTS: Canellos GP et al. Chemotherapy of advanced Ilodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N ENGL J MED 327: 1478-84, 1992. Galleto G and Levine A. AIDS-associated primary central nervous system lymphoma (commentary). JAMA 269:92-3, 1993. Levine A et al. Multicenter phase II study of mitoguazone (MGBG) in relapsed or refractory AIDS-lymphoma. Proc Am Soc Clin Oncol, 1995. Levine A. Lymphoma in acquired immunodeficiency syndrome. Sern in Oncol 17(1): 104-112, 1990. Levine A et al. Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma. JAMA 266: 84-8, 1991. Marco M. The lymphoma project report: current issues in research and treatment of AIDS-associated lymphoma. Treatment Action Group, 1995. Remick SC et al. Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin's lymphoma. J Clin One 11: 1691-1701, 1993. Urba WJ and Longo DL. Hodgkin's disease (review article). N ENGL J MED 326: 678-87, 1992. 105

Page  106 Opportunistic Infections and Related Disorders PROTOZOAL INFECTIONS CRYPTOSPORIDIOSIS Trials, page 191 PATHOGEN: Cryptospordiosis is an infection of the lower GI tract caused by a parasite (Cryptosporidium parvum). Infection is spread through fecal-oral contact, usually in the setting of exposure to animals or food or water contaminated by fecal material. SITES OF INFECTION: Typically, the intestine(s). Biliary-tract involvement and pulmonary-pleural involvement may also occur. SYMPTOMS: Watery diarrhea, abdominal cramping, weight loss, anorexia, flatulence, and malaise. One retrospective chart review (McGowan et al.) suggests that spontaneous remissions may occur with some frequency in AIDS patients with cryptosporidiosis. In this series, 11/38 patients had a clinical remission of their diarrhea. Remission was correlated with a higher CD4+ count (>200/cells mm3). Blanshard et al. also report that transient cryptosporidiosis occurs more frequently in patients who are less immunosuppressed, and that fulminant disease generally is seen only in patients with CD4+ counts below 50/mm3. DIAGNOSIS: By fecal smear or intestinal biopsy. TREATMENT RESULTS There is no standard treatment for cryptosporidiosis. A double-blind placebo-controlled study of azithromycin (escalating from 900 mg/day to 1,800 mg/day) for cryptosporidiosis is under way at Cornell. Patients who do not respond are crossed over to an open-label extension of the study. Preliminary observations of Soave and co-workers in 80 patients suggest some patients have significant clinical responses, especially at higher doses. Since clinical responses appear to correlate with blood levels of azithromycin, the investigator plans to study regimens including higher doses and intravenous induction. An open-label study of azithromycin for patients with cryptosporidiosis who have failed other treatments is underway. Blanshard et al. conducted pilot studies of azithromycin (1 gram loading dose, then 500 mg/day for 2-4 weeks), letrazuril (50 mg/day increasing by 50 mg every 2 weeks to 150 mg/day) and paromomycin (500 mg/day for 1 month) in AIDS patients with cryptosporidiosis. Responses were measured in terms of changes in stool frequency and volume, and reductions in numbers of cryptosporidial oocysts in the stool and on biopsy. There were no changes in any parameters for 13/15 azithromycin recipients. Diarrhea stopped in 2/15 but Cryptosporidia were still present in stool and biopsy. 4/10 letrazuril recipients had reduced stool volume and Cryptosporidia disappeared from the stool in 9/10. However, Cryptosporidia were detected in 7/7 post-treatment gut biopsies performed. 9/10 patients who received paromomycin (aminosidine) had reductions in stool frequency, but Cryptosporidia were detected in the stool of 5/10 and in all patients upon gut biopsy. Two small placebo-controlled studies, and several larger uncontrolled studies, suggest that paromomycin may be effective in controlling the symptoms of cryptosporidiosis. White et al. randomized ten patients with cryptosporidiosis to receive paromomycin 25-35 mg/kg/d PO or matching placebo for 14 days, at which point patients crossed over to the alternate arm. Significant improvements in stool frequency, character and oocyst secretion were observed while patients received paromomycin. Kanyok et al. randomized eleven AIDS patients with cryptosporidiosis to receive paromomycin 500 mg q6h or placebo. After 14 days of treatment, 1/5 paromomycin recipients had a complete response, one had a partial response, and 3/5 had no response (2/3 of the nonresponders were co-infected with microsporidium). None of 6 patients randomized to placebo had a response. Eighty-nine AIDS patients with cryptosporidiosis received paromomycin (1500 - 2000 mg/day) in an open-label study reported by Walmsley et al. Complete responses were observed in 31/89 (35%), partial responses in 38/89 (43%), and no response in 20/89 (22%). Microbiological eradication was documented in 21/51 (41%) patients tested. Drake et al. report that 40 patients with AIDS and a diagnosis of cryptosporidiosis received paromomycin 500 mg four times daily PO for a mean of 25 days. In this open-label study, the number of daily bowel movements was observed to decrease in 27/40 patients, and GI symptoms improved during therapy. Ramratnam et al. treated 39 patients with confirmed cryptosporidiosis in a prospective, uncontrolled study of paromomycin 500 mg four times daily. At four weeks, diarrhea had resolved or improved in 19/39 patients, and 18/39 had gained weight (mean weight gain 3.2 kg). Another 24 patients received paromomycin 2 g/day for four weeks followed by paromomycin 1 g/day for maintenance (Bissuel et al.). 22/24 patients had clinical responses to treatment. 6/22 responders relapsed on maintenance therapy; 4/6 experienced remission when the maintenance dose was doubled to 2 g/day. 106

Page  107 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 A retrospective chart review of 23 patients with cryptosporidiosis was reported by Gathe et al. All patients were treated with paromomycin (1,500-2,000 mg/d for a median of 14 days). 16/23 patients had a complete response (symptom improvement, diarrhea eradication, and weight gain), 7/23 had a partial response (symptomatic improvement with at least 50% decrease in stool frequency). Seven of the complete responders had negative stool cultures after treatment. No hematologic, hepatic, renal or CNS toxicities were noted. A double-blind placebo-controlled efficacy study of paromomycin has been completed (ACTG 192). Thirty five patients out of target enrollment number of 68 were randomized to receive paromomycin 2000 mg/day or placebo for 21 days. Data analysis is underway. Soave et al. treated 68 patients in a placebo-controlled, dose-escalating study (with crossover to open-label treatment for non-responders) of diclazuril (50-600 mg PO x 7d); at the highest dose, very limited efficacy was observed. Poor bioavailability may limit diclazuril's efficacy. A double-blind placebo-controlled clinical trial (ACTG 198) of letrazuril has been completed, and data analysis is under way. No clinical benefit was observed for patients receiving letrazuril. Preliminary data suggested that significant reductions in stool oocysts occurred in patients receiving letrazuril. However, Soave and co-workers have suggested that these reductions resulted from letrazuril-induced alterations in the acid-fastness of the Cryptosporidium oocysts. Rash occurred in five patients. Preliminary results from an open-label safety and efficacy study of nitazoxanide for the treatment of cryptosporidiosis has been reported. Thirty HIV+ patients with confirmed cryptosporidiosis were assigned to receive nitazoxanide at either 500, 1000, 1500, or 2000 mg/day. Changes in bowel movement frequency, stool oocyst shedding, weight, and associated symptoms were measured. Reductions in bowel movement frequency were reported in 2/6 (33%) patients receiving 500 mg, 7/7 (100%) patients receiving 1000 mg, 4/6 (67%) receiving 1500 mg, and 2/3 (67%) receiving 2000 mg nitazoxanide. Parasitologic improvement was reported in 9/22 (41%) of patients. Two trials of roxithromycin for the treatment of cryptosporidiosis have been reported (Urst et al. and Strinz et al). Both were open-label studies of roxithromycin 300 mg PO bid for four weeks in 22 and 18 patients, respectively. The mean CD4+ count in the first trial was 257 cells/mm3; in the second trial 187 cells/mm3. Complete responses were 11/22 and 10/18; partial responses were 6/22 and 4/18, respectively. A phase II open-label trial of Immuno-C, a bovine antibody found in milk, has been completed. Kotler and co-workers report that no significant anticryptosporidial activity was detected. Kotler and co-workers has reported that the somatostatin analogue, octreotide acetate (100 mg SC tid) is an ineffective treatment for diarrhea caused by cryptosporidiosis, based on a recently completed randomized, placebo-controlled trial. ONGOING TREATMENT STUDIES: A phase I open-label trial of clarithromycin is currently underway. Patients will receive clarithromycin 500 mg bid for 3 weeks. If no response is seen, patients will then receive clarithromycin 1000 mg bid for an additional 4 weeks. REFERENCES: Blanshard C et al. Azithromycin, paromomycin and letrazuril in the treatment of cryptosporidiosis. Abstract P28, Third European Conference on Clinical Aspects and Treatment of HIV Infection. Paris, 1992. Blanshard C et al. Cryptosporidiosis in HIV-seropositive patients. Q J Med 85:307-8, 1992. Bissuel F et al. Paromomycin therapy for cryptosporidial diarrhoea in 24 AIDS patients. Abstract WS-B13-6, IX Intl Conf AIDS, Berlin, 1993. Cook DJ et al. Somatostatin treatment for cryptosporidial diarrhea in a patient with AIDS. Ann Int Med 108(5): 708-9, 1988. Drake J et al. Efficacy and tolerability of oral aminosidine [paromomycin] (Gabbroral TM) for the treatment of cryptosporidial diarrhea in patients with AIDS. Abstract P45, Intl Cong on Drug Ther in HIV Infection, Glasgow, 1992. Kanyok TP et al. Preliminary results of a randomized, blinded, controlled study of paromomycin vs. placebo for the treatment of Cryptosporidium diarrhea in AIDS patients. Abstract PO-B10-1508, IX Intl Conf AIDS, Berlin, 1993. Gathe J et al. Treatment of gastrointestinal cryptosporidiosis with paromomycin. VI Intl Conf AIDS San Francisco, 2: 384(2121), 1990. McGowan I et al. The natural history of cryptosporidial diarrhoea in HIV-infected patients. AIDS 7:349-54, 1993. Ramratnam B et al. Prospective, multicenter, open-label, nonrandomized trial of paromomycin for cryptosporidiosis in AIDS. Abstract 046, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994. Simon D et al. Resolution of Cryptosporidium nfection in an AIDS patient after improvement of nutritional and immune status with octreotide. Case report, Amer J Gastroenterol 5: 615-618, 1991. Soave R et al. Oral diclazuril therapy for cryptosporidiosis (abstract). VI Intl Conf AIDS San Francisco, 1:252(Th.B.520), 1990. Vakil MB et al. Biliary cryptosporidiosis in HIV-infected people after the waterborne outbreak of crytosporidiosis in Milwaukee. N ENGL J MED 334:19-23, 1996. 107

Page  108 Opportunistic Infections and Related Disorders Walmsley S et al. Effectiveness of paromomycin in cryptosporidiosis in AIDS. Abstract PO-B10-1473, IX Intl Conf AIDS, Berlin, 1993. White AC et al. Paromomycin for cryptosporidiosis in AIDS: a prospective double-blind trial. J Infect Dis 170: 419-429, 1994. OTHER REPORTS: Centers for Disease Control. Assessing the public health threat associated with waterborne cryptosporidiosis: report of a workshop. MMWR 44:1-15, 1995. Connoly GM et al. Diclazuril in the treatment of severe cryptosporidial diarrhea in AIDS patients. AIDS 4: 700-1, 1990. Fanning M et al. Pilot study of Sandostatin (octreotide) therapy of refractory HIV-associated diarrhea. Dig Dis Sci 36: 476-80, 1991. Katz MD et al. Treatment of severe cryptosporidium related diarrhea with octreotide in a patient with AIDS. Drug Intell Clin Pharmacol 22: 134-6, 1988. Marshall RJ and Flanigan TP. Paromomycin inhibits Cryptosporidium infection of a human enterocyte cell line. J INFECT DIS 165: 772-4, 1992. ISOSPORIASIS PATHOGEN: Isosporiasis belli, a parasite most commonly found in tropical and subtropical climates. SITE OF INFECTION: Intestines. SYMPTOMS: Watery, noninflammatory diarrhea; abdominal cramping; and weight loss. These symptoms are clinically indistinguishable from those of cryptosporidiosis. DIAGNOSIS: Fecal smear. Antibody tests are not available. TREATMENT RESULTS Oral TMP/SMX is effective against isosporiasis. Pape et al. successfully treated 32 AIDS patients with isosporiasis with TMP/SMX (one double-strength tablet PO four times daily). For maintenance, the patients were randomized to receive TMP/SMX (one double-strength tablet three times weekly), sulfadoxine/pyrimethamine (500 mg/25 mg weekly), or placebo. One patient receiving TMP/SMX relapsed three weeks after initiation of maintenance. All others remained asymptomatic. 5/10 on placebo relapsed a mean of 1.5 months after randomization. Weiss et al. successfully treated two AIDS patients, unable to tolerate sulfonamides, for isosporiasis with pyrimethamine (50-75 mg PO qd) and leucovorin (10 mg PO qd); recurrence was prevented by maintenance treatment with pyrimethamine (25 mg PO qd) and leucovorin (5 mg PO qd). REFERENCES: Pape JW et al. Treatment and propliylaxis oflso.pora helliinlection in patients with AIDS. N ENGL J MED 320:1044-7, 1989. Weiss LM et al. Isospora belli infection: treatment with pyrimethamine. Ann Int Med 109(6): 47475, 1988. MICROSPORIDIOSIS Trials, page 191 PATHOGEN: Several species of microsporidia infect HIV+ patients. Most frequent is Enterocytozoon bieneusi, a microsporidian parasite. Encephalitozoon hellem and cuniculi, and a new species designated Septata intestinalis, have also been reported. SITES OF INFECTION: E. bieneusi is found in the small intestine (and has been reported as a cause of sinusitis). Encephalitozoon hellem, cuniculi and Septata intestinalis have produced disseminated infections with symptoms mainly in the sinus or eyes. A recent report (Schwartz) et al. describes several patients with symptomatic and asymptomatic pulmonary microsporidiosis resulting from E. hellem, and suggests that disseminated microsporidial infections are increasing in significance. Pol et al. report that microsporidia may be a frequent cause of otherwise unexplained cholangitis in HIV+ patients. Bile samples were examined from a series of eight patients with unexplained AIDS-related cholangitis; all eight were found to have biliary microsporidiosis. The presence of E. bieneusi was confirmed by electron microscopy. SYMPTOMS: Diarrhea and weight loss are thought to be associated with microsporidial infection. However, a recent case-control study was unable to demonstrate such an association. Rabeneck et al. studied 106 HIV+ men, 55 with and 51 without chronic diarrhea. E. bieneusi was detected with equal frequency in duodenal biopsies of men from the two groups. E. Bieneusi was found in 18/55 (33%) of men with diarrhea and 13/51 (23%) of men without diarrhea (RR 1.42, 95% CI 0.61 - 3.31). The difference remained nonsignificant after controlling for CD4+ count and the presence of other enteric pathogens. DIAGNOSIS: E. bieneusi infection is now readily diagnosed by the examination of stool samples using one of three staining techniques. The disseminated species of microsporidia may be diagnosed by similar techniques in stool, urine, or nasal washings. Kotler et al. studied 112 HIV+ patients with diarrhea, 82 of whom had a diagnosis of AIDS. 27/82 AIDS patients and 0/32 non-AIDS patients had microsporidiosis. 108

Page  109 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199,7 TREATMENT RESULTS There is no standard treatment for microsporidiosis. Blanshard et al. treated six AIDS patients with small-intestinal microsporidiosis with albendazole 400 mg bid for 4 to 6 weeks. All patients improved clinically (reduced daily stool frequency and weight gain). No patient cleared the infection on post-treatment biopsy, and subsequent analysis of a further 12 patients indicated a symptomatic response in only half. However, electron microscopy showed degenerative changes in the parasites, suggesting a direct effect of albendazole. The investigator is developing larger phase I/II placebo-controlled studies. A larger placebo-controlled study of albendazole is currently underway. All patients with microsporidiosis who may also receive albendazole on a case-by-case compassionate basis from the manufacturer, see page 207 Eeftinck-Schattenkerk et al. treated 19 patients with Microsporidium-associated diarrhea with metronidazole (Flagyl) 500 mg tid PO. Diarrhea improved in 10 and resolved completely in five. 12/15 responders relapsed within 4 weeks of stopping drug. The effect of metronidazole was symptomatic only; duodenal biopsies showed microsporidia regardless of response to treatment. Sharpstone et al. recently treated 12 HIV+ patients with thalidomide (100 mg PO qd) for microsporidial diarrhea. All had diarrhea for a minimum of 12 months and had failed prior treatment with albendazole. After three weeks, bowel frequency fell from a mean of six per day to 2.8 per day. In all cases stools, which had previously been liquid, became semi-solid. Mean weight loss prior to therapy was 8.4 kg and after three weeks of treatment patients had gained 1.2 kg. One out of twelve patients reported a relapse of chronic diarrhea at one week of therapy. The primary dose-limiting toxicity in three patients was daytime drowsiness. REFERENCES: Blanshard C et al. Treatment of intestinal microsporidiosis with albendazole. AIDS 6:311-3, 1992. Dieterich D et al. Treatment with albendazole for intestinal disease due to Enterocytozoon bieneusi in patients with AIDS. J INFECT DIS 169:178-83, 1994. Dore GJ et al. Septata intestinalis microsporidiosis in 8 HIV-infected patients. Abstract #PB0653, X Intl Conf AIDS, Yokohama, 1994. Eeftinck Schattenkerk JM et al. Metronidazole for Microsporidium-associated diarrhoea in symptomatic HIV-1 infection. VII Intl Conf AIDS, Florence Vol 2: 248(W B 2267), 1991 Kotler DP et al. Prevalence of microsporidiosis in AIDS patients with chronic diarrhea. Abstract PoB 3340, VIII Intl Conf AIDS, Amsterdam, 1992 Orenstein JM et al. A microsporidian previously indescribed in humans, infecting enterocytes and macrophages, and associated with diarrhea in an acquired immunodeficiency syndrome patient. Hum Pathol 23: 722-8, 1992. Orenstein JM et al. Systemic dissemination by a newly recognized intestinal microsporidia species in AIDS. AIDS 6:1143-50, 1992. Pol S et al. Microsporidia infection in patients with the human immunodeficiency virus and unexplained cholangitis. N ENGL J MED 328:95-9, 1993. Rabeneck L et al. The role of Microsporidia in the pathogenesis of HIV-related chronic diarrhea. Ann Int Med 119:9: 895-99, 1993. Sandfort J et al. Albendazole treatment in patients with intestinal microsporidiosis. Abstract PO-B10-1491, IX Intl Conf AIDS, Berlin, 1993. Sharpstone D et al. The treatment of microsporidial diarrhea with thalidomide. AIDS 9:658-9, 1995. Schwartz DA et al. Pulmonary microsporidiosis - an emerging opportunistic lung infection in AIDS. Abstract WS-B14-6, IX Intl AIDS Conf Berlin, 1993. OTHER REPORTS: Beaugerie L et al. Cholangiopathy associated with Microsporidia infection of the common bile duct mucosa in a patient with HIV infection. Ann Int Med 117:401-2, 1992. Eeftinck Schattenkerk JKM et al. Clinical significance of small-intestinal microsporidiosis in HIV-1 infected individuals. Lancet 337: 895-8, 1991. Shadduck JA et al. Microsporidia and human infections. Clin Microbiol Rev 2(2): 158-65, 1989. Simon D et al. Light microscopic diagnosis of human microsporidiosis and variable response to octreotide. Gastroenterology 100: 271-3, 1991. 109

Page  110 Opportunistic Infections and Related Disorders II PNEUMOCYSTIS CARINII PNEUMONIA (PCP) Trials, page 191-192 PATHOGEN: Pneumocystis carini has generally been classified as a protozoan parasite; some studies indicate it may be a fungus, with which it shares certain genetic sequences. SITES OF INFECTION: Usually the lungs. Rarely, in extrapulmonary sites, including the lymph nodes, bone marrow, spleen, and liver. SYMPTOMS: Fever; dry, nonproductive cough; chest tightness; difficulty breathing. DIAGNOSIS: By microscopic examination of induced sputum, bronchoalveolar lavage, transbronchial or open lung biopsy. TMP/SMX (trimethoprim 15 mg/kg/day and sufamethoxazole 75 mg/kg/day PO or IV for 21 days) is the standard treatment for acute PCP. Alternative regimens include intravenous pentamidine (3 - 4 mg/kg/day IV for 14 - 21 days), clindamycin with concurrent primaquine (600 mg IV q6-8h or 300 - 450mg PO q6h and primaquine 15 mg PO daily for 21 days), atovaquone (750 mg suspension PO bid for 21 days), Trimetrexate with concurrent leucovorin (trimetraxate 45 mg/m2 IV daily and leucovorin 20 mg/m2 PO or IV qid). TREATMENT RESULTS FIRST-LINE THERAPY: TMP/SMX has been compared to both atovaquone (Hughes et al.) and trimetrexate with concurrent leucovorin (Sattler et al.) for the treatment of mild to moderate PCP. In the TMP/SMX versus atovaquone study, therapy was successful in 99/160 (62%) patients randomized to atovaquone and 103/162 (64%) patients randomized to TMP/SMX. More patients in the atovaquone group failed due to lack of response, while more patients in the TMP/SMX group failed due to drug toxicity (20% of atovaquone recipients and 7% of TMP/SMX recipients discontinued due to inadequate response, while 7% of atovaquone recipients and 20% of TMP/SMX recipients discontinued due to drug toxicity). Mortality within four weeks of the completion of treatment was higher in the atovaquone group (11 patients) than in the TMP/SMX group (1 patient) (P = 0.003). In the study comparing TMP/SMX and trimetrexate with concurrent leucovorin in 215 patients, the response rates were similar for both drugs, survival was greater in the TMP/SMX arm (mortality was 12% in the TMP/SMX group and 20% in the TMTX group (P =.088). The investigators of both studies concluded that TMP/SMX is a superior first-line therapy for moderately severe PCP. SECOND-LINE THERAPY: For reasons not yet determined, the rates of adverse reactions to TMP/SMX (mainly rash and fever) are significantly higher in HIV+ patients than in HIV-negative patients. Because of the high incidence and severity of adverse reactions in HIV+ patients, only 45% to 50% who start therapy with TMP/SMX are able to complete a 21-day course (Wharton et al.). Thus, an alternative therapy is often required. Pentamidine is the most common alternative drug to treat PCP in patients who have adverse reactions or fail therapy with TMP/SMX. While pentamidine has been found to be an effective therapy for mild to severe PCP, it has been associated with higher mortality rates than TMP/SMX (Sattler et al.) and, like TMP/SMX, is associated with a high incidence of adverse reactions (anemia, creatinine elevations, LFT elevations, pancreatitis, and hyponatremia) (Wharton et al.). Waskins et al. found that the incidence of transient diabetes among PCP patients was 22% with IV pentamidine and 6% among long-term users of aerosolized pentamidine for PCP prophylaxis. A second alternate regimen for the treatment of PCP is TMP and dapsone combined. Leoung et al. treated 15 patients for a first episode of mild to moderate PCP with TMP (20 mg/kg PO qd x21d) and dapsone (100 mg PO qd x21 d). All improved within 3-10 days. Side effects (nausea, vomiting, rash) occurred in 14/15, with treatment discontinued in 2/15 (severe rash). Medina et al. randomized 60 patients with AIDS and mild to moderately-severe PCP to receive either TMP/dapsone (20 mg/day and 100 mg/day PO respectively) or TMP/SMX (20 mg/kg/day and 100 mg/kg/day PO respectively). 2/30 patients in the TMP/dapsone group failed, and 3/30 in the TMP/SMX group failed. TMP/SMX was associated with significantly greater toxicity: 9/30 patients who received TMP/dapsone and 17/30 who received TMP/SMX had a major adverse reaction requiring a switch to IV pentamidine. The most frequent toxicity in the TMP/dapsone group was rash; in the TMP/SMX group elevated LFTs, neutropenia, and rash were most frequently observed. Clindamycin, in combination with primaquine, has been reported to be an effective alternative to TMP/SMX for HIV+ patients with mild to moderate PCP. However, this combination has not yet been compared to either pentamidine or TMP/SMX. An open-label study conducted by Black et al. reported that eight patients treated with clindamycin/primaquine reported marked improvement after seven days of therapy. Two of the eight patients enrolled required a change in therapy at day 14 due to adverse events (diarrhea and rash). A second open-label study in nine patients (Kay et al.) reported similar results; all nine improved significantly. One patient required a change in therapy due to severe rash. 110

Page  111 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199: 7 Trimetrexate and leucovorin has also been shown to be an effective alternative to TMP/SMX and pentamidine for the treatment for PCP. ACTG 039 investigated trimetrexate in patients who did not respond to or were intolerant of TMP/SMX and IV pentamidine (Allegra et al.). 84/159 (53%) patients intolerant to both standard therapies and 48/160 (30%) patients either unresponsive to both or unresponsive to one and intolerant of the other tolerated at least 14 days of treatment with trimetrexate and survived at least one month. Investigators concluded that trimetrexate is a useful and well-tolerated salvage therapy. Feinberg et al. evaluated the results of an expanded-access program which provided trimetrexate to 752 patients unable to take TMP/SMX and IV pentamidine. 34% of patients were classified as responders. Atovaquone has been reported to be a moderately effective PCP treatment. Hughes et al. have reported results from a randomized, double-blind clinical trial comparing TMP/SMX to atovaquone for first-line treatment of PCP. Of 408 patients enrolled, 322 had documented PCP and 284 were evaluable. There was no statistically significant difference in the success rates reported between the two groups (62% for the atovaquone group and 64% for the TMP/SMX group). No statistically-significant difference in treatment-limiting adverse events were reported between the two groups; 34% of both treatment groups required alternate therapies for successful treatment completion. Although no deaths in the trial were due to PCP, the mortality rate was higher in the atovaquone group, 11 versus 1 in the TMP/SMX group. (P = 0.001). Atovaquone has also been compared to intravenous pentamidine for mild to moderate PCP (Dohn et al.). Success was achieved in 32/56 (57%) and 21/53 (40%) of patients randomized to atovaquone and pentamidine, respectively (P = 0.085). Lack of response was observed in 15/56 (29%) and 10/53 (19%) of atovaquone and pentamidine recipients, respectively (P =.176). Adverse events requiring discontinuation of therapy occurred in 5/56 (7%) and 29/53 (55%) of atovaquone and pentamidine recipients, respectively (P <.001). Seven patients in the atovaquone group and 13 in the pentamidine group died within the first four weeks (P =.529). Two reports have demonstrated that atovaquone's oral bioavailability is highly dependent on concurrent food intake (Hughes et al. 1991, Falloon et al.). Atovaquone must be administered on a full stomach with a high fat content. Aerosolized pentamidine has also been compared to TMP/SMX. Montgomery et al. enrolled 379 patients with PCP and a pO2 less than 55 mmHg in a randomized, double-blind trial comparing TMP/SMX to aerosolized pentamidine (AP) for treatment of acute PCP. AP was associated with a slower clinical response and more relapses than TMP/SMX, while TMP/SMX was associated with more adverse reactions (rash, elevated liver-enzyme levels, fever, neutropenia, and nausea). Investigators also noted that the risk of pneumothorax and extrapulmonary PCP is greater with AP than with TMP/SMX. Adjunctive corticosteroid administration (used in conjunction with TMP/SMX or alternative regimens), when initiated at the beginning of treatment of an acute episode of moderate to severe PCP improves clinical outcome by decreasing the potentially life-threatening inflammatory response and respiratory distress. A consensus conference convened by NIAID to review the results of five separate studies concluded that early adjunctive steroid therapy reduces the likelihood of death, respiratory failure and deterioration in moderate to severe PCP when initiated as early as possible; no benefit has been demonstrated in milder cases of PCP. Adjunctive corticosteroids are now standard therapy for moderate to severe PCP, defined by a room air PO2 less than 70 mmHg, although long-term benefit of adjunctive use of corticosteroids has not been established. Adjunctive corticosteroid treatment has not been shown to reactivate tuberculosis or fungal diseases with a detectable increase in frequency. A non-randomized retrospective chart review found that corticosteroid use was associated with a reduced incidence of adverse skin reactions to TMP/SMX in AIDS patients receiving treatment for acute PCP (Caumes et al.). 38 patients in the review received TMP/SMX alone, and 23 received TMP/SMX plus corticosteroids for hypoxemia. Rashes occurred in 18/38 (47%) patients receiving TMP/SMX alone and 3/23 (13%) receiving TMP/SMX and corticosteroids. A higher rate of mucocutaneous herpes simplex infections was observed in the patients receiving corticosteroids (P = 0.012). PROPHYLAXIS RESULTS ADULTS: TMP/SMX (Bactrim, Septra) is the treatment of choice for the prevention of PCP. The United States Public Health Service and the Infectious Disease Society of America has published guidelines for the prevention of PCP (CDC, 1995). Adults and adolescents with HIV infection should receive prophylaxis against PCP if they have a CD4+ count of less than 200 cells/mm3, unexplained fever for greater than or equal to 2 weeks, or a history of oropharyngeal candidiasis. Schneider et el. (1995) studied 260 HIV+ patients with a CD4+ count < 200 cells/mm3. Patients were randomized to receive 480 mg (n=131) or 960 mg (n=129) TMP/SMX. Of the 260 participants, 104 completed the study. 63/156 dropped out of the study because the could not tolerate TMP/SMX; 50/156 died during the study; and 43/156 were noncompliant. The median follow-up time was 409 days. No episodes of PCP occured in either TMP/SMX group. After 1 year, 111

Page  112 Opportunistic Infections and Related Disorders II there was no difference in the cumulative incidence of death between the low and high-dose groups (15% and 12%, respectively). Several studies suggest that TMP/SMX one DS tablet daily delivered three times a week (as opposed to daily), is effective as primary prophylaxis for PCP with reduced incidence of adverse reactions. Ruskin et al. conducted a retrospective analysis of TMP/SMX three times weekly in 116 patients (71 had a prior history of active PCP, mean follow-up 18.5 months; 45 never had PCP, but CD4+ below 200/mm3, mean follow-up 24.2 months). None of 116 patients developed PCP; 28% had side effects (rash, pruritus, nausea); 15/116 discontinued treatment, with 11/15 clearly drug intolerant. A number of studies have also suggested that TMP/SMX desensitization is possible in patients with a history of intolerance to the standard prophylaxis dose. Carl et al. recently reported the results of a TMP/SMX desensitization study in 39 intolerant HIV+ patients. An eight-day regimen of serial dilutions of TMP/SMX oral suspension was administered. No antihistamines or corticosteroids were administered. 15/39 (37%) were successfully desensitized and continued on TMP/SMX; 13/39 (32%) were successfully desensitized, but did not continue on TMP/SMX due to non-allergic toxicities; and 11/39 (27%) failed desensitization. The AmFAR Community-Based Clinical Trials Network (CBCTN) is conducting a randomized, double-blind trial comparing the success of two approaches to the reintroduction and maintenance of TMP/SMX for prophylaxis of Pneumocystis carinii pneumonia (CBCT 06). A second TMP/SMX desensitization protocol is currently being conducted by the AIDS Clinical Trials Group (ACTG 268). Aerosolized pentamidine, administered by the Respirgard II nebulizer, is approved for the primary prophylaxis of PCP in HIV+ patients with less than 200 CD4+ cells/mm3 and as secondary prophylaxis. The U.S. Public Health Service Task Force on PCP prophylaxis recommends aerosolized pentamidine as primary or secondary prophylaxis in patients who cannot tolerate TMP/SMX or dapsone. The Task Force recommends either the Respirgard II nebulizer (300 mg/month) or the Fisons nebulizer (five 60 mg loading doses over a two-week period, followed by 60 mg every 2 weeks). Common side effects include cough and bronchospasm; less common side effects include pneumothorax and transient diabetes. AP is not effective in preventing extrapulmonary PCP. Schneider et al. randomized 213 HIV+ patients with CD4+ counts <200/mm3 and no history of PCP to receive one of two regimens of TMP/SMX (one single strength or double strength tablet daily) or aerosolized pentamidine (300 mg monthly via Respirgard II nebulizer). After a mean followup of 264 days, 6/71 pentamidine recipients had a confirmed episode of PCP, while no patient in either TMP/SMX group had PCP (P = 0.002). Adverse reactions requiring treatment discontinuation were higher in both TMP/SMX groups (17/71 on 480 mg/day and 18/71 on 960 mg/day) compared to the aerosolized pentamidine group (2/71). Adverse effects occurred earlier in the higher-dose TMP/SMX group than in the lower-dose TMP/SMX group. Hardy et al. randomized 310 AIDS patients who had recovered from one episode of PCP to receive either one double-strength TMP/SMX tablet a day or aerosolized pentamidine 300 mg delivered by a Respirgard II nebulizer every 4 weeks (ACTG 021). All patients received zidovudine. After a mean followup of 17.4 months, PCP had recurred in 14/154 (9%) patients randomized to TMP/SMX and 36/156 (23%) patients randomized to aerosolized pentamidine. Adverse reactions requiring a change in treatment occurred in 42/154 (27%) of TMP/SMX recipients and 6/156 (4%) of aerosolized pentamidine recipients. Rash and fever accounted for most of the toxicities. There were no differences in the rates of hematologic or hepatic abnormalities between the two groups. Survival was equivalent in the two groups. Borleffs et al. randomized 230 patients with CD4+ < 200/mm3 and no previous PCP to receive aerosolized pentamidine (300 mg once monthly) or one of two doses of TMP/SMX (one single-strength or double-strength tablet daily). After 9 months' follow-up, an interim analysis showed that 11% of aerosolized pentamidine recipients and no TMP/SMX recipients had developed PCP. Adverse reactions requiring a switch in treatment occurred in 2% of the aerosolized pentamidine group, 17% of the low-dose TMP/SMX group and 18% of the high-dose TMP/SMX group. Bozzette et al. have reported results from a trial (ACTG 081) comparing three regimens for the primary prophylaxis of PCP. 842 patients with CD4+ counts <200/mm3 and no prior history of PCP were randomized to receive TMP/SMX (one double-strength tablet daily), aerosolized pentamidine (300 mg monthly), or dapsone (50 mg twice daily). The median follow-up was 39 months. Upon intent-to-treat analysis, PCP occurred with equal frequency in the three groups. Forty-two, 54 and 41 cases of PCP occurred in the TMP/SMX, aerosol pentamidine, and dapsone groups, respectively (P= 0.22). Among patients entering the trial with fewer than 100 CD4+ cells/mm3, the estimated 36 month cumulative risks or reported PCP were 19%, 22%, and 33%, respectively. Survival was equivalent in the three groups (134, 131, and 138 deaths). Fewer side effects requiring a switch in treatment assignment occurred in the aerosol pentamidine group (P < 0.001). The mean time to discontinuation of assigned treatment was 14.6, 17.1, and 13.7 months in the TMP/SMX, aerosolized pentamidine, and dapsone groups respectively. 112

Page  113 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Blum et al. prospectively compared dapsone (100 mg/day) and TMP/SMX (one double-strength tablet/day) as primary prophylaxis for PCP in HIV+ patients with CD4+ counts below 200/mm3. After 1,638 patient months of followup, 1/47 (2%) patients randomized to dapsone and 1/39 (3%) patients randomized to TMP/SMX developed PCP. 33/47 (70%) dapsone recipients and 25/39 (64%) TMP/SMX recipients discontinued their study therapy, most frequently for rash. Ten patients switched from dapsone to TMP/SMX, 4 successfully; and 11 patients crossed over from TMP/SMX to dapsone, 6 successfully. Salmon-Ceron et al. have reported results from a randomized, unblinded study that compared aerosolized pentamidine, 300 mg every month, and dapsone, 50 mg/day, for secondary prophylaxis in 196 HIV+ patients. The study was prematurely discontinued due to excess mortality in the dapsone group. After a mean follow-up of 13 months, 22/103 (21%) of patients in the pentamidine group were dead compared with 39/93 (42%) receiving dapsone; the estimated mortality rates at 18 months were 24.6% and 53.1%, respectively (P < 0.003). Slavin et al. conducted a randomized comparison of dapsone (100 mg PO twice weekly) and aerosolized pentamidine (400 mg nebulized monthly) for PCP prophylaxis in patients with CD4+ counts below 200/mm3 or a previous episode of PCP. 37/50 (74%) dapsone recipients and 32/46 (70%) AP recipients had a previous episode of PCP. Mean CD4+ counts at entry were 128/mm3 and 124/mm3 in the dapsone and AP groups, respectively. All patients received AZT. After a median followup of 18 months, 9/50 (18%) dapsone recipients and 8/46 (17%) AP recipients had developed PCP (no difference). The rates of adverse reactions were equal in the two groups (4 rash and 2 nausea on dapsone, and 5 cough and 1 dizziness on AP). Opravil et al. randomized 528 patients to receive either dapsone/pyrimethamine (200 mg daily/75 mg once weekly) or aerosolized pentamidine (300 mg once monthly via Respirgard II nebulizer). All patients had CD4+ counts below 200/mm3 at baseline and 20% had previous PCP. After 335 days' mean followup, intent-to-treat analysis showed that 12/291 (4%) dapsone/pyrimethamine recipients and 13/242 (5%) AP recipients had developed PCP (no significant difference). Intolerance requiring a switch in treatment occurred in 30% of dapsone/pyrimethamine recipients and 4% of AP recipients. Most frequent side effects were nausea, fever, and hematologic toxicity. Girard et al. randomized 349 symptomatic patients with CD4+ counts below 200/mm3 to receive dapsone/pyrimethamine (50 mg daily/50 mg weekly) or aerosolized pentamidine (300 mg monthly) on an open-label basis. After a median follow-up of 539 days, 10/173 (6%) dapsone/pyrimethamine recipients and 10/176 (3%) aerosolized pentamidine recipients had developed PCP. 42 dapsone/pyrimethamine recipients and 3 aerosolized pentamidine recipients discontinued therapy due to toxicity. No difference in survival was observed. Two randomized studies indicate that low-dose dapsone (100 mg/week) with pyrimethamine is less effective than other strategies for PCP prophylaxis. Antinori et al. randomized 197 patients with CD4+ counts below 200/mm3 and no prior PCP to receive dapsone/pyrimethamine (100 mg weekly/25 mg twice weekly), aerosolized pentamidine (300 mg monthly via Respigard 11 nebulizer), or TMP/SMX (one double-strength tablet every other day). After a median follow-up of 7.7 months, PCP had developed in 9/63 (14%), 4/68 (6%) and 1/66 (2%) of dapsone/pyrimethamine, aerosolized pentamidine and TMP/SMX recipients respectively. Upon intent-to-treat analysis, the difference between the TMP/SMX and D/P groups was significant (P = 0.0008). Other comparisons did not show significant differences. Podzamczer et al. randomized 166 patients with CD4+ counts below 200/mm3 to receive dapsone/pyrimethamine (100 mg weekly/25 mg weekly) or TMP/SMX (2 double-strength tablets three times weekly). After a mean follow-up of 380 days, intent-to-treat analysis showed that PCP had developed in 13/85 (15.2%) of dapsone/pyrimethamine recipients and 3/81 (3.7%) of TMP/SMX recipients (P = 0.01). By contrast, the results of another randomized study (Mallolas et al.) suggest that weekly dapsone/pyrimethamine may be comparable to standard therapies. 331 HIV+ patients with CD4+ counts <200/mm3 or a previous diagnosis of AIDS were randomized to receive dapsone/pyrimethamine (100/25 mg weekly), aerosolized pentamidine (300 mg monthly) or TMP/SMX (160/800 mg three times weekly). The mean follow-up was 313 days. Upon intention-to-treat analysis, the PCP rates per year of observation were 8.3%, 5.6%, and 3.0% in the D/P, AP and TMP/SMX groups, respectively. These differences were not statistically significant. CHILDREN: In March 1991, the CDC published guidelines for the prophylaxis of PCP in HIV+ children. A revised version of these guidelines were released in April 1995, based on surveillance data suggesting that a significant decline in pediatric PCP cases had not been achieved (Simonds et al.). Since young children have much higher CD4+ counts than adults, the recommendations are stratified according to age. Prophylaxis is recommended when CD4+ counts fall below 1,500/mm3 in children between one and 11 months, below 1000/mm3 in children between one and 5 years, and below 500/mm3 in children six years or older. For any child whose CD4+ percentage fall between 15%-24%, prophylaxis is recommended regardless of age or absolute CD4+ count. The recommended regimen is TMP 150 mg/m'/d PO with SMX 750 mg/m'/day PO in divided doses three times weekly on consecutive days (e.g. M-Tue-W). Alternative schedules include the same dosages given as a single daily dose three 113

Page  114 Opportunistic Infections and Related Disorders times weekly on consecutive days; the same dosages given in two divided doses every day; and the same dosages given as two divided doses three times weekly on alternating days (e.g. M-W-F). In the case of intolerance to TMP/SMX, alternative regimens are aerosolized pentamidine 300 mg/month via the Respirgard II nebulizer; dapsone (for children older than 1 month of age) 1 mg/kg/day PO; or IV pentamidine 4 mg/kg every two or four weeks. The safety of aerosolized pentamidine in infants was evaluated by Hand et al. Seven infants (mean age 6.7 months) with HIV infection were given monthly treatments with aerosolized pentamidine, with the dose calculated to be equivalent to an adult dosage of 300 to 600 mg/month. The side effects observed were similar to those seen in adults, with mild coughing and wheezing being most frequent. The investigators concluded that aerosolized pentamidine is safe in this population. REFERENCES: Antinori A et al. Failure of low-dose dapsone-pyrimethamine in primary prophylaxis of Pneumocystis carinii pneumonia. Lancet (letter) 340:788, 1992. Blum RN et al. Comparative trial of dapsone versus trimethoprim/sulfamethoxazole for primary prophylaxis of Pneumocystis carinii pneumonia. J AIDS 5:341-7, 1992. Borleffs JCC et al. Pentamidine versus two doses of cotrimoxazole in primary prophylaxis of Pneumocystis carinii pneumonia in HIV-infected patients. Abstract O-8A.3, Intl Cong Drug Ther HIV Infect, Glasgow, 1992. Bozzette SA et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N ENGL J MED 332:693-9, 1995. Camus E et al. Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim-sulfamethoxazole during treatment of AIDS-associated Pneumocystis carinii pneumonia. Clin Infect Dis 18:319-23, 1994. Carl JL et al. Evaluation of the cost effectiveness of TMP/SMX desensitization in HIV-infected patients with intolerance to TMP/SMX. 35th ICAAC, Abstract 1221 B, San Francisco, 1995. CDC. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24, 1995. Dohn M et al. Oral atovaquone vs.intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Int Med 121: 174-180, 1994. Feinberg J et al. Trimetrexate (TMTX) salvage therapy for PCP in AIDS patients with limited therapeutic options. Abstract PoB 3297, VIII Intl Conf AIDS, Amsterdam, 1992. Gilquin J et al. Efficacy and safety of trimethoprim-sulfamethoxazole desensitization in HIV-infected patients. Abstract PB0616, X Intl Conf AIDS, Yokohama, 1994. Girard PM et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N ENGL J MED 328:1514-20, 1993. Hand IL et al. Aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in infants with human immunodeficiency virus infection. Pediatr Infect Dis J 13:100-4, 1994. Hardy WD et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N ENGL J MED 327: 1842-8, 1992. Hughes WT et al. Comparison of atovaquone (566C80) and trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N ENGL J MED 328:1521-7, 1993 Leoung GS et al. Dapsone-Trimethoprim for Pneumocystis carinii Pneumonia in the Acquired Immunodeficiency Syndrome. Ann Int Med 105(1): 45-8, 1986. Medina I et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N ENGL J MED 323:776-82, 1990. Montgomery AB et al. Aerosolized pentamidine vs. rimethoprim/sulfamethoxazole for Pneumocystis carinii pneumonia in acquired immune deficiency syndrome. Am Journ Respir Crit Care Med 151:1068-74, 1995. Murphy RL et al. Aerosol pentamidine prophylaxis following PCP in AIDS patients: results of a blinded dose-comparison study using an ultrasonic nebulizer. Am J Med 90: 418-26 1991.. Nguyen MT et al. Trimethoprim-sulfamethoxazole desensitization in HIV patients with previously documented TMP/SMX intolerance. Clin Infect Dis 3:563, 1993. Opravil M et al. Dapsone-pyrimethamine vs. aerosolized pentamidine for combined prophylaxis of PCP and toxoplasmic encephalitis. Abstract PO-B10-1429, IX Intl Conf AIDS, Berlin, 1993. Podzamczer D et al. Thrice weekly co-trimoxazole is better than weekly dapsone- pyrimethamine for the prevention of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 7:501-6, 1993. Rohde I et al. Efficacy of clindamycin/primaquine vs. trimethoprim/sulfamethoxazole in acute treatment of Pneumocystis carinii pneumonia. VI Intl Conf AIDS San Francisco, 1:221(Th.B.397), 1990. Ruskin J and LaRiviere M. Low-dose co-trimoxazole for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus disease. Lancet 337:468-71, 1991. Rizzardi GP et al. Risks and benefits of aerosolized pentamidine and cotrimoxazole in primary prophylaxis of Pneumocystis carinii pneumonina in a 2-yr randomized controlled trial. Abstract P202, 4th Euro Conf on Clin Treat of HIV Infect, Milan, 1994. Salmon-Ceron D et al. Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis pneumonia. J INFECT DIS 172:656-64, 1995. Sattler et al. Trimetrexate with Leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: A prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis 170: 165-172. 1994. Schneider MME et al. A controlled trial of aerosolized pentamidine or trimethoprim- sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N ENGL J MED 327: 1836-41, 1992. Schneider MME et al. Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. Journ Infect Dis 171:1632-6, 1995. Simonds et al. Prophylaxis against Pneumocystis carinii pneumonia among children with perinatally acquired human immunodeficiency virus infection in the United States. N ENGL J MED 332:786-90, 1995. Slavin M et al. Oral dapsone versus nebulized pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and hematological toxicity. AIDS 6 1169-74, 1992. OTHER REPORTS: Bozzette SA et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. N ENGL J MED 323: 1451-7, 1990. Falloon J et al. The pharmacokinetics of atovaquone suspension in patients with HIV infection. Abstract 242, 1st Natl Conf on Hum Retrovir, 1993. Falloon J et al. Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for prevention of Pneumocystis pneumonia. Antimicrob Agents Chemother 30 1580-1587, 1994. 114

Page  115 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Gagnon S et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in the Acquired Immunodeficiency Syndrome - a double-blind, placebo-controlled trial. N ENGL J MED, 323: 1444-50,1990. Hirschel B et al. A controlled study of inhaled pentamidine for primary prevention of PCP. N ENGL J MED 324: 1087-83, 1991. Kovacs A et al. CD4 T-lymphocyte counts and Pneumocystis carinii pneumonia in pediatric HIV infection. JAMA 265: 1698-703, 1991. King C et al. Survival, death, and desensitization to trimethoprim-sulfamethoxazole (TMP/SMX). Abstract #388B, X Intl Conf AIDS, Yokohama, 1994. Leoung GS et al. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia - the San Francisco Community Prophylaxis Study N ENGL J MED 323(12) 769-75, 1990. Lidman C et al. Aersolized pentamidine as primary prophylaxis for Pneumocystis carinii pneumonia: efficacy, mortality and morbidity. AIDS 8: 935-939, 1994. Masur H et al. Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodef<%-5>iciency syndrome. N ENGL J MED 323(21). 1500-4, 1990. Masur H. Prevention and treatment of Pneumocystis pneumonia (review article). N ENGL J MED 327:1853-60, 1992. Saah AJ et al. Predictors for failure of Pneumocystiscariniipneumonia prophylaxis. JAMA 273:1197-02, 1995. Safrin S et al. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis 170: 912-917, 1994. TOXOPLASMOSIS Trials, page 193 PATHOGEN: Toxoplasma gondii is a protozoan and is among the most prevalent causes of latent infection of the central nervous system throughout the world. Infection occurs primarily via the oral route through ingestion of raw or undercooked meat or contact with cat excrement. SITES OF INFECTION: Most commonly the brain (cerebral toxoplasmosis), although other organs can be infected. T gondii is the most common cause of focal intracerebral lesions in AIDS (Wong and Remington). SYMPTOMS: Most frequent symptoms include headache, confusion, and fever. Focal neurologic deficits occur in most patients. DIAGNOSIS: Since T gondii is the most common opportunistic pathogen of the brain in AIDS patients, the practice of presumptive therapy for patients with a characteristic finding on CT/MRI (e.g., one or more focal lesions) and positive Toxoplasma serology is widely accepted. Porter and Sande report that the absence of detectable antitoxoplasma IgG antibodies does not exclude the diagnosis. In their retrospectively reviewed series, 4/18 patients with pathologically proven toxoplasmosis did not have detectable antitoxoplasma antibodies. The risk of developing cerebral toxoplasmosis is greatly increased in toxo seropositive HIV+ people with CD4+ counts below 50/mm3 (Luft et al.). In patients who are treated empirically, a clear clinical response should be evident within 14 days and there should be a clear radiographic response of all lesions within 3 weeks. In patients who fail to respond to therapy, brain biopsy should be considered relatively early in the course of treatment (7-10 days), with or without change in treatment. TREATMENT RESULTS The combination of pyrimethamine and sulfadiazine is standard treatment for toxoplasmic encephalitis. Because of the high incidence of adverse reactions, alternative regimens are under investigation. Tenant-Flowers et al. enrolled 16 AIDS patients with cerebral toxoplasmosis and known allergies to sulfonamides in a sulfadiazine desensitization protocol. Patients received pyrimethamine 25 mg bid and folinic acid 7.5 mg/day. 8 patients received concomitant steroids. Sulfadiazine was administered every three hours over five days in doses gradually escalating from 10 pg. Success, defined as tolerance of sulfadiazine 2 to 4 g/day, was achieved in 10/16 patients. It is not known whether results are better than re-challenge without desensitization. Katlama et al. compared the combination of pyrimethamine (50 mg/day) and clindamycin (2.4 g/day) (P/C) to the combination of pyrimethamine (50 mg/day) and sulfadiazine (4 g/day) (P/S) in AIDS patients with first-episode toxoplasmic encephalitis. Three hundred forty two patients were randomly assigned to receive open-label P/C (n = 175) or P/S (n = 167) for six weeks. In the P/C group, 47% had a complete response, 21% had a partial response, and 18% died during acute therapy. In the P/S group, 55% had a complete response, 22% had a partial response, and 14% died during acute therapy. These differences were not statistically significant. Significantly more patients had to discontinue therapy due to side effects in the pyrimethamine/sulfadiazine compared with the pyrimethamine/clindamycin group (44 v. 17, P = 0.0001). Skin rash and fever occurred in more patients in the pyrimethamine/sulfadiazine group (58 v. 44, P = 0.073), while diarrhea occurred in more patients on pyrimethamine/clindamycin (29 v. 8, P = 0.0007). Dannemann et al. studied pyrimethamine (200 mg loading dose, then 75 mg/day) and leucovorin in combination with clindamycin (1200 mg IV four times daily 115

Page  116 Opportunistic Infections and Related Disorders for 3 weeks, then 300-450 mg PO four times daily) or sulfadiazine (100 mg/kg PO four times daily) in a study that assessed only the first 6 weeks of therapy. 59 patients with AIDS and a definitive diagnosis of toxoplasmic encephalitis were randomized between the two regimens. After three weeks, 20/26 (77%) of patients randomized to pyrimethamine/clindamycin (P/C) and 26/33 (79%) of patients randomized to pyrimethamine/sulfadiazine (P/S) had a complete or partial clinical response. After six weeks, 17/26 (65%) of patients randomized to P/C and 23/33 (70%) of patients randomized to P/S showed a partial or complete clinical response. No patient on either regimen who exhibited a complete response after three weeks had deteriorated at six weeks. The investigators concluded that P/C is an acceptable alternative regimen for patients unable to tolerate P/S. P/S showed enhanced efficacy based on some parameters. After six weeks, 5/26 (19%) patients randomized to P/C and 2/33 (6%) patients randomized to P/S had died. This difference was not significant. Frequency of adverse reactions was equivalent in the two groups. Saba et al. enrolled 14 AIDS patients with toxoplasmic encephalitis in an open-label study of the combination of pyrimethamine (200 mg loading dose, then 75 mg/day) and azithromycin (1000 mg loading dose, then 500 mg/day). 8/14 patients with cerebral toxoplasmosis were treated for more than 21 days and were evaluated for efficacy; 5/8 had a favorable clinical response. (A favorable response was defined as >50% improvement.) Nine patients were evaluable for a radiologic response; 6/9 had favorable responses. Toxicities included rash (n = 5), abnormal liver function (n = 2), vomiting (n = 3) and hypoacusia (n = 1). A total of 45 patients have enrolled in ACTG 156, a dose-escalation trial of the combination of pyrimethamine and azithromycin for toxoplasmic encephalitis. Although the optimal dosages have not been determined, azithromycin when used alone has been associated with early relapse. Azithromycin is available on a compassionate-use basis for patients who have failed or are intolerant of pyrimethamine, sulfadiazine, or clindamycin. See page, 207. Clumeck et al. enrolled 32 AIDS patients with toxoplasmosis in a pilot study of atovaquone (750 mg qid PO) for 6 weeks. 26/32 were evaluable. At day fourteen, 12 patients had a complete and 10 had a partial clinical response; 3 had a complete and 17 had a partial radiologic response. Adverse reactions included elevated LFTs (13 patients), rash (6), and GI disturbances (3). Torres et al. treated 93 AIDS patients with toxoplasmosis with atovaquone 750 mg qid as salvage treatment. Response to treatment and median survival were correlated with the plasma concentration of atovaquone. After six weeks of therapy, clinical improvement or stability was noted in 22/25 (88%), 15/24 (63%), and 7/13 (54%) of patients with atovaquone plasma concentrations greater than 13 mg/ml, between 7 and 13 mg/ml, and less than 7 mg/ml, respectively. Median survival was 426, 424, and 116 days for patients with atovaquone plasma concentrations greater than 13 mg/ml, between 7 and 13 mg/ml, and less than7 mg/ml, respectively. ACTG 237 is comparing the combination of atovaquone/pyrimethamine with atovaquone/sulfadiazine in patients with acute toxoplasmosis; the trial is still underway with 45/100 patients enrolled. Additionally, an open-label study of atovaquone/pyrimethamine is under way at NIH. Canessa et al. treated 25 patients with toxoplasmosis with TMP/SMX 40-50 mg/kg qd IV. Radiological and clinical improvements were seen in 18/25 patients. Stellini et al. retrospectively analyzed 37 AIDS patients with toxoplasmosis treated with TMP/SMX (8-10 mg/40-50 mg/kg qd IV and PO) for 4-6 weeks. 33/37 had both clinical and radiological improvement. Rashes requiring drug discontinuation occurred in 7 patients. The results of a small open-label study suggest that trimetrexate is not adequate as a single-agent therapy for toxoplasmosis. Masur et al. enrolled nine sulfonamide-intolerant AIDS patients with toxoplasmosis in the study. Patients received trimetrexate IV at doses ranging from 30 - 280 mg/m2 daily with leucovorin calcium 20 mg/m2 IV or PO every 6 hours. Partial clinical and/or radiologic responses were observed in 8/9 patients; however, these responses were transient, and all eight patients deteriorated within 13 - 109 days of their initial responses. Trimetrexate was well tolerated in this group. One report suggests that tetracycline derivatives (doxycycline and minocycline) may be effective for toxplasmic encephalitis. Bockmon et al. treated seven patients with either doxycycline 4 mg/kg/day, minocycline 4 mg/kg/day, or minocycline 4 mg/kg/day in combination with pyrimethamine. All patients responded to therapy. MAINTENANCE RESULTS Maintenance therapy is required since recurrence is nearly invariable. For maintenance, sulfadiazine (2-4 g in divided doses) is administered with pyrimethamine (25-50 mg/day). Other treatment regimens are also under investigation. Katlama et al. conducted the maintenance phase of a trial for acute toxoplasmic encephalitis. For maintenance, 83 patients received pyrimethamine 25 mg/day with sulfadiazine 2 g/day, and 92 patients received pyrimethamine 25 mg/day and clindamycin 1.2 g/day. After a median follow-up of 60 weeks, toxoplasmosis relapses were proven in 6 patients receiving pyrimethamine/sulfadiazine and 26 receiving pyrimethamine/clindamycin (P = 0.0007). The investigators conclude, 116

Page  117 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 based on the results of the acute and maintenance phases of this trial, the pyrimethamine/sulfadiazine appears to be the most effective treatment of toxoplasmosis. The investigators also conclude that pyrimethamine/clindamycin is a valuable alternative but is less effective for long-term prevention of relapses. One report (Mouthon et al.) describes the open-label use of atovaquone 750 mg four times daily as a maintenance therapy for patients who have recovered from acute toxoplasmosis. 22 patients were included in the study; 12/22 had received atovaquone as therapy for acute toxoplasmosis, while the other 10 had received other therapies. Relapses occurred in 5/22 patients. All five relapses occurred in patients who had received atovaquone for acute therapy. No side effects requiring drug discontinuation occurred. PROPHYLAXIS RESULTS The United States Public Health Service and Infectious Disease Society of America have published guidelines for the prevention of toxoplasmosic encephalitis. Toxoplasma-seropositive patients with a CD4+ count less than 100 cells/mm3 should receive prophylaxis against toxoplasmic encephalitis. The doses of TMP/SMX recommended for PCP prophylaxis appear to be effective against toxoplasmosis as well. If patients cannot tolerate TMP/SMX, dapsone plus pyrimethamine is recommended. The efficacy of dapsone alone is uncertain. A cooperative French/American study (ANRS 005/ACTG 154) compared pyrimethamine 50 mg/week plus leucovorin to placebo as prophylaxis for toxoplasmosis in patients with T gondii antibodies and CD4+ counts under 200/mm3 (Leport et al.). 554 patients were randomized (274 to pyrimethamine and 280 to placebo) and followed for a mean of 14 months. 86% of the patients were receiving AZT and 86% received PCP prophylaxis with aerosolized pentamidine. On an intent-to-treat analysis, statistically equivalent rates of cerebral toxoplasmosis (12% on pyrimethamine and 13% on placebo) and survival (85% vs. 80%) were observed. Side effects requiring the discontinuation of therapy (in particular, skin rash) were significantly more frequent in the pyrimethamine group (20% vs. 8%, P <0.0001). Pyrimethamine (25 mg three times weekly) without leucovorin was compared with placebo (CPCRA 001, Jacobson et al.). The study began as a comparison of clindamycin (300 mg twice daily), pyrimethamine, and placebo, but the clindamycin arm was discontinued early due to a high toxicity rate. The trial continued as a comparison of pyrimethamine and placebo. Patients with hematologic toxicity received leucovorin. All patients had a CD4 count <200/mm3 or an AIDS diagnosis, and antibodies to T gondii. 264 patients were randomized to pyrimethamine and 132 to placebo. Toxoplasmosis occurred at lower rate than expected, preventing the evaluation of pyrimethamine's efficacy. The study was terminated when a significantly higher mortality rate was observed in the pyrimethamine group (relative risk, 2.5; 95% confidence interval 1.3 - 4.8, (P = 0.006). A significant difference remained after adjustment for factors predictive of survival. Although the reason for the mortality difference has not been determined, it was noted that patients who entered the trial with low hemoglobin levels had a high risk of death associated with pyrimethamine (relative risk, 7.7; 95% confidence interval, 2.0 - 29.7, P = 0.003). This result suggests the hypothesis that pyrimethamine's anti-folate activity accounted for the excess mortality, since leucovorin was not used routinely. A double-blind dose-randomized trial of pyrimethamine (50 mg once or three times weekly) as prophylaxis in HIV+ patients with antibodies to T gondii has been completed by AmFAR's Community Based Clinical Trials Network (CBCTN). Data are under analysis. A French trial (ANRS 003) compared aerosolized pentamidine (300 mg/month) with dapsone (50 mg/day)/pyrimethamine (50 mg/week) plus leucovorin as primary prophylaxis for both toxoplasmosis and PCP. 75% of patients were positive for T gondii antibodies at baseline, and the mean entry CD4+ count was 115/mm3. Girard et al. reported that toxoplasmosis developed in 32/176 and 19/173 of patients receiving aerosol pentamidine and dapsone/pyrimethamine respectively. Patients assigned to aerosol pentamidine had a significantly higher risk of developing toxoplasmosis compared to dapsone/pyrimethamine recipients (relative risk 1.81, 95% confidence interval, 1.12 - 2.94, P = 0.02). Survival was statistically equivalent (41 and 45 deaths in the aerosol pentamidine and dapsone/pyrimethamine groups, respectively). More patients in the dapsone/pyrimethamine group than in the aerosolized pentamidine group discontinued treatment due to toxicity (42 vs.3, P <0.001). Most frequent toxicities were cutaneous and hematological. Opravil et al. presented interim results from an ongoing multi-center Swiss study comparing aerosolized pentamidine (300 mg/month) with dapsone/pyrimethamine (75/200 mg/week) as primary prophylaxis for toxoplasmosis and PCP. 533 HIV+ patients who are symptomatic or have a CD4+ count below 200/mm3 have enrolled; 47% are positive for T gondii antibodies. After a median follow-up of more than a year, 14/291 (4.8%) patients receiving dapsone/pyrimethamine and 20/242 (8.26%) patients receiving aerosol pentamidine have developed toxoplasmosis (P = NS). Intolerance to dapsone/pyrimethamine occurred significantly more frequently than to aerosol pentamidine. Torres et al. conducted a randomized comparison of dapsone (100 mg twice weekly) and aerosolized pentamidine (100 mg every two weeks) for the 117

Page  118 Opportunistic Infections and Related Disorders I prevention of toxoplasmosis and PCP. 278 patients with AIDS or ARC and CD4+ counts <250/mm3 were randomized. The mean follow-up time was 42 and 44 weeks in the dapsone and aerosolized pentamidine groups, respectively, Significantly fewer cases of toxoplasmosis occurred in the dapsone group (0 vs. 6, P = 0.01). Some evidence suggests that TMP/SMX prevents toxoplasmosis. Podzamczer et al. randomized 230 HIV+ patients with CD4+ < 200 cells/mm3 to receive thrice-weekly double strength TMP/SMX (800 mg PO bid) or dapsone/pyrimethamine (50 mg twice-weekly) as prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis. The median CD4+ count was 140 cells/mm3. During a median follow-up of 14 months, rates of toxoplasmosis did not differ significantly between the two groups; 4% of those receiving TMP/SMX and 7% of those receiving dapsone/pyrimethamine developed toxoplasmosis. One small randomized study (Stellini et al.) is under way to compare TMP/SMX (one double-strength tablet every other day) with pyrimethamine (50 mg twice weekly). (Patients randomized to pyrimethamine also receive aerosol pentamidine 300 mg monthly.) 49 patients with CD4+ counts <200/mm3 with T. gondii antibodies have been randomized. An interim analysis after a mean follow-up of 20 months showed that toxoplasmosis had developed in I and 7 patients in the TMP/SMX and pyrimethamine groups respectively (P = 0.03), and PCP developed in 0 and 2 patients (NS). Adverse reactions were observed in 7 and 4 patients (NS). A multi-center, randomized Italian study is under way to compare TMP/SMX (one double-strength tablet daily) with dapsone/pyrimethamine (50 mg daily/50 mg weekly). Patients randomized to dapsone/pyrimethamine will also receive folinic acid 25 mg weekly. All participants have CD4+ counts below 200/mm3; the presence of T. gondii antibodies is not required. Several retrospective chart reviews also support the efficacy of TMP/SMX. Lipman et al. conducted a chart review of all patients who had received TMP/SMX or aerosol pentamidine as prophylaxis for PCP. Of 210 patients who received prophylaxis with aerosolized pentamidine, 8/210 (3.8%) developed toxoplasmosis; 1/154 (0.6%) patients who received prophylaxis with TMP/SMX developed toxoplasmosis. Another non-randomized retrospective chart review was reported by Carr et al. This study included Australian AIDS patients who received TMP/SMX or pentamidine as secondary prophylaxis after an episode of PCP. 60 patients received TMP/SMX (two double-strength tablets twice weekly), and 95 received pentamidine (aerosolized in 78 and intravenous in 17). Thrity seven percent of patients in each group had antibodies to T. gondii. No patient who received TMP/SMX and 12/36 seropositive patients who received pentamidine developed toxoplasmosis (P = 0.008). REFERENCES: Bockmon K et al. Utility of tetracycline derivatives in treatment of CNS toxoplasmosis. Ninth Intl Conf AIDS, abstract PO B10-1427, 1993. Centers for Disease Control. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44:1-24, 1995. Canessa A et al. Cotrimoxazole treatment of Toxoplasma encephalitis in AIDS patients. VI Intl Conf AIDS San Francisco, 1: 241(Th.B.477), 1990. Carr A et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis. Ann Int Med 117: 106-11, 1992. Clumeck N et al. Atovaquone (1,4-hydroxynaphthoquinone, 566C80) in the treatment of acute cerebral toxoplasmosis in AIDS patients. 32nd ICAAC, abstract #1217, 1992. Dannemann Bet al. Treatmentof toxoplasmicencephalitisin patientswith AIDS. Ann Int Med, 116: 33-43, 1991. Girard PM et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii and toxoplasmosis in HIV infection. N ENGL J MED 238: 1514-20, 1993 Godofsky EW. Treatment of presumed cerebral toxoplasmosis with azith<%4>romycin (correspon dence). N ENGL J MED 330:575-6, 1994. Jacobson M et al. Primary prophylaxis with pyrimethamine for toxoplasmic encephalitis in patients with human immunodeficiency virus disease: Results of a randomized trial. J INFECT DIS 169;384-94, 1994. Katlama C et al. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. CID 22:268-75, 1996. Kovacs JA et al. Evaluation of azithromycin or the combination of 566C80 and pyrimethamine in the treatment of toxoplasmosis. Abstract PoB 3199, VIII Intl Conf AIDS, Amsterdam, 1992. Leport C et al. Combination of pyrimethamine-clarithromycin for acute therapy of toxoplasmic encephalitis (TE). A pilot study in 13 AIDS patients. 30th ICAAC, abstract #1158, 1990. Lipman MCI et al. Reduced incidence of toxoplasmosis in patients taking cotrimoxazole as Pneumocystis carinii prophylaxis. Abstract PO-B10-1443, IX Intl Conf AIDS, Berlin, 1993. Luft B et al. Risk factors for development of cerebral toxoplasmosis. Abstract 474, 1st Natl Conf on Hum Retrovir, 1993. Masur H et al. Salvage trial of trimetrexate-leucovorin for the treatment of toxoplasmosis in patients with AIDS. J INFECT DIS 167:1422-6, 1993. Leport C et al. Pyremethamine for primary prophylaxis of toxoplasmic encephalitis in patients with human immunodeficiency virus infection: a double-blind, randomized trial. J INFECT DIS 173:91-7, 1996. Mouthon B et al. Atovaquone as long-term suppressive therapy in toxoplasmosis. Abstract 026, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994. Opravil M et al. Dapsone/pyrimethamine vs. aerosolized pentamidine for combined prophylaxis of PCP and toxoplasmic encephalitis. Abstract PO-B10-1429, IX Intl Conf AIDS, Berlin, 1993. Opravil M et al. Combined prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis: prospective randomized trial of dapsone+pyrimethamine vs. aerosolized pentamidine. Abstract PoB 3315, VIII Intl Conf AIDS, Amsterdam, 1992. Podzamczer D et al. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients with HIV. Ann Intern Med 122:755-61, 1995. Porter SB and Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N ENGL J MED 327:1643-8,1992. Saba J et al. Pyrimethamine plus azithromycin for treatment of acute toxoplasmic encephalitis in patients with AIDS. Eur J Clin Microbiol Infect Dis 12: 853-6, 1993. 118

Page  119 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Stellini R et al. Cotrimoxazole versus pynmethamine in the primary prophylaxis of toxoplasmic encephalitis in HIV infected patients: a randomized prospective study. Abstract P193, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994. Stellini R et al. Effectiveness of trimethoprim/sulfamethoxazole in AIDS patients with toxoplasmic encephalitis. Abstract #P76, Third European Conference on Clinical Aspects and Treatment of HIV Infection. Paris, 1992. Tenant-Flowers M et al. Sulphadiazine desensitization in patients with AIDS and cerebral toxoplasmosis. AIDS 5:311-5, 1991. Torres R et al. Multicenter clinical trial of atovaquone (ATQ) for salvage treatment and suppression of toxoplasmic encephalitis (TE). Abstract PO-B10-1453, IX Intl Conf AIDS, Berlin, 1993. Torres RA et al. Randomized trial of dapsone and aerosolized pentamidine for the prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis. Amer J Med 95:573-83, 1993. Wong SY and Remington JS. Biology of Toxoplasma gondii (Editorial review). AIDS 7:299-16, 1993. OTHER REPORTS: Beaman MH et al. Prophylaxis for toxoplasmosis in AIDS. Ann Int Med 117: 163-4, 1992. Luft BJ et al. Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. N ENGL J MED 329.995-1000, 1993. VIRAL INFECTIONS CYTOMEGALOVIRUS (CMV) Trials, pages 193-197 PATHOGEN: Cytomegalovirus is a herpesvirus that infects directly through mucous-membrane contact or via tissue transplant or blood transfusion. Approximately half the adult population in developed countries, virtually all gay/bisexual men with AIDS, and 75% of other HIV risk groups have been infected with CMV. SITES OF DISEASE: Most frequently the retina, colon and esophagus in AIDS patients; also the lungs, brain, heart, thymus, pancreas, larynx, thyroid, kidneys, gallbladder, liver, and adrenal glands. SYMPTOMS: CMV RETINITIS: May include blurred vision, blind spots and moving spots before the eyes and scotoma progressing to blindness. Ophthalmologic signs may include cotton-wool spot appearance, necrotizing retinitis, hemorrhages and minimal vitreal inflammation. CMV ENCEPIHALI, IS: While CMV is not generally considered to be a neurotropic disease, cases of CMV encephalitis have been reported. Symptoms include headache, confusion, and fever. CMV ESOPHAGITIS: Most commonly includes painful swallowing or the sense of food sticking in the throat. May also include chest pain or hiccups. CMV COLITIS: May include intermittent or persistent diarrhea with cramping, abdominal pain, involuntary rectal spasms, weight loss and general status deterioration. CMV GASTRITIS: May be asymptomatic but often results in severe continuous upper abdominal pain, fever, hemorrhage or obstruction, and diarrhea. CMV RADICULOPATHY: CMV infection of the spine and nerve roots. The most common symptoms are usually isolated to the lower extremity; pain, tingling, or numbness of the legs, urinary or bowel disfunction may also be present. DIAGNOSIS: Histologic findings of viral inclusion bodies in colonic, esophageal, or lung tissue, as well as identification of virus by special stains or culture, are necessary. CMV retinitis, however, is typically diagnosed by ophthalmologic findings alone in high risk patients. A diagnosis of CMV encephalitis can be made by brain biopsy or by detection of CMV DNA in cerebrospinal fluid (CSF). Recovery of CMV by culture is not sufficient to diagnose acute infection. However, periodic assessment of CMV DNA load in peripheral blood by quantitative PCR may be useful for identification of patients at high risk of developing CMV disease and for monitoring the effects of antiviral therapy (Boivin et al). A study reported by Bowen et al. concluded that CMV DNA levels in the blood is an important fact in the progression of CMV retinitis. Blood plasma and urine samples from 45 patients with active CMV retinitis were analyzed using PCR. Kaplan-Meier analysis showed no difference in the rates of retinitis progression (post-therapy) between patients who were found to be PCR-positive or PCR-negative in blood. When the analysis was restricted to those patients who were PCR-positive in blood, those with high viral loads (>4.95 log genomes/ml) appeared to have a shorter time to first progression of retinitis than those with lower viral loads, although this difference did not reach statistical significance. TREATMENT RESULTS CMV RETINITIS (SYSTEMIC): Intravenous formulations of ganciclovir (5 mg/kg IV twice daily), foscarnet (90 mg/kg IV two times daily), and cidofovir (5 mg/kg IV once a week) are approved for the treatment of CMV retinitis in immunocompromised individuals. Upon completion of induction therapy with these doses, lower daily maintenance doses of either ganciclovir, foscarnet, or cidofovir are recommen below). Ganciclovir is the preferred treatment of most practitioners ded (discussed. The major side 119

Page  120 Opportunistic Infections and Related Disorders effect associated with ganciclovir is bone-marrow suppression, which may prevent or limit concomitant use of AZT. Ionized hypocalcemia, reversible renal insufficiency, and penile ulcers (mainly in uncircumcised men) are associated with foscarnet treatment. Foscarnet appears equivalent to ganciclovir in limiting the spread of CMV retinitis; however, it may confer a survival benefit over ganciclovir in patients with advanced HIV, presumably because of its intrinsic anti-HIV activity. The NEI/ACTG study for ocular complications of AIDS (Meinert et al.) randomized 234 patients with CMV retinitis to receive ganciclovir (107 patients) or foscarnet (127 patients). The trial was suspended after 19 months when a significant mortality benefit associated with foscarnet was observed. Although both drugs were equally effective in halting progression of CMV retinitis, the median survival was 12.6 months in the foscarnet group and 8.5 months in the ganciclovir group. This survival benefit could not be attributed to differences in antiretroviral therapy between the two groups. However, foscarnet was associated with substantial toxicity: 22/39 treatment switches from foscarnet to ganciclovir were attributed to foscarnet toxicity, while only 1/14 switches from ganciclovir to foscarnet was attributed to ganciclovir toxicity. Ganciclovir has been demonstrated to delay progression of peripheral CMV retinitis in AIDS patients (peripheral CMV retinitis is not immediately sight threatening). Spector et al. randomized 22 patients to deferred treatment and 13 to immediate treatment with ganciclovir (5 mg/kg bid for 14 days followed by 5 mg/kg qd for 14 weeks). Patients in the deferred group were offered ganciclovir if retinitis progressed. 10/13 in the immediate group and 20/22 in the deferred group had progressive CMV retinitis. The median time to progression was 13.5 days for the deferred group versus 49.5 days for the immediate treatment group (P = 0.001). Cidofovir (formerly known as HPMPC), a cytosine-derived nucleotide analogue with a long intracellular half-life, has been approved by the Food and Drug Administration for patients with either newly-diagnosed or refactory CMV retinitis. Cidofovir must be administered with probenecid (4000 mg) to protect against renal toxicities. Lalezari et al. have reported results from a phase II/III immediate versus deferred trial of intravenous cidofovir. In this study, 40 patients were randomized to receive either immediate treatment with cidofovir (5 mg/kg every week for two weeks) or placebo until disease progressed. Time to progression in the immediate treatment group was 120 days, whereas time to progression in the deferred treatment arm was 22 days. Eleven patients (27%) reported renal toxicities. Toxicities attributed to concomitant probenecid use were reported in 38% of patients enrolled. Lalezari et al. have presented data from a study comparing two maintenance doses of cidofovir (3 mg/kg vs. 5 mg/kg every other week) in 60 patients who failed induction therapy with either ganciclovir or foscarnet. All patients received weekly cidofovir (5 mg/kg) for two weeks as induction therapy. No statistically significant difference was seen between the two maintenance doses; a median of 115 days to progression was reported in the 5 mg/kg group and a median of 49 days to progression in the 3 mg/kg group. Adverse reactions due to concomitant use of probenecid were reported in 29/60 (48%) patients enrolled. Phase I/11 dose-escalating studies of intravenous cidofovir have been reported in HIV+ asymptomatic subjects with CMV viruria. Polis et al. administered HPMPC 0.5, 1.5 or 5 mg/kg weekly or twice weekly, with or without probenecid, to 20 patients. CMV urine cultures became negative in 4/6 evaluable patients receiving the highest doses of cidofovir. The maximum tolerated dose was determined to be about 5 mg/kg weekly, with proteinuria, glycosuria, and creatinine elevations being the dose limiting toxicities. Concomitant probenecid administration appeared to protect against renal toxicity. The results of a clinical trial in patients who required retreatment of CMV after maintenance therapy has failed were recently reported (Jabs et al.). The study (ACTG 228) compared ganciclovir to foscarnet to a foscarnet/ganciclovir combination in treated patients who reported CMV disease progression. A total of 271 patients were randomized to one of three arms; foscarnet (90 mg/kg ql2h x 14 days with 120 mg/kg qd maintenance), ganciclovir (5.0 to 7.5 mg/kg ql2h x 14 days with 10 mg/kg qd maintenance), or a combination of foscarnet (90 mg/kg ql2h x 14 days with 90 mg/kg qd maintenance) and ganciclovir (5 mg/kg qd x 14 days with 5 mg/kg qd maintenance therapy). CMV retinitis progression was reported at 4.8 months in the combination group, 2.1 months in those who received ganciclovir alone, and 1.6 months in those who received foscarnet alone (P = 0.00002). Those who reported disease progression in the monotherapy groups were switched to the alternate monotherapy treatment; those who progressed in the combination group received higher doses of both drugs. For patients originally receiving either ganciclovir or foscarnet monotherapy, a median of 1.6 relapses were reported. There was no significant difference between switching to the alternate treatment and remaining on the inititial regimen. However rates of visual field loss were significantly lower in the combination group (16-degrees/month compared to 18- and 31-degrees/month) (P = 0.003). Quality of life scores reported were significantly better in the ganciclovir monotherapy group. 120

Page  121 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Studies of MSL-109, a human anti-CMV monoclonal antibody, have been halted due to lack of efficacy and excess mortality rates associated with the compound. In a randomized, placebo-controlled study recently reported by Dieterich et al., efficacy of MSL-109 was not determined and suggested higher mortality in patients receiving MSL-109. Two hundred nine patients with active CMV retinitis, either newly-diagnosed or relapsed, were randomized to adjunctive therapy with MSL-109, 60 mg IV every two weeks, or placebo. All patients in the trial received standard doses of either ganciclovir or foscarnet. The rates of retinitis progression were similar between the MSL-109-treated and placebo-treated groups; the median time to progression were 65 days in the MSL-109 group and 66 days in the placebo group. There was an observed mortality difference in the trial; the mortality rate in the MSL-109 group was twice that in the placebo group (P = 0.016). The excess mortality rates were reported only in patients with relapsed CMV retinitis; patients with newly-diagnosed CMV retinitis did not report a statistically significant difference in mortality rates between those treated with MSL-109 or placebo. CMV RETINITIS (LOCALIZED): An intraocular ganciclovir implant has been approved by the Food and Drug Administration for the treatment of CMV retinitis. The Chiron Ganciclovir Implant Study Group (Kupperman et al.) has reported the results from a randomized trial examining two release rates of an intraocular ganciclovir implant (1 ig/h and 2 jig/h) versus standard dose intravenous ganciclovir. A total of 188 patients with symptomatic CMV retinitis were evenly divided to receive either of the two intraocular ganciclovir doses or IV ganciclovir. While no significant differences in disease progression were reported between the two intraocular dose groups, significant delays in disease progression were reported after 182 days in the 2 pg/h ganciclovir implant group and 72 days in the IV ganciclovir group (P = 0.0001). The rate of other eye involvement was 40% in the implant group and 16% in the IV group (NS). Extraocular disease occurred in 15% of the patients in the implant groups combined. There was a slight decrease in visual acuity in the immediate post-operative period for implant patients, although visual acuity returned to preoperative levels within 2-4 weeks. No statistical differences in survival were reported. Incidences of endophthalmitis, retinal detachment, and vitreous hemorrhage were higher in the implant groups. Martin et al. randomized 26 patients (30 eyes) to either immediate treatment with a 1 jig/h intraocular ganciclovir implant or deferred treatment. None of the patients enrolled had received prior treatment for CMV retinitis. The median time to progression of retinitis was 15 days in the deferred group (n = 16) versus 226 days in the immediate treatment group (n = 14)(P <.00001). In the entire study population, biopsy-proven visceral CMV disease developed in 8/26 (31%) patients and 67% of the 26 patients developed retinitis in the fellow eye. Seven patients (18%) suffered a treatment-induced retinal detachment, with five occuring between days 30 and 64. There were two cases of persistent hypotony reported. Two recently reported small case studies (Kirsch et al.) of intravitreal cidofovir suggest that prolonged control of CMV retinitis may be achieved with a single injection. In the first study, patients who had failed or were non-compliant with standard therapy received one 10, 20, 40 or 100 jig injection with concomitant oral probenecid. Patients were assigned to doses in a non-randomized fashion. The median progression time reported in those patients who received a single 20 pg injection was 64 days; data from other doses were inevaluable. No cases of endophthalmitis were reported. In the second case study, 17 patients (24 eyes) received a single dose of intravitreal HPMPC (20 pig) with oral probenecid. The median time to progression after the initial injection was 55 days. Disease progression was reported in 8/24 eyes treated. These eyes were retreated; median time to progression in retreated eyes was 64 days. A phase I/I1 dose-ranging study of ISIS 2922, an antisense compound for the itravitreal treatment of CMV retinitis, has been reported. The manufacturer reports that 10 patients with CMV retinitis were treated intravitreally with ISIS 2922 once a week for 4 weeks and every two weeks thereafter. Two patients received 75 pig (low-dose), 3 received 150 jig (middle-dose) and 5 received 300 pg (high-dose). Responses were observed in 0/2, 2/3, and 5/5 in the low, middle, and high dose groups, respectively. Side effects observed were vitreal inflammation, temporary loss of color vision and ocular discomfort. Three clinical trials of ISIS 2922 are still underway. A compassionate use program for ISIS 2922 is also available for patients who continue to progress while in the clinical trials. See page Error! Bookmark not defined.. RESISTANCE/INTOLERANCE: Development of ganciclovir-resistant CMV infection has been reported to occur in approximately 10% of AIDS patients receiving ganciclovir for > 3 months. Most CMV strains resistant to ganciclovir are susceptible to foscarnet, which may be useful for patients who cannot tolerate or are clinically resistant to ganciclovir. Jacobson et al. enrolled 156 patients with CMV retinitis in ACTG 093, a study of foscarnet as salvage therapy. 72 patients were categorized as ganciclovir-intolerant and 84 121

Page  122 Opportunistic Infections and Related Disorders I as ganciclovir-resistant. The median interval between initiating ganciclovir therapy and switching to foscarnet was 180 days. The first 87 patients were randomized to foscarnet either 60 or 90 mg/kg/day and the remaining 69 patients received 120 mg/kg/day. Median time to retinitis progression for all patients was 8, 9 and 9 weeks for the 60, 90 and 120 mg/kg/day groups, respectively. Overall, moderate or severe adverse effects to foscarnet (renal toxicity, seizure, hypocalcemia, nausea, ataxia and altered mental status) were observed in 95% of patients with a trend toward dose-limiting renal toxicity in the 90 and 120/mg/kg/day groups. There was no survival difference among the three treatment groups. Overall median survival was 25 weeks. GASTROINTESTINAL DISEASE: Dieterich et al. treated 62 AIDS patients with biopsy-proven CMV colitis with ganciclovir (5 mg/kg IV twice daily) or placebo for 14 days. At entry all patients had diarrhea (>6 stools/day), malabsorption, or unintentional weight loss of >4.5 kg after 14 days, the groups did not differ for clinical end points (diarrhea, temperature, body weight, abdominal pain, fatigue, serum albumin, cholesterol or magnesium) or for adverse effects. A reduction in colonoscopy scores from baseline to day 14 was seen in 20/32 (62.5%) subjects treated with ganciclovir compared to 11/30 (36.7%) placebo recipients (P =.042). CMV disease at new sites developed in seven placebo recipients (5 retinitis, I gastritis, I pneumonitis) and three ganciclovir recipients (3 gastritis). The investigators suggest that the treatment might be more effective if extended to 21 or 28 days. A randomized controlled study compared ganciclovir with foscarnet for induction therapy in patients with CMV gastrointestinal disease (Blanshard et al.). Twenty-two patients were randomized to receive ganciclovir and 26 to foscarnet. In each treatment group 73% had a complete or good clinical response; 83% of foscarnet-treated and 85% of ganciclovir-treated patients showed response by endoscopy, and inclusion bodies disappeared from follow-up biopsies in 73% of these. 35 patients developed further evidence of CMV disease during follow-up. No significant difference in times to progression were seen between the two groups. Survival in both treatment groups was < 40 weeks and was unaffected by maintenance therapy. Dietrich et al. treated 10 patients, 5 with upper GI CMV disease and 5 with lower GI disease with foscarnet (90 mg/kg IV ql2h). Mild edema was noted in 2/10 patients (20%) but resolved. 8/10 patients (80%) required 6 weeks of treatment for complete response. 9/10 (90%) responded histopathologically (P =.0067) and 9/10 responded endoscopically (P =.0004). A phase III randomized, open-label trial of foscarnet for the treatment of CMV colitis is currently underway. CMV NEUROLOGICAL DISEASE: A recently completed study has reported results in using polymerase chain reaction (PCR) to measure CMV's DNA in the cerebrospinal fluid (CSF) of seven patients with presumed neurologic CMV involvement treated with ganciclovir (Cinque et al.). After three weeks of treatment with ganciclovir, all seven patients reported significant decreases or clearance of CMV DNA from CSF. Clinical improvements were reported in 4/7 patients. A pilot study is being developed by the AIDS Clinical Trials Group (ACTG 305) of cerebrospinal fluid penetration and response to ganciclovir and foscarnet in presumed CMV neurologic disease. CMV DISEASE IN CHILDREN: A phase I, open-label trial (ACTG 226) of oral ganciclovir for the treatment of general CMV in children between the ages of 2 weeks and 20 years is currently underway and closed to enrollment. Upon completing induction therapy with a single dose of intravenous ganciclovir, patients will be randomized to receive one of four doses of the oral formulation in either syrup or pill form. MAINTENANCE RESULTS CMV RETINITIS: Intravenous formualtions of ganciclovir (5 mg/kg IV qd), foscarnet (90 mg/kg IV qd), and cidofovir (5 mg/kg IV every two weeks) are approved as maintenance therapy for CMV retinitis. Oral ganciclovir (1000 mg tid) has been approved by the Food and Drug Administration as maintenance therapy for CMV retinitis, following induction therapy with IV ganciclovir or foscarnet at higher doses. Results from a clinical trial comparing the safety and efficacy of oral ganciclovr 3000 mg qd, 4500 mg qd, or 6000 mg qd to IV ganciclovir 5 mg/kg qd as maintenance therapy for CMV retinitis have been reported (Friedberg et al.). The average time to progression at 150 days of follow-up was 41 days in the 3000 mg group, 50 days in the 4500 mg group, 57 days in the 6000 mg group, and 70 days in the 5mg/kg (IV) group. The only statistically significant difference reported was between the 3000 mg oral ganciclovir group and the IV ganciclovir group (P = 0.045). There was no statistically significant difference between the three oral ganciclovir dosing groups or between the 4500 mg and 6000 mg oral group and the IV group. There was no significant differences in the incidences of extraocular CMV disease between the four groups. Moreover, there was no statistically significant difference in the incidences of dose-limiting adverse events. The investigators conclude that oral ganciclovir at daily doses of 4500 mg and 6000 mg is well tolerated as maintenance treatment for CMV retinitis. The 122

Page  123 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 investigators also conclude that these two doses appear to offer efficacy falling between 3000 mg and IV ganciclovir 5 mg/kg. Drew et al. compared oral and intravenous ganciclovir in 123 patients with newly diagnosed CMV retinitis. 123 patients received induction therapy with IV ganciclovir for three weeks. 117 patients had stable CMV after induction therapy and were entered in the maintenance phase of the study. 57 were randomized to receive induction and maintenance therapy with intravenous ganciclovir (5 mg/kg/day) and 60 were randomized to oral ganciclovir 1000 mg tid for 20 weeks. When photographic exams were compared on a blinded basis, there was no statistical difference in the mean time to progression (62 days in the IV group vs. 57 days in the oral group. However, median time to progression was 49 days for the IV group and 29 days for the oral group. When progression was monitored by unmasked fundoscopic exam, the mean time to progression was 98 days in the IV group vs. 68 days in the oral group (P = 0.027). No statistically significant difference in visual acuity was observed between groups. Twenty (34%) patients in the IV group compared to 12 (19%) in the oral group developed neutropenia (NS); 13 patients (22%) in the IV group developed sepsis compared to 3 (5%) in the oral group (P < 0.05). A European study by Volker et al. enrolled 159 patients with newly diagnosed CMV retinitis to compare oral ganciclovir to IV ganciclovir for the maintenance of CMV retinitis. After induction therapy with IV ganciclovir, patients were randomized to receive in a 2:1 ratio oral ganciclovir (500 mg PO q4h) or IV ganciclovir (5 mg/kg IV qd) for 20 weeks. When photographic exams were compared on a blinded basis, there was no statistical difference in the mean time to progression (62 days in the IV group vs. 51 days in the oral group). When progression was monitored by unmasked fundoscopic exam, the mean time to progression was 109 days in the IV group vs. 86 days in the oral group (P = 0.02). GI disturbances were more frequent in the oral treatment group, and neutropenia and leukopenia occurred more frequently in the IV group. In a study by Squires et al., 220 patients with stable CMV retinits who were receiving intravenous ganciclovir for <4 months were randomized to receive IV ganciclovir 5 mg/kg/d (n = 70), oral ganciclovir 500 mg six times daily (n = 74) or oral ganciclovir 1000 mg three times daily (n = 76) for 20 weeks. When photographic exams were compared on a blinded basis, the mean time to progression was 66, 53, and 54 days in the IV, 500 mg PO, and 1000 mg PO groups, respectively (difference not significant). When progression was monitored by unmasked fundoscopic exam, the mean time to progression was 99 days in the IV group vs. 75 days in the 500 mg oral group (P = 0.023) vs. 77 days for the 1000 mg oral groups (P = 0.082). No statistically significant differences in mortality, treatment failure, opthalmic change, or neutropenia were observed among groups. Sepsis occurred more frequently in the IV group. Jacobson et al. (1992) treated 30 patients with CMV retinitis who completed a two-week induction course with ganciclovir with either combined or alternating ganciclovir and foscarnet. Patients were randomized to either ganciclovir (3.75 mg/kg/d) plus foscarnet (60 mg/kg/d), or ganciclovir (6 mg/kg/d) alternating daily with foscarnet (120 mg/kg/d). 12/15 subjects in the combination group and 15/15 in the alternating group were evaluable. Median time to retinitis progression was greater than 12 weeks for the combination group and greater than 20 weeks for the alternating groups (difference not significant). Grade 4 neutropenia was seen in 6/12 patients on the combination and 4/15 on the alternating regimen. In a randomized dose-comparison study of maintenance foscarnet (90 or 120 mg/kg/day), Jacobson et al. (1993) demonstrated that survival was significantly greater at the higher dose without statistically significant evidence of increased serious toxicity. However, there was significantly greater minor toxicity and a trend toward greater serious toxicity at the higher dose. 32 patients who completed a two-week induction treatment with foscarnet (60 mg/kg three times daily) were randomized; 15 patients received foscarnet 90 mg/kg/day and 17 received 120 mg/kg/day. Median survival from the time of study entry was 157 days and 336 days for subjects in the 90 and 120 mg/kg/day groups, respectively (P <0.001). Transient ionized hypocalcemia occurred significantly more often in the 120 mg/kg group. PROPHYLAXIS RESULTS Oral ganciclovir has been approved by the Food and Drug Administration (FDA) for the prevention of CMV disease in patients with advanced HIV infection. Spector et al. randomized 725 patients with CD4+ counts < 50 cells/mm3 or CD4+ counts < 100 cells/mm3 and a history of an AIDS-related opportunistic infection to receive oral ganciclovir 1000 mg q8h or placebo. After 20 months, the Data Safety Monitoring Board (DSMB) halted the trial due to significant differences between the two arms and all participants were offered open-label ganciclovir. The mean CD4+ count at the time of entry was 26 cells/mm3; median CD4+ count at baseline was 21 cells/mm3. All patients enrolled were followed by an ophthalmologist and were examined every three months regardless of symptoms. At the time of analysis, CMV disease occured in 76/239 (30%) patients in the placebo group and 76/486 (16%) patients in the ganciclovir group (P =.0001). Death occured in 66/239 (29%) patients in the placebo group and 109/486 (22%) patients in the ganciclovir group (P =.08). Drew et al. have recently reported that the prevelence of ganciclovir resistance was low (< 1%) after a mean of 8.3 months of prophylaxis. 123

Page  124 Opportunistic Infections and Related Disorders Brosgart et al. recently reported the results of a randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of CMV disease (CPCRA 023). 954 patients with fewer than 100 CD4+ cells/mm3 were randomized to either 1000 mg q8h oral ganciclovir (n = 622) or placebo (n = 332). The mean CD4+ count upon entry was 44 cells/mm3; median CD4+ count at baseline was 34 cells/mm3. All patients were followed by a primary care physician and referred to an ophthalmologist if symptoms were reported by the patient. No statistical difference was reported between the two groups in terms of CMV disease development or survival. 99/622 (15.9%) in the ganciclovir group and 55/332 (16.7%) in the placebo group developed CMV disease. Reported deaths were 221/622 (35.5%) and 132/332 (37.7%), respectively. The development of CMV retinitis was reported in 74/622 (11.9%) patients receiving ganciclovir and 44/332 (13.3%) patients receiving placebo. CMV colitis rates were 21/622 (3.4%) and 12/332 (3.6%), respectively. Valacyclovir has been found to be moderately effective in preventing CMV disease in HIV+ people (Feinberg et al). ACTG 204 was a phase III randomized, placebo-controlled study of valacyclovir versus two doses of acyclovir for the prevention of CMV disease. While the trial was prematurely closed due to higher mortality rates in the valacyclovir group, these differences were not statistically significant. This study treated 1227 patients with CD4+ cell counts under 100 cells/mm3 with either valacyclovir (2 g qid) or acyclovir (800 mg qid or 400 mg bid). The diagnosis of CMV retinitis was based on clinial examination by an ophthalmologist every 6 months. Confirmed CMV endpoints were reached in 51/523 (11.7%) in the valacyclovir group and 123/704 (17.5%) in the acyclovir groups combined (P = 0.03). Oral acyclovir is' not effective in preventing CMV disease in HIV infected people. Drew et al. randomized 93 HIV+ symptomatic patients to receive AZT 600 mg daily with acyclovir 4800 PO mg/d (n = 52) or with placebo (n = 41) to determine if high-dose ACV suppresses CMV viruria. Urine was obtained at 3 month intervals for at least 6 months. The addition of acyclovir did not suppress CMV excretion in the urine in these patients. Youle et al. enrolled 302 CMV-seropositive subjects with CD4+ count <150/mm3 in a double-blind placebo-controlled trial studying oral high-dose acyclovir (800 mg PO four times daily for 48 weeks) in combination with anti-retroviral treatment for the prevention of CMV disease. All patients received AZT, ddl or AZT/ddC; in addition half received acyclovir and half received placebo. After more than one year follow-up 16/153 acyclovir-recipients and 9/149 placebo recipients developed confirmed CMV disease (difference not significant). REFERENCES: Blanshard C et al. Treatment of AIDS-associated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison. J INFECT DIS 172:622-8, 1995. Boivin G et al. Evaluation of the cytomegalovirus DNA load in polymorphonuclear leukocytes (PMNL) of HIV-infected patients using quantitative PCR (Q-PCR). Abstract #11, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Bowen EF et al. Cytomegalovirus retinitis in AIDS patients: influence of cytomegaloviral load on response to ganciclovir, time to recurrence and survival. AIDS 10:1515-20, 1996. Cinque P et al. Ganciclovir therapy for cytomegalovirus infection of the central nervous system in AIDS patients: Monitoring by CMV DNA detection in cerebrospinal fluid. J INFECT DIS 171:1603-6, 1995. Cochereau-Massin I et al. Intravitreal ganciclovir: a 3-year experience. Abstract 023, Third European Conference on Clinical Aspects and Treatment of HIV Infection. Paris, 1992. Cribbin K et al. Intravitreal ganciclovir in patients resistant to ganciclovir and /or foscarnet. Abstract PoB3159, VIII Intl Conf AIDS, Amsterdam, 1992. Crumpacker C et al. Oral vs. intravenous ganciclovir (GCV) as maintenance treatment of newly diagnosed cytomegalovirus retinitis (CMVR) in AIDS. 1st Nat Conf Hum Retrov, abstract 538: 154, 1993. Dieterich D et al. Ganciclovir treatment of cytomegalovirus colitis in AIDS: A randomized, double-blind placebo-controlled multicenter study. J INFECT DIS 167: 278-282, 1993. Dietrich D et al. Treatment of gastrointestinal cytomegalovirus infection using twice daily administration of foscarnet in AIDS patients. 1st Nat Conf Hum Retrov, abstract 513: 146, 1993. Dieterich D et al. Monoclonal antibody CMV retinitis trial: preliminary results. Abstract LB8b, 36th ICAAC, New Orleans, 1996. Drew WL et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N ENGL J MED 333:615-20, 1995. Drew WL et al. Failure of acyclovir to suppress excretion in symptomatic HIV antibody positive patients. Abstract 1115, 32nd ICAAC, Anaheim, 1992. Drew WL et al. Prevelence of ganciclovir resistant cytomegalovirus during oral ganciclovir prophylaxis. Abstract #LB16, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Feinberg J et al. Phase III study of valacyclovir for cytomegalovirus prophylaxis in patients with advanced HIV disease. 35th ICAAC, Abstract #1214, San Francisco, 1995. Friedberg D et al. A comparison of the safety and efficacy of 3g, 4.5g, and 6g doses of oral ganciclovir versus IV ganciclovir for maintenance treatment of CMV retinitis. Abstract Th.B.305, XI International Conference on AIDS, Vancouver, 1996. Jabs D et al. Combination therapy for retinitis: Results of ACTG 228. 20th ACTG, Washington DC, 1995. Jacobson MA et al. Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG protocol 093). AIDS 8: 451-459, 1994. Jacobson MA et al. A dose-ranging study of daily maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in AIDS. J INFECT DIS 168: 444-448, 1993. Jacobson MA et al. Randomized phase I study of combined vs. alternating foscarnet (PFA) / ganciclovir (GCV) maintenance therapy (Rx) for CMV retinitis. 32nd ICAAC, abstract #1223, 1992. Kirsch LS et al. Phase I/Il study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 119:466-76, 1995. Kirsch LS et al. Intravitreal cidofovir treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology 102:533-42, 1995. Kuppermann B et al. A randomized controlled multicenter trial of sustained-release intraocular ganciclovir implant in AIDS patients with CMV retinitis. 35th ICAAC, Abstract # 1215, San Francisco, 1995. 124 I

Page  125 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17 Lalezari J et al. A randomized, controlled study of cidofovir for relapsing cytomegalovirus retinitis in patients with AIDS. 35th ICAAC, Abstract #LB-9, San Francisco, 1995. Martin EF et al. Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant: A randomized controlled clinical trial. Arch Opthalmol 112:1521-1539, 1994. Meinert CL et al. Studies of the Ocular Complications of AIDS Research Group, AIDS Clinical Trials Group. Mortality in patients with the acquired immune deficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N ENGL J MED 326(4): 213-220, 1992. Nightingale SD et al. An intraocular slow-releasing ganciclovir drug delivery system for treatment of CMV retinitis. VII Intl Conf AIDS, Florence. Vol 2: 245(W.B.2255), 1991. Polis M et al. A phase I/11 dose escalation trial of (s)-1-[3-hydroxy-2-(Phos-phonymethoxy)propyli]otosine (HPMPC) in HIV-infected persons with CMV viruria. 33rd ICAAC, Abstract #98, 1993. Salzberger B et al. Foscarnet and ganciclovir combination therapy for severe CMV-disease in HIV-infected patients. Abstract PO-B08-1233, IX Intl Conf AIDS, Berlin, 1993. Spector S et al. Pharmacokinetics, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: a phase 1/11 study. J INFECT DIS 171:1431-7, 1995. Spector S et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. J INFECT DIS 168: 557-563, 1993. Squires K et al. Oral ganciclovir (POG) versus intravenous ganciclovir (IVG) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS: preliminary results of a phase III study. 1st Nat Conf Hum Retrov, abstract 540: 154, 1993. Verdejo J et al. Intravitreal ganciclovir for cytomegalovirus treatment (CMV) retinitis. Abstract PoB3175, VIII Intl Conf AIDS, Amsterdam, 1992. Volker K et al. Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS 9:471-477, 1995. Youle M et al. Effects of high-dose acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study. AIDS 8: 641-649, 1994. OTHER REPORTS: Balfour H et al. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N ENGL J MED 20(21): 1381-7, 1990. Lalezari JP et al. The safety, pharmacokinetics, and anti-CMV activity of weekly HPMPC in HIV-positive patients excreting CMV. 1st Nat Conf Hum Retrov, abstract 541: 154, 1993. Leach CT et al. A longitudinal study of cytomegalovirus infection in human immunodeficiency virus type 1-seroposetive homosexual men: molecular epidemiology and association with disease progression. J Infect Dis 170: 293-298, 1994. Medina DJ et al. Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. Ant Agnt Chemo 36(5): 1127-1130, 1992. Nelson M et al. Foscarnet in the treatment of cytomegalovirus infection of the esophagus and colon in patients with the acquired immunodeficiency syndrome. Am J Gastroenterology. 86(7): 876-881, 1991. Plotkin SA et al. Vaccines for varicella-zoster virus and cytomegalovirus: recent progress. Science 265: 1383-1385, 1994. Studies of Ocular Complications of AIDS Research Study Group. Antiviral effects of foscarnet and ganciclovir therapy on human immunodeficiency virus p24 antigen in patients with AIDS and cytomegalovirus retinitis. J INFECT DIS 172:613-21, 1995. Whitcup SM et al. Ocular manifestations of AIDS. JAMA 275:142-44, 1996. -----------------*X II*~~O~I~ ~ - r--^--~--rr--~^rrrr---~r -rc~-- ~-u-~-rx - _-~- -~-~ - - - HEPATITIS Trials, page 197-198 PATHOGEN: Non-opportunistic hepatotrophic viruses including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) and non-A non-B non-C (NANBNC) hepatitis virus (hepatitis G). HEPATITIS A: Most cases of HAV are subclinical. The virus disappears following acute infection. HAV has no known carrier state and plays no role in the production of chronic active hepatitis or cirrhosis. Transmission is primarily through oral-fecal contact. HEPATITIS B: More than 84 percent of the HIIV+ population present with HBV blood markers. This high frequency of superinfection is consistent with the similar transmission pathways of HBV and HIV. HBV is transmitted parenterally, typically by contaminated blood or blood products, and through sexual, perinatal, and occupational contact with infected body fluids. Previous conclusions by Eskild et al. that the presence of hepatitis B antibodies in HIV+ patients is associated with more rapid clinical progression to AIDS have not been confirmed. Recent studies (Stevenson M et al., Meier K et al.) have shown that co-infection appears to make no difference in clinical outcome. HEPATITIS C: The incidence of HCV in HIV+ individuals, predominantly injection drug-users and hemophiliacs, has been increasing. Transmission, traditionally thought to occur solely through exposure to contaminated blood, can also be attributed to non-parenteral routes. Eyster at al. has shown that the frequency of HCV sexual transmission is higher when HIV is present, suggesting that HIV may be a cofactor for the sexual transmission of HCV. Eyster has also shown that progression of HCV to cirrhosis and liver failure is hastened by HIV infection, though HCV has no effect on HIV. HEPATITIS D (DELTA): HDV can only replicate in the presence of HBV and occurs either as a co-infection with HBV or a superinfection in established HBV carriers. Clinically, HDV is a serious and often progressive disorder manifested by an unusually aggressive course. NON-A NON-B NON-C (HEPATITIS G): The term non-A, non-B non-C hepatitis (NANBNC) refers to infections not due HAV, HBV, or HCV. The hepatitis G virus (HGV) appears to be the cause of most sporadic NANBNC hepatitis cases. SYMPTOMS: After an incubation period of 60 to 160 days, most HIV+ patients infected with HBV develop acute inflammation of the liver characterized by diffuse or 125

Page  126 Opportunistic Infections and Related Disorders patchy hepatocellular necrosis. Cases often present with malaise, anorexia, fever, jaundice and mild splenomegaly. Infection is followed by recovery and subsequent immunity in more than 95 percent of infected persons. Approximately 5 percent will fail to eliminate the virus from the liver and become chronic carriers. Chronic hepatitis is more likely to develop in HIV+ individuals with HBV because of reduced cell-mediated immunity. HBV DNA levels can be followed and are prognostic. With HCV, illness may develop following an average 50 day incubation period. At least 50 percent of these infections progress to chronic disease. Many remain asymptomatic yet present with cirrhosis and/or hepatocellular carcinoma after a 5-10 year follow-up. Eyster et al. have shown that the presence of HIV can worsen the clinical course of HCV infection and contribute to the progression to liver disease. DIAGNOSIS: Elevated liver enzymes and urinary bile provide early indications of hepatocellular inflammation and may be clues to viral hepatitis infection. The HBV surface antigen is detected in serum and is usually the first indication of acute HBV infection. Core antigens may be found in infected hepatocytes. Corresponding antibodies develop after clinical recovery and usually persist throughout life; thus, their detection indicates past infection and immunity. Antibodies fail to develop in those cases which progress to chronic or asymptomatic carrier status. Serum tests for HCV itself became available in 1989. HCV antigens can be detected in the cytoplasm of infected hepatocytes. HCV antibodies may take several months to appear in serum after acute infection. HCV RNA levels can be followed at commercial laboratories and correlate with disease progression. Chronic hepatitis diagnosis is by needle biopsy of the liver. TREATMENT RESULTS Alpha interferon 2b (Intron A) is approved for the treatment of chronic hepatitis in individuals who are not HIV+. Intron A is typically administered by injection for either 16 weeks (HBV) or for 52 weeks (HCV). In HIV+ individuals, studies of alpha interferon 2b and AZT have shown only limited response rates with high relapse rates for responders who discontinued treatment. Common side effects include flu-like symptoms that make long-term administration difficult. Farci et. al showed favorable response rates (50%) for individuals with hepatitis-D who were treated with short-term high-dose alpha interferon 2a (Roferon A) as compared to low-dose or no treatment. 3TC (lamivudine) is under investigation for the treatment of chronic hepatitis. Benhamou et al. recently reported results from a prospective open-label study of 3TC in 37 consecutive patients infected with both HIV and HBV. All patients received 3TC 600 mg/day. Two groups were retrospectively identified at baseline: patients with high HBV replication (serum HBV DNA concentrations > 5 pg/mL) and patients with low HBV replication (serum HBV DNA concentrations < 5 pg/mL. After 12 months of treatment, 26 of 27 patients (96.3%) who had high HBV replication at baseline had serum HBV DNA concentrations less than 5 pg/mL. However, PCR could still detect HBV DNA in 11.5% of these patients. Among patients who had low HBV replication at baseline, the results of PCR for serum HBV DNA became negative in the 6 patients who had a positive result at baseline. No serious adverse events occurred during treatment. Results from randomized, controlled trials are not yet available. The only established therapy for hepatitis C is alpha interferon. The three dimensional structure of the HCV protease has recently been determined (Kim et al.). This should prove useful for the future development of therapeutics for disease caused by HCV. REFERENCES: Benhamou Y et al. Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Ann Intern Med 125:705-12, 1996. Cribier B et al. High hepatitis C viraemia and impaired antibody response in patients with HIV. AIDS 9:1131-1136, 1995. Dorucci M et al. Coinfection of hepatitis C virus with human immunodeficiency virus and progression to AIDS. J INFECT DIS 172:1503-8, 1995. Eskild A et al. Hepatitis B antibodies in HIV infected homosexual men are associated with more rapid progression to AIDS. AIDS 6:571-574, 1992. Eyster ME et al. Heterosexual co-transmission of hepatitis C virus (HCV) and Humman Immunodeficiency Virus (HIV). Ann Int Med 115: 764-768, 1991. Dienstag JL et al. A preliminary trial of lamivudine for chronic hepatitis B infection. N ENGL J MED 333: 1657-61, 1995. Farci P et al. Treatment of chronic hepatitis-D with interferon alph-2a. N ENGL J MED 330:88-94, 1994. Hadler SC et al. Outcome of hepatitis B virus infection in homeosexual men and its relation to prior human Immunodeficiency Virus Infection. Journal Inf Dis 163:454-459 1991. Jia-Horng Kao et al. Sexual transmission of HCV. Lancet 342: 626, 1993. Kim JL et al. X-ray crystal structure of the hepatitis C virus NS3 serine protease domain, completed with a synthetic Ns4A cofactor peptide. Abstract LB2, 36th ICAAC, New Orleans, 1996. Korenman J et al. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Int Med 114:629-634, 1991. Scharschmidt BF et al. Hepatitis B in patients with HIVilnfection: relationship to AIDS and patient survival. Ann Int Med 117:837-838, 1992. Stevenson M et al. Hepatitis B markers do not predict decline in CD4 count. Abstract PO-B02-0947, IV Intl Conf AIDS, Berlin, 1993. Zanetti AR et al. Mother-to-infant transmission of hepatitis C virus. Lancet 345:289-90, 1995. 126

Page  127 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 r HERPES SIMPLEX VIRUS Trials, page 198 PATHOGEN: Herpes simplex virus types I and type 2 (HSV-1, HSV-2). SITES OF INFECTION: Herpesviruses typically infect epithelial and nerve tissues. Reactivation of these infections are common in AIDS patients. Lesions resulting from HSV-I most commonly affect the mouth and lips, and those resulting from HSV-2 affect the genitals and anus. A recent report (Heng et al.) showed that in vitro co-infection with HSV-I allows HIV-1 to infect cells not normally permissive to HIV-I infection (in this case, keratinocytes which do not express the CD4 receptor). The authors also noted unique morphological and replicative characteristics of the virions in the co-infected cells which suggested the presence of an HSV-I/HIV-I hybrid virus. These data may support the concept of suppressive treatment for herpes simplex in HIV-1 infected people. SYMPTOMS: Herpes simplex virus infection usually causes painful blisters on an inflamed base. DIAGNOSIS: By virus culture of the lesion or fluorescent antibody testing. TREATMENT RESULTS Oral acyclovir (800 mg tid) is approved for the treatment of HSV-related syndromes and reduces the severity and duration of HSV symptoms. Famciclovir and valacyclovir have been shown to be effective treatments for herpes simplex infection. However, neither compound has demonstrated superiority to acyclovir. ACYCLOVIR-RESISTANT HERPES SIMPLEX: The development of acyclovir-resistant herpes simplex has been well documented in HIV+ patients who were receiving long-term acyclovir treatment (1 - 5 months). Foscarnet is the only available agent in the U.S. shown to be effective for acyclovir-resistant HSV infection and is used frequently for this indication. Foscarnet has been approved by the Food and Drug Administration (FDA) for the treatment of acyclovir-resistant herpes simplex in immunecompromised patients. Recent evidence reported by Safrin et al. (1994) suggest that foscarnet-resistant HSV infections may be recognized with increasing frequency. Erlich et al. treated 4 AIDS patients with severe acyclovir-resistant HSV-2 disease with foscarnet (60 mg/kg IV every 8 hours) for 12 to 50 days. Marked clinical improvement, marked clearing of lesions, and eradication of HSV from mucous membranes were noted. Tan et al. treated 6 patients with acyclovir-resistant HSV with foscarnet. Significant or complete healing of lesions occurred in all patients by the end of day 14. Foscarnet maintenance suppressed the recurrence of lesions for up to 10 weeks. Recurrent lesions were successfully treated with a second induction course of foscarnet. No significant renal or neurological toxicities were seen. One patient developed persistent penile ulcerations. A randomized multicenter trial (ACTG 095) established that foscarnet is superior to vidarabine (Ara-A) for acyclovir-resistant mucocutaneous HSV (Safrin et al.). Eight patients received foscarnet (40 mg/kg IV three times daily) and 6 received vidarabine (15 mg/kg IV daily). Lesion reduction and healing were observed in foscarnet recipients after 10 - 24 days of therapy; no patient on vidarabine healed. Recurrences in acyclovir-resistant HSV occurred in all patients who had healed; the median time to relapse was 42.5 days after discontinuing foscarnet. Hardy et al. recently completed an open-label study of topical foscarnet cream in 20 patients with acyclovir-resistant herpes simplex. Median time to 50% and 100% decrease in lesion size was 22 days and 44 days, respectively. Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had 50% reduction; among 5 patients with no pain at baseline, 2 remained pain free and 3 developed pain. Adverse events included skin ulcerations in 6 patients and fever in 4 patients. Kessler et al. enrolled 26 AIDS subjects in an open-label study (ACTG 172) of topical trifluridine (TFT) for ACV-resistant chronic mucocutaneous HSV. Interim data reported on 9 subjects showed that 7/9 subjects responded to treatment. Lesions completely healed in 5/7 responders (mean duration to healing 32 days) and 2/7 had a partial response. No toxicities were reported. Weaver et al. treated two AIDS patients with acyclovir-resistant HSV with topical TFT solution. TFT was applied three times daily; all lesions healed completely within 11 to 34 days. Lalezari J et al. has reported results from a randomized, double-blind, placebo-controlled study of cidofovir topical gel for the treatment of acyclovir-resistant herpes simplex. A total of 30 patients were randomized to receive either one of two concentrations (1% and 0.3%) topical HPMPC or placebo. Complete responses to treatment were reported in 3/11 patients receiving 127

Page  128 Opportunistic Infections and Related Disorders the 0.3% topical gel and 3/9 patients receiving the 1% topical gel at day 15. However, these data were not statistically significant. A phase I trial (ACTG 253) to evaluate the pharmacokinetics, safety, and tolerance of valacyclovir in HIV+ children (ages 12 and under) with herpes zoster or herpes simplex infection in currently underway. REFERENCES: Bentley et al. Absolute bioavailability of acyclovir is substantially increased following oral valaciclovir. Abstract #PB0523, X Intl Conf AIDS, Japan, 1994. Erlich KS et al. Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with AIDS. Ann Int Med 110: 710-13, 1989. Hardy et al. Phase I pilot study of the safety and efficacy of foscarnet cream for treatment of acyclovir-resistant herpes simplex. Abstract #167, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Heng M et al. Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet 343: 255-260, 1994. Kessler H et al. ACTG 172: treatment of acyclovir-resistant (ACV-R) mucocutaneous herpes simplex virus (HSV) infection in patients with AIDS: open label pilot study of topical trifluridine (TFT). Abstract WeB1056, VIII Intl Conf AIDS, Amsterdam, 1992. Lalezari J et al. A randomized, double-blind, placebo-controlled study of cidofovir topical gel for acyclovir-resistant herpes simplex virus infections in patients with AIDS. Abstract #174, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Safrin S et al. Foscarnet-resistant herpes simplex virus infection in patients with AIDS. J INFECT DIS 169: 193-6, 1994. Safrin S et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in acquired immunodeficiency syndrome. N ENGL J MED 325: 551-5, 1991. Tan C et al. Foscarnet induction and maintenance therapy for acyclovir-resistant herpes simplex infections in AIDS. VI Intl Conf AIDS San Francisco, abstract #Th.B. 447, 1990. Weaver D et al. Topical trifluridine treatment of acyclovir-resistant herpes simplex disease. 31st ICAAC, abstract #507, 1991. OTHER REPORTS: Kaplowitz L et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection. JAMA 265(6): 747-751, 1991. Murphy M et al. Topical trifluridine for mucocutaneous acyclovir-resistant herpes simplex II in AIDS patients. Lancet 340: 1040, 1992. Pottage J et al. Acyclovir resistant (ACV-R) herpes simplex: susceptibility to alternative antiviral agents. Abstract PoB3238, VIII Intl Conf AIDS, Amsterdam, 1992. HERPES ZOSTER VIRUS Trials, page 199 PATHOGEN: Varicella-zoster virus (herpes zoster, VZV). SITES OF INFECTION: VZV, the chicken-pox virus, resides in the nerve roots adjacent to the spine; herpes zoster (shingles) represents an acute reactivation of VZV. These lesions typically affect the face and trunk. SYMPTOMS: Herpes zoster is a painful, blistery rash that follows the path of a sensory nerve. DIAGNOSIS: By virus culture of the lesion or fluorescent antibody testing. TREATMENT RESULTS Treatment of severe herpes zoster infection may require hospitalization and treatment with intravenous acyclovir or other antiherpetic agents. The Antiviral Drugs Advisory Committee to the FDA recently failed to recommend approval to the manufacturer of sorivudine (BV ara-U), based on data that indicated an unfavorable risk/benefit ratio. Results from a phase III study (ACTG 169) of sorivudine (BV ara-U) (40 mg once daily for 10 days) vs acyclovir (800 mg five times daily for 10 days) in localized zoster demonstrated superiority of BV ara-U (Gnann et al.). All patients were enrolled within 72 hours of rash onset and evaluated daily until lesions were completely crusted. The median time to cessation of new vesicle formation was shorter in the sorivudine group (3 days) than in the acyclovir group (4 days). Median time to 100% crusting was also shorter in the sorivudine group (7 days) than in the acyclovir group (8 days). Time to resolution of zoster-associated pain was not different between the two groups. Similar findings from a European study of the safety and efficacy of sorivudine were presented by Dehertogh et al. Sorivudine (40 mg once daily) was compared with the standard acyclovir dose (800 mg 5 times qd) among 137 HIV+ individuals. This study was halted when the second interim analysis revealed a statistical diffence between the two therapies in favor of BV ara-U. Patients were followed for 6 months. Sorivudine reduced the mean number of days to cessation of new lesion formation and time to 100% crusting by one-third compared to acyclovir. Time to cessation of acute pain and time to resolution of postherpetic neuralgia was not different between the two therapies. 128

Page  129 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 Safrin et al. treated 5 AIDS patients with acyclovir-resistant VZV with foscarnet (40 mg/kg IV three times daily for more than 10 days). 4/5 patients had complete or nearly complete healing of lesions. 2/4 had a relapse 7-14 days after completing foscarnet therapy; isolates from both patients showed susceptibility to acyclovir in vitro. One relapse patient responded to intravenous acyclovir; one patient did not respond to oral acyclovir (4,000 mg daily for 12 days). Famciclovir is being investigated in a clinical trial for the treatment of first time herpes zoster infection in HIV+ people. CHILDREN: A phase I trial (ACTG 253) to evaluate the pharmacokinetics, safety, and tolerance of valacyclovir in HIV+ children with herpes zoster or herpes simplex infection is currently underway. A second trial in HIV+ children (ACTG 265) is examining the safety and immunogenicity of live-attenuated varicella vaccine. REFERENCES: Dehertogh et al. The safety and efficacy of sorivudine (BV-ara-U) for the treatment of zoster in HIV-infected adults. Abstract #A/7, 34th ICAAC, Orlando, 1994. Gnann J et al. Sorivudine (BV-araU) versus acyclovir for herpes zoster in HIV-infected patients. Abstract #12, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Jacobson MA et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immune deficiency syndrome (AIDS). Ann Int Med 112(3): 187-91, 1990. Safrin S et al. Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann Int Med 115(1): 19-21, 1991. Veenstra J et al. Complications of varicella zoster virus reactivation in HIV-infected homosexual men. AIDS 10:393-99, 1996. HUMAN PAPILLOMA VIRUS (HPV) Trials, page 199 DESCRIPTION: Human papilloma virus-related anogenital neoplasms are being reported with increasing frequency in HIV+ people in the United States and Europe. Klein et al. found that HIV+ women have a higher rate of squamous intraepithelial lesions (SIL) on PAP smear than HIV-negative women. SIL was detected on PAP smear in 28/111 (25%) HIV+ and 11/107 (10%) HIV-negative women. Vernon et al. reported that asymptomatic HIV+ women have a significantly higher risk of cervical intraepithelial neoplasias (CIN) with HPV than HIV-negative women do. It was discovered that HIV with associated HPV co-localized in CIN lesions frequently and that co-localization was independent of both clinical status and CD4+ counts. Data from the Women's Interagency HIV Study reports a ten fold increase in genital warts in HIV+ women (Greenblat et al.). Regevik et al. found that HIV+ women with CD4+ counts below 500/mm3 and with evidence of HPV infection may be at higher risk for developing neoplastic changes in the cervix. SITES OF DISEASE: HPV-related anogenital abnormalities can manifest as a field disease, potentially involving the cervix, vagina, vulva, perianal area and anal canal, as well as the penis and urethra. Bouchaud et al. reports that HPV has also been found in the esophagus. DIAGNOSIS: Field examination, including vagina, vulva, cervix, perianal region, anal canal, as well as the penis, may be indicated. Pap smears (both cervical and anal), HPV viral typing, and colposcopy and anoscopy with biopsy are commonly used diagnostic procedures. TREATMENT RESULTS Carbon dioxide laser, cryotherapy, electrocautery, excision and surgery, radiation treatment and systemic chemotherapy are used for the treatment of HPV infection. Intralesional alpha interferon is approved for use in condylomata acuminata. Local chemotherapy with cytotoxic agents includes the use of trichloroacetic acid, podophyllum resin, and 5-Fluorouracil (5-FU). An ACTG study (ACTG 216) of interferon alpha and isotretinoin for anal dysplasia is about to begin. A clinical trial of Imiquimod, a heterocyclic amine in a topical form which stimulates the production of interferon, has been shown to be effective in treating genital and perianal warts. REFERENCES: Greenblat RM et al. Lower genital tract infections among HIV infected women and high risk seronegatives: the Women's Interagency HIV Study. XI International Conference on AIDS, Vancouver, 1996 Klein RS et al. A prospective study of genital neoplasia and human papillomavirus (HPV) in HIV infected women. Abstract TuB0527, VIII Intl ConfAIDS, Amsterdam, 1992. Regevik N et al. Cervical human papillomavirus (HPV) in correlation with immune status and papanicolaou smear abnormalities. Abstract TuB0528, VIII Intl Conf AIDS, Amsterdam, 1992. Vemon S et al. Localisation of HIV-1 to human papillomavirus associated cervical lesions. Lancet 344(8927): 54,1994. OTHER REPORTS: Baggish M. Carbon dioxide laser treatment for condylomata acuminata venereal infections. Obstetrics and Gynecology, 55(6)711-714,1980. Bouchaud O et al. Human papilloma virus in the esophagus in HIV patients. Abstract PB0171, X Intl Conf AIDS, Yokohama, 1994. Brown D et al. Detection of Multiple human papillomavirus types in condylomata acuminata from immunosuppressed patients. J Infect Dis 170(4): 759-765, 1994. Byme M et al. The common occurrence of human papillomavirus infection and intraepithelial neoplasia in women infected by HIV. AIDS, 3: 379-82, 1989. Krown S. Treatment of AIDS-assocated malignancy. Cancer Detect & Prev 14(3): 405-9, 1990. Lowry D et al. Genital human papillomavirus infection. PNAS 91: 2436-2440,1994. Mandelblatt JS et al. Association between HIV infection and cervical neoplasia: implications for clinical care of women at risk for both conditions. AIDS 6:173-8,1992. Schrager et al. Cervical and vaginal squamous cell abnormalities in women infected with human immunodeficiency virus. J AIDS 2: 570-5, 1989. 129

Page  130 Opportunistic Infections and Related Disorders MOLLUSCUM CONTAGIOSUM PATHOGEN: Researchers have recently determined the entire DNA sequence of the virus that causes molluscum contagiosum (MCV) (Senkevich et al.). MCV is one of two poxviruses known to infect people. The other human poxvirus is variola virus, which causes smallpox. SITES OF INFECTION: An infection of the skin that can result in small, flesh-colored papules on the forehead, beard area and upper trunk. It is common in young children and people with HIV infection. The condition is not life-threatening and treatment is primarily cosmetic. TREATMENT RESULTS Cryotherapy may be effective. Tappero et al. enrolled 16 HIV+ patients with molluscum contagiosum (MC) and a CD4+ count <200/cells/mm3 in a study of alpha interferon (5 MU SC qd for 8 weeks). 15/16 subjects completed the study. Overall, no decrease in the number of MC lesions was observed. REFERENCES: Senkevitch TG et al. Complete genome sequence of a hman tumorigenic poxvirus predicts novel host-response evasion genes. Science 273:813-6, 1996. Tappero JW et al. Alpha interferon for severe HIV-associated molluscum contagiosum. Abstract PoB3886, VIII Intl Conf AIDS, Amsterdam, 1992. ORAL HAIRY LEUKOPLAKIA PATHOGEN: Oral hairy leukoplakia (OHL) has been associated with Epstein-Barr virus (EBV) and with Human Papilloma Virus (HPV). The clinical significance of OHL in otherwise healthy, asymptomatic individuals is that it can be an early manifestation of HIV infection. One report (Torres et al.) suggested that the incidence of OHL is significantly higher for males than for females. SITES OF INFECTION: White lesions usually appear on the lateral borders of the tongue but can also appear on the buccal and labial mucosae. The lesions of HL are corrugated or have a shaggy or "hairy" appearance. DIAGNOSIS: By clinical presentation and confirmed by biopsy. TREATMENT RESULTS Lozada-Nur et al. treated 10 HL patients with one application of topical podophyllin resin. All patients responded within 4 to 5 days of treatment. Period of clinical remission ranged from 2 to 28 weeks. Investigators have noted that oral high-dose acyclovir (> 3 grams/day) can reduce or eliminate lesions. REFERENCES: Lozada-Nur F et al. Podophyllin resin 25% for treatment of oral hairy leukoplakia: an old treatment for a new lesion. J AIDS 4(5): 543-546, 1991. Torres R et al. Oral lesions in patients with HIV infection enrolled in CPCRA trials. Abstract PB0165, X Intl Conf AIDS, Japan, 1994. _ _ __~1 _1. 1,~-~ -~~. 1-~ - 1-- ~I-- --- --1--- ------- au~r uwaraurr PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) PATHOGEN: The JC virus (JCV). SITES OF INFECTION: JCV infects oligodendrocytes, the cells in the brain that produce myelin. PML is a rare neurological disease believed to be caused by reactivation of latent JCV infection, resulting in demyelination of the central nervous system. Initial brain lesions occur around blood vessels, suggesting dissemination via the blood. PML occurs at a much higher frequency in people with AIDS than it does in patients with other immunosuppressive disorders, developing in 3 to 4% of AIDS patients. Approximately 70% of adults in the U.S. have antibodies to JCV. PML does not appear to be contagious, and the primary infection probably occurs in childhood. SYMPTOMS: Mental status changes followed by speech or language deficits, visual deficits, and generalized or focal weakness. Neurologic signs include lack of coordination (weakness of one limb or one side of the body), cranial nerve palsies, loss of vision on one side, sensory loss in one limb or one side of the body, language disturbance, and unsteadiness. DIAGNOSIS: JCV has been isolated from the brain and urine. Definitive diagnosis of PML requires brain biopsy although sensitivity ranges from 40% to 96%. Clinically, diagnosis is made by detecting focal lesions and abnormalities of the white matter on neuroimaging studies (CT or MRI). Recently, polymerase chain reaction of DNA of JCV from cerebrospinal fluid (CSF) has been used in diagnosis. 130 I

Page  131 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199; 7 TREATMENT RESULTS No effective treatment for PML has been identified. The disorder is usually rapidly progressive and fatal, although rare prolonged survival and occasional remissions have been documented. Britton et al. treated 13 PML patients (mean CD4+ count 106) with intrathecal cytosine arabinoside (ara-C, cytarabine). 8/13 subjects stabilized and improved after treatment. Other investigators (de Truchis et al., Nicoli et al., Urtizberea et al., Fong et al., and Antinori et al.) have reported that ara-C offered no prolonged clinical improvement to patients with PML. A trial of IV versus intrathecal ara-C is currently underway and closed to enrollment (ACTG 243). It has been reported by Allegre et al. that no improvement was observed when intrathecal AZT was given for 3 months to 2 PML patients. Topotecan, a topoisomerase 1 inhibitor, has been shown in vitro to be active against the JC virus. Trials of topotecan for PML are in development. REFERENCES: Allegre T et al. Intrathecal zidovudine (IT-AZT) treatment of patients with HIV associated progressive multifocal leukoencephalopathy (PML). Abstract PO-B16-1727, IX Intl Conf AIDS, Berlin, 1993. Antinori et al. Failure of cytarabine and increased JC virus-DNA in the cerebrospinal fluid of patients with AIDS-related progressive multifocal leukoencephalopathy. AIDS 8: 1022-1024, 1994. Britton CB et al. Progressive multifocal leukoencephalopathy: disease progression, stabilization and response to intrathecal ARA-C in 26 patients. Abstract ThB3886, VIII Intl Conf AIDS, Amsterdam, 1992. De Truchis P et al. Inefficacy of cytarabine in progressive multifocal leucoencephalopathy in AIDS. Lancet 342: 622, 1993. Dubois V et al. Detection of JC virus DNA in the peripheral blood leukocytes of HIV-infected patients. AIDS 10:353-8, 1996. Fong IW et al. The natural history of progressive multifocal leucoencephalopathy (PML) Abstract PO-B01-0864, IX Intl Conf AIDS, Berlin, 1993. Nicoli F. et al. Efficacy of cytarabine in progressive multifocal leucoencephalopathy in AIDS. Lancet 339: 306, 1992. Urtizebera JA et al. Cytarabine for progressive multifocal leucoencephalopathy (PML) in AIDS patients. Abstract PO-B16-1717, IX Intl Conf AIDS, Berlin, 1993. OTHER REPORTS: Berger J et al. Progressive multifocal leukoencephalopathy in HIV-1-infected children. AIDS 6: 837-841, 1992. Guarino M et al. Progressive multifocal leukoencephalopathy in AIDS: treatment with cytosine arabinoside. AIDS 9:815-816, 1995. NEUROLOGICAL COMPLICATIONS Dementia trials, page 200 Peripheral neuropathy trials, page 201 See also: Peripheral neuropathy text, page 134 Central nervous system (CNS) and peripheral nervous system ((PNS) disorders in HIV+ individuals may result from opportunistic infections, neoplasms, and processes that appear to be primary effects of human immunodeficiency virus (HIV) itself. The nervous system may also be damaged as a result of the toxic effects of various treatments. Indeed, the majority of AIDS patients will eventually manifest one or more of these neurological conditions. AIDS DEMENTIA COMPLEX The most important CNS complication, that has been attributed to a primary effect of HIV, has been described using a variety of terms including the AIDS dementia complex (ADC), subacute encephalitis and HIV encephalitis. This syndrome may represent more than one type of disease process. It is characterized by decreased concentration and rapidity of thought, loss of interest in activities, and slowness of motor movements. The link between HIV infection in the brain or in the body and this neurological condition still remains uncertain. While it is clear that patients severely affected by this disorder have HIV-infected macrophages within the brain, those with milder disease have not been shown to have active virus infection within the brain. TREATMENT RESULTS AZT has been demonstrated to improve and possibly prevent HIV-induced cognitive dysfunction in certain patients. Sidtis and co-workers enrolled 39 patients with AIDS dementia in a placebo-controlled study (ACTG Protocol 005) of AZT (1,000 or 2,000 mg/d). Final analysis showed neuropsychologic function improved in those patients receiving AZT compared with placebo, and raised the question of whether the very high dose of AZT (2,000 mg daily) might have been most effective. This result is consistent with those of earlier studies in adults and children showing similar AZT effect in both treatment and prevention. An open study of three doses of AZT (1,000 mg, 750 mg, or 500 mg/day) in 30 patients with ADC was conducted by Tozzi et al. Response to treatment was sometimes transient, and was not associated with the dose of AZT. 131

Page  132 Opportunistic Infections and Related Disorders Yarchoan et al. reported on five patients with HIV-related neuropsychiatric impairment who received ddl in a dose-ranging phase I study; all patients experienced significant improvement. A multicenter open label pilot trial of ddl (375 mg or 250 mg) in mild or severe ADC is under way. ACTG 140, a comparative trial of ddl vs. AZT (ddl 250 or 375 mg qd or AZT 1,000 mg qd) is underway at Tulane University and Washington University in St. Louis. Clear evidence of ddl, ddC, d4T, or other antiretroviral effect in AIDS dementia complex awaits further study. These results are anecdotal and some clinicians report less favorable experiences, particularly when setting of AIDS dementia develops or recurs in patients already being treated with AZT. In such patients the choices include raising the AZT dose to 1,000 mg per day or more if there has not been evidence of drug intolerance or toxicity (perhaps in concert with GM-CSF if needed); switching to or combining therapy with another antiretroviral drug; adding an adjunct therapy aimed at interfering with some of the toxic processes underlying brain injury as described below. At least 3 drugs are being evaluated for their ability to improve neurological function without directly inhibiting virus replication. These adjunctive therapies include: cytokine antagonists, antioxidants and neuroprotective agents. They are in various stages of testing. Peptide T, which was thought to have some promise as a potential therapy, was found ineffective in a large randomized study. Some cell-culture studies suggest that the HIV envelope protein gpl20 is toxic to neurons by virtue of its effect on calcium channels. A trial (ACTG 162) with the calcium channel blocker nimodipine has been completed. Psychostimulants such as methylphenidate hydrochloride (Ritalin) may be helpful in some patients with characteristic psychomotor slowing. In those with agitation or frank mania, lithium or neuroleptics (see below) may be helpful, although therapy should start with very low doses. CHILDREN: A parallel syndrome is very common in children with AIDS, eventually causing major developmental delay, loss of milestones, cognitive impairment, and motor deficits in perhaps 75% of patients. Therapeutic studies indicate that AZT is effective in ameliorating neurological deficit in these patients. Preliminary studies suggest that ddl may also be helpful in children with AIDS. Wolters et al. evaluated the effects of ddl on 64 children with symptomatic HIV infection. All patients received ddl for at least 6 months. 42/64 patients received ddl for 12 months. Age-appropriate general intelligence tests were administered to children prior to treatment and after 6 and 12 months of ddl. Overall there was no change in IQ scores associated with ddl. Individually, over the first 6 months of ddl treatment 21% of the children showed significant improvement in IQ (10% change and 8 points), 9% declined, and 70% remained stable. There was little further change in IQ scores after the second 6 months of treatment. The investigators suggest a correlation between plasma ddl concentrations and improved IQ scores. OPPORTUNISTIC INFECTIONS AND NEOPLASMS OF THE CENTRAL NEVROUS SYSTEM (CNS) Opportunistic infections of the central nervous system eventually develop in one-third or more of patients with AIDS. The most common opportunistic infections of the CNS are cerebral toxoplasmosis developing in 5-10% of AIDS patients depending on geographic location, cryptococcal meningitis in perhaps 5-10% of AIDS patients, and progressive multifocal leukoencephalopathy (PML) in 2-5% of AIDS patients. Cytomegalovirus commonly infects the brain, although usually this is not of major clinical significance; however, 5% of patients may develop more severe CMV infection of brain or nerves. Much less common are mycobacterial (M. tuberculosis) infections, neurosyphilis and viral (herpes simplex encephalitis or myelitis) infections. Other fungal (Aspergillus and Candida) infections are rare. In the case of CMV, infection of peripheral nerves (more accurately, infection of nerve roots) presents as an acute condition causing weakness and numbness beginning in the legs which then affect urinary and bowel functions. Diagnosis is assisted by examination of the cerebrospinal fluid (CSF), which shows a characteristic cell response (Polymorphonuclear leukocytes); many patients have been reported to respond to ganciclovir treatment or combination treatment with ganciclovir and foscarnet. Hence, diagnostic evaluation and rapid implementation of such treatment should be pursued aggressively. HIV+ patients are susceptible to the development of lymphomas, including primary CNS lymphomas (i.e., originating in the CNS rather than spreading secondarily from the body). Whole-brain radiotherapy is the treatment of choice. Lymphomas can also spread to the CNS, usually to the meninges (the membranes covering the brain) rather than to the brain tissue. Treatment of systemic lymphomas, which may develop earlier in HIV infection than primary CNS lymphomas, usually involves intensive systemic therapy and sometimes intrathecal (into the spinal fluid) chemotherapy (see Lymphomas, page 103). 132

Page  133 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 17.......l..:,..,,x. .i..i.<..^!,i;i~g~i~3~br~Nlsa~~aus~sbsiP~~ OTHER CNS CONDITIONS COMPLICATING HIV INFECTION In addition to the HIV-specific CNS complications of infection discussed above, patients can develop a number of other neurological disorders that occur in those with severe systemic illness. These include metabolic encephalopathies due to hypoxia, hepatic insufficiency of disseminated intravascular coagulation. Strokes may also complicate the course of AIDS. Likewise, many medications may cause disturbances of cognition or alertness. Clinical experience suggests that AIDS patients may be particularly sensitive to the side effects of antipsychotics and other CNS-active drugs. Because of this wide array of possible CNS complications and the importance of clear cognition for the quality of life, accurate diagnosis is an important part of patient management. PRIMARY EFFECTS OF HIV ON THE CNS While it is clear that the CNS may be exposed to HIV early in the course of infection, this does not characteristically result in clinically evident neurological dysfunction until much later. Thus, studies of asymptomatic seropositives have shown that the CSF is frequently mildly abnormal (elevated white blood cells and protein, locally produced antibody, and, in up to 30%, detectable virus), yet the study subjects remained clinically normal even when evaluated using careful quantitative neuropsychological testing. Additionally, prospective studies (including the Multicenter AIDS Cohort Study) have shown that systemically asymptomatic subjects remain neurologically intact. Nonetheless, HIV does cause symptomatic neurological disease later in HIV infection, although the mechanisms involved remain uncertain. Very early in the course of HIV infection, at or near the time of seroconversion, some patients develop acute encephalitis, aseptic (nonbacterial) meningitis, or various neuropathies. These unusual syndromes appear to relate either to direct viral infection of the nervous system or to host immune responses (immunopathology triggered by the virus). They are generally self-limiting and usually resolve with little or no residual effect. HIV+ individuals may develop aseptic meningitis at the time of seroconversion or after, which is presumed to be caused by HIV itself. Presenting symptoms are headache and stiff neck, and the diagnosis is made by spinal tap and examination of the CSF that reveal an increased number of cells but negative cultures for bacteria and absence of cryptococcus. This generally benign condition must be differentiated from more important causes of headache (such as toxoplasmosis) or CSF cell abnormality (such as cryptococcal meningitis). It also should be differentiated from the more common headache that complicates and is common in HIV infection. Such headache may be severe and persistent, yet no cause is established after thorough evaluation. Some patients appear to respond to low doses of the anti-depressant amitriptyline, while others may require the use of narcotic analgesics. REFERENCES: Tozzi V et al. Effects of zidovudine in 30 patients with mild to end-stage AIDS dementia complex. AIDS 7:683-92, 1993. Wolters P et al. The effects of dideoxyinosine (ddl) on the cognitive functioning of children with HIV infection after 6 and 10 months of treatment VII Intl Conf AIDS, Florence. Vol 2: 194(W.B.2051), 1991. Yarchoan R et al. Long term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex. Lancet 336: 526-29, 1990. OTHER REPORTS: Aronow H et al. The management of the neurological complications of HIV infection and AIDS. AIDS 2(suppl 1): S151-9, 1988. Brouwers P et al. Effect of continuous-infusion zidovudine therapy on neuropsychologic functioning in children with symptomatic human immunodeficiency virus infection. J Pediatr 117: 980-5, 1990. De Girolami U et al. Neuropathology of the acquired immunodeficiency syndrome. Arch Pathol Lab Med 114: 643-655, 1990. Gabuzda DH. Neurologic disorders associated with HIV infections. J Am Acad Dermatol 22: 1232-6, 1990. Heyes, M P et al. Quinolinic acid in cerebrospinal fluid and serum in H!V-1 infection: Relationship to clinical and neurological status. Ann Neurol 29(2): 202-9, Feb. 1991. Ingraham L et al Neuropsychological effects of early HIV-1 infection: assessment and methodology. J Neuropsych & Clin Neurosci 2: 174-182, 1990. Kramer E et al. Brain imaging in acquired immunodeficiency syndrome dementia complex. Sem Nuc Med 20(4): 353-63, 1990. Lechtenberg R. AIDS in the brain. Intl J STD & AIDS 1: 311-317, 1990. Lipton S. Models of neuronal injury in AIDS: another role for the NMDA receptor? Trends in Neurosci, 15(3):75-79, 1992. Maj M. Organic mental disorders in HIV-1 infection. AIDS 4: 831-840, 1990. McArthur J. Low prevalence of neurological and neuropsychological abnormalities in otherwise healthy HIV-1-infected individuals: Results from the Multicenter AIDS Cohort Study. Ann Neurol 26: 601-611, 1989. McArthur J. Neurologic manifestations of AIDS. Medicine (66) 6: 407-437, 1987. McGrail M et al. Peptide T studies: Neurophysiologic results. VII Intl Conf AIDS, Florence. Vol 1: 194(M.B. 2049), 1991. Mclntyre K et al. Pilot study of zidovudine (AZT) and zalcitabine (ddC) combination in HIV-associated dementia. Abstact #PB0233, X Intl Conf AIDS, Yokohama, 1994. Perdices M et al. Neuropsychological investigation of patients with AIDS and ARC. J AIDS 3: 555-564, 1990. Perry S. Organic mental disorders caused by HIV: update on early diagnosis and treatment. Am J Psych 147(6): 696-710, 1990. Portegies P. Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. B Med J 299(6703): 819-21, 1989. Price R et al. The brain in AIDS: Central nervous system HIV-1 infection and the AIDS dementia complex. Science 239: 586-92, 1988. 133 I

Page  134 Opportunistic Infections and Related Disorders Price R et al. Central and peripheral nervous system complications of HIV-1 infection and AIDS. In: AIDS, Etiology, Diagnosis, Treatment and Prevention, eds. DeVita VT, Hellman S and Rosenberg SA. J.B. Lippincott Company, Philadelphia, 3rd ed. 14:237-257, 1992. Pulliam L et al. Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 87(2): 503-12, Feb. 1991. Satriano, J et al. Central nervous system stimulants as symptomatic treatment for AIDS dementia complex. VII Intl Conf AIDS, Florence. Vol 1: 195(M.B. 2053), 1991. Sei S et al. Increased human immunodeficiency virus (HIV) type 1 DNA content and quimolinic acid concentration in brain tissues from patients with HIV encephalopathy. J INFECT DIS 172:638-47, 1995. Sidtis et al. Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial. Ann Neur (in press) 1993. Simpson DM et al. Neurologic Manifestations of HIV Infection. Ann Intern Med 121: 769-785, 1994. Stover E et al. CNS aspects of HIV-1 infection and AIDS in infants and children: A collaborative research agenda. Ped AIDS and HIV Infection 1: 109-119, Nov. 6, 1990. Wiley C et al. Human immunodeficiency virus: infection of the nervous system. Curr Topics Microbiol 160: 157-72, 1990. Worley JM et al. Clinical manifestations of the HIV-1 infection of the nervous system. In: Handbook of Neurovirology, W Stroop and R McKendall, eds. Marcel Dekker (in press), 1992. Worley JM et al. Management of neurologic complications of HIV-1 infection. In: The Medical Management of AIDS, M Sande and P Volberding, eds. Philadelphia: W.B. Saunders Co., third edition. 13:193-217, 1992. PERIPHERAL NEUROPATHY Trials, page 201 Two types of neuropathy are common in HIV infection. The first type, subacute are uncommon and occur relatively early in HIV infection, before susceptibility to major opportunistic infections. A second type, predominantly sensory axonal polyneuropathy, develops as a late complication in up to 30% of people with AIDS. The first is felt to have an autoimmune pathogenesis. Like subacute (Guillain-Barrd syndrome), which develops in non-HIV+ persons, it responds favorably to plasma exchange, IVIG or glucocorticoids, with the former being the currently recommended treatment. The major morbidity of axonal predominantly-sensory polyneuropathy relates to pain and to the fact that patients may have to stop neurotoxic antiretrovirals (i.e., ddl, ddC, or d4T). In some cases, painful burning or tingling may be so severe that the patient avoids shoes or bedclothes. Treatment is symptomatic; anecdotal experience suggests AZT is usually ineffective. The mainstay is amitriptyline (Elavil) or other tricyclics initiated at low doses. For patients with lancinating brief bursts of pain, phenytoin, carbamazepine, and topical capsaicin can also be tried. In a study by Dejard and co-workers in 16 patients with chronic painful diabetic neuropathy, mexiletine (10 mg/kg/d PO) relieved the symptoms but not the signs of neuropathy. Mexiletine is a congener of lidocaine currently used as a treatment for ventricular arrhythmias. A placebo-controlled trial of mexiletine (10 mg/kg/d) for HIV-related neuropathy is underway at the AIDS Community Research Consortium in Redwood City, CA. Preliminary results indicate 8/10 evaluable patients experienced 50% pain relief on subjective assessment. Two did not improve. One patient was withdrawn due to disseminated MAC and CMV retinitis. Improvement was most likely to occur during the first 3 weeks of treatment, and symptoms returned within I week of cessation of treatment. Side effects included transient GI upset, nausea and vomiting. ACTG 242 is a placebo-controlled trial comparing mexiletine and amitriptyline for the treatment of peripheral neuropathy. The trial closed to enrollment with 146 patients enrolling. The target number of participants was 240 The ACTG is conducting a trial of nerve growth factor, which has the potential to stimulate the regeneration of damaged nerve fibers (ACTG 291). This study remains open to enrollment ddC, d4T, and ddl induce a similar neuropathy in a dose-dependent manner (most common with ddC, least with ddl). Patients on such drugs must be monitored for the onset of pain or numbness in the feet. When these therapies are stopped, the symptoms may progress for a few weeks, but usually then gradually reverse. Chronic AZT therapy can lead to muscle weakness and wasting, perhaps due to an effect on mitochondrial DNA polymerase. Serum creatine kinase is usually elevated and muscle biopsy may show "ragged red" fibers. Discontinuation of AZT allows gradual recovery. A multi-center randomized clinical trial (CPCRA 022) is underway to study acupuncture alone and in combination with amitriptyline for the relief of the symptoms of peripheral neuropathy. REFERENCES: Doob PR et al. Role of peptide T in palliation of HIV-1 related painful peripheral neuropathy. VII Intl Conf AIDS, Florence. Vol 2: 225(W.B.2173), 1991. Gabuzda DH. Neurologic disorders associated with HIV infections. J Am Acad Dermatol 22: 1232-6, 1990. Kent G et al. The safety and efficacy of mexiletine in HIV-associated painful peripheral neuropathy (PPN). VII Intl Conf AIDS, Florence. Vol 1: 199(M.B. 2068), 1991. Levy D et al. Topical capsaicin in the treatment of painful diabetic neuropathy. Lancet (letter) 324: 776, 1991. McGrail M et al. Peptide T studies: Neurophysiologic results. VII Intl Conf AIDS, Florence. Vol 1: 194(M.B. 2049), 1991. Parry GJ. Peripheral neuropathies associated with human immunodeficiency virus infections. Ann Neurol 23 suppl(): 49-53, 1988. Price R et al. Central and peripheral nervous system complications of HIV-1 infection and AIDS. In: AIDS, Etiology, Diagnosis, Treatment and Prevention, eds. DeVita VT, Hellman S and Rosenberg SA. J.B. Lippincott Company, Philadelphia, 3rd ed. 14:237-257, 1992. 134 I

Page  135 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 OTHER COMPLICATIONS OF HIV APHTHOUS ULCERS PATHOGENESIS: Oral and genital ulcers resembling recurrent aphthous ulcers (RAUs) in HIV+ patients are being reported with increasing frequency (MacPhail et al.). Recurrent aphthous ulcers are commonly diagnosed in two forms. The first form of RAUs resemble clusters of herpetiform type ulcerations. The second and more severe RAUs are large, painful necrotic ulcers. The etiology of RAUs remain unknown, however a number of factors have been cited including stress, infectious agents, and circulating growth factors (TNF). RAUs are commonly reported adverse events of treatment with ddC. SITES OF INFECTION: Most commonly, the tongue and mucosal membranes of the oral cavity and esophagus. Aphthous genital ulceration has also been reported in various reports. DIAGNOSIS: Because most RAUs take on the characteristics of various viral manifestations (herpes), diagnosis can be problematic. However, unlike lesions caused by herpes simplex, RAUs generally occur on nonkeratinized mucosa. A biopsy may be required of large RAUs to exclude a malignancy or opportunistic infection diagnosis. TREATMENT RESULTS Topical corticosteroids like flucinonide and dexamethasone have been found to be relatively effective in treating minor RAUs. Prednisone is commonly prescribed for larger ulcerations. Thalidomide has been reported recently as an effective treatment for RAUs (ACTG 251). Jacobson et al. randomized 44 HIV+ patients with recurrent aphthous ulcers to receive thalidomide 200 mg/day or placebo. 14/23 (61%) patients receiving thalidomide reported a complete response; 1/21 (5%) patients receiving placebo reported a complete response (P < 0.0001). Drowsiness was the primary toxicity reported. REFERENCES: Jacobson JM et al. Thalidomide for treatment of HIV associated oral aphthous ulcers (ACTG 251). 20th ACTG, Washington DC, 1995. MacPhail LA et al. Recurrent aphthous ulcers in assocation with HIV infection: diagnosis and treatment. Oral Surg Oral med Oral Pathol 73:283-8, 1992. DIARRHEA & MALABSORPTION Trials, page 202-203 Malabsorption is impaired uptake of nutrients from the intestines. Nutrients are normally absorbed from food in the intestines by cells that make up the finger-like villi lining the intestinal wall. Certain disease processes-including HIV infection-can cause the villi to become atrophied and shortened. This cell malfunction results in impaired absorption of nutrients. Diarrhea occurs at some point in the clinical course of most people with AIDS or HIV infection. It may occur early on or in end-stage infection, and may be sporadic or continuous. Diarrhea is a major source of mortality in HIV+ children in Africa (Thea et al.); HIV+ Zairian infants have an 1-fold increased risk of dying from diarrhea compared with uninfected infants. The GI symptoms of AIDS were originally attributed to opportunistic enteric pathogens or to malignancy. Smith et al. report that specific pathogens can be isolated in the majority of patients. Grohmann et al. detected viruses in 35% of fecal specimens from 65 HIV+ patients with diarrhea compared to only 12% of specimens taken at the same time from 65 HIV+ patients without diarrhea. Patients with diarrhea were more likely to have astrovirus, picomavirus, caliciviruses and adenoviruses. However, Ullrich et al. suggest that abnormalities of the intestinal lining can also result from HIV infection itself. The gastrointestinal tract can be affected by many types of infectious agents: Parasitic diseases: * Cryptosporidiosis (see page 106 ). * Isosporiasis (see page 108). * Microsporidiosis (see page 108). * Entamoeba histolytica and Giardia lamblia Viral infections * Cytomegalovirus. Colitis is the most commonly recognized GI manifestation of CMV disease in AIDS (see page 119). Bacterial infections * Mycobacterium avium complex (MAC) (see page 81). * Salmonellosis (see page 86). * Campylobacter and Shigella dysentery present with symptoms similar to those of salmonellosis. Standard treatments are effective. High rates of Clostridium difficile-associated diarrhea resulting from antibiotic therapy have been reported as well. 135

Page  136 Opportunistic Infections and Related Disorders TREATMENT RESULTS Tierney et al. treated 9 HIV+ patients with chronic diarrhea and no enteric pathogens with 5-ASA (Mesalamine) 6 g/day PO. Diarrheal symptoms improved in 7/9 patients, and rectal p24 content was significantly reduced over 2 months. No side effects were reported. A randomized, double-blind, placebo-controlled trial of octreotide acetate (Sandostatin) in 129 HIV+ patients with refractory diarrhea. Patients were randomized to receive octreotide acetate (100 |tg SC three times daily) or placebo. No significant differences between the treatment group and control group were reported. At three weeks, 46% of the octreotide acetate group reported a 30% decrease in stool volume, versus 36% of the patients in the placebo group (NS). In an open-label extension of the trial, all patients received octreotide acetate 500 pg SC three times daily. Patients from the previously randomized arms reported a decrease in stool volume during the open-label extension; 42% and 39%, respectively. Cello et al. enrolled 51 patients with HIV-related wasting in an open-label dose-escalating study of octreotide acetate (Sandostatin) (50, 100, 250, 500 Pg SC three times daily). 21/51 patients (41.2%) had a complete response (reduction in daily stool volume by 50% or reduction to < 250 mL/d). 14/21 responders (67%) had no identifiable pathogens at initial screening compared to 9/30 (30%) nonresponders (P < 0.01). Reduction in stool volume from baseline was associated with doses higher than 50 pig. Side effects included burning at injection site, nausea and vomiting. Octreotide acetate may inhibit pancreatic secretion, but this side effect is manageable with pancreatic enzyme replacement therapy. A phase I trial of diethylhomospermine (DEHSPM), a polymine analog, is under way for refractory AIDS-related diarrhea. REFERENCES: Cello et al. Effect of octreotide on refractory AIDS-associated diarrhea. Ann Int Med 115: 705-10, 1991. Grohmann G et al. Enteric viruses and diarrhea in HIV-infected patients. N ENGL J MED 329(1): 14-20, 1993. Simon DM et al. Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea. Gastroenterology 108:1753-60, 1995. Smith PD, moderator. Gastrointestinal infections in AIDS. Ann Int Med 116: 63-77, 1992. Thea DM et al. A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants. N ENGL J MED 329:1696-702, 1993. Ullrich R et al. Small intestinal structure and funimction in patients infected with human immunodeficiency virus (HIV): evidence of HIV-induced enteropathy. Ann Int Med 111: 15-21, 1989. OTHER REPORTS: Chlebowski R et al. Nutritional status, gastrointestinal dysfunction, and survival in patients with AIDS. J Gastro 84: 1288-93, 1989. Connolly G et al. Non-cryptosporidial diarrhoea in human immunodeficiency virus (HIV) infected patients. Gut 2: 195-200, 1989. THROMBOCYTOPENIA Trials, page 203 DESCRIPTION: Thrombocytopenia is a common HIV-related disorder. HIV-related thrombocytopenia bears some similarity to idiopathic thrombocytopenic purpura (ITP). However, it is distinct from ITP in several respects, including its tendency to respond to AZT treatment. Ballem et al. report that both platelet survival and platelet production (by megakaryocytes) are decreased'in HIV-related thrombocytopenia. This latter finding, together with the in vitro observation that HIV can infect megakaryocytes, suggest that HIV infection of megakaryocytes may be a direct cause of thrombocytopenia. TREATMENT RESULTS There is no standard treatment for HIV-related thrombocytopenia. While some treatments have been reported to be effective, spontaneous remission occurs without treatment in 10 - 20% of patients. Several groups (Hymes et al., Swiss Group for Clinical Studies on AIDS, Jackson et al.) have reported that AZT can rapidly increase platelet counts in patients with HIV-related thrombocytopenia. This increase generally occurs within several weeks of initiating treatment, but is not sustained after treatment cessation. In patients with AZT-resistant thrombocytopenia, alpha interferon (IFN-a) has been reported to be a safe and effective treatment. Marroni et al. treated 15 patients with platelet counts less than 25,000/mm3 who were refractory to 1 month of full dose (1000 mg/day) AZT. Patients were randomized to either IFN-ac> (3 million units) or placebo three times a week subcutaneously for 4 weeks, followed by a 4-week washout period, then switched to the alternative treatment. Complete responses were observed in 12/15 patients. Rarick et al. treated 14 adults with HIV-related thrombocytopenia with IVIG (1 g/kg on days 1, 2 and 15). The median platelet count increased from 17,000/mm3 at baseline to a maximum of 220,000/mm3. All patients had responded by day eight, but the effect was transient, with the median platelet count declining to 40,000/mm3 by day 15. The investigators suggested that IVIG may be used in patients with HIV-related thrombocytopenia who required an immediate increase in platelet count. Results from an open label study of WinRho, a freeze-dried gamma globulin, have been reported (Bussel et al.). Eleven children and 52 adults with HIV and thrombocytopenia (platelet counts < 30,000/mm3) were enrolled. All patients were 136

Page  137 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 treated with 100 to 375 IU/kg WinRho for an average of 7.3 courses over a mean period of 407 days. 57/63 responded (median increase > 20,000/mm3) during the first six courses of therapy for an overall response rate of (90%). The overal mean change in platelet count for six courses was 60,900/mm3. Total infusion time is 3-5 minutes. Kemeny et al. reported the results of a retrospective chart review of 22 HIV+ patients who underwent splenectomy. The patients were classified as having ITP (n = 13) or a splenic infiltrative process, MAC, KS, or lymphoma (n = 9). The investigators defined a complete response to the surgery to be a platelet count >150,000 one month post-operatively. Complete responses were observed in 11/13 patients with ITP and 6/9 with splenic infiltrative processes. REFERENCES: Ballem PJ et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N ENGL J MED 327: 1779-84, 1992. Hymes KB et al. The effect of azidothymidine on HIV related thrombocytopenia. N ENGL J MED 318: 516-7, 1988. Jackson GG et al. Human immunodeficiency virus antigenemia in the acquired immunodeficiency syndrome and the effect of treatment with zidovudine. Ann Int Med 108: 175-80, 1988. Kemeny MM et al. Splenectomy in patients with AIDS and AIDS-related complex. AIDS 7:1064-7, 1993. Rarick MU et al. Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia. Am J Hematol 38: 261-6, 1991. Marroni M et al. Interferon-<F128M>a<F255D> is effective in the treatment of HIV-1-related, severe, zidovudine-resistant thrombocytopenia. Ann Intern Med 121:423-429, 1994. Swiss Group for the Clinical Studies on AIDS: Zidovudine for the treatment of thrombocytopenia associated with the human immunodeficiency virus (HIV). Ann Int Med 109: 718-21, 1988. OTHER REPORTS: Bussel JB et al. Intravenous anti-D treatment of immune throbocytopenic purpura: analysis and efficacy, toxicity, and mechanism of effect. Blood 77:1884-93, 1991. Lessinger et al. Role of splenectomy in the management of hemophilic patients patients with human immunodeficiency virus-associated immunopathic thrombopenic purpura. Am J Hematol 40:207-9, 1992. Louache F et al. Infection of megakaryocytes by human immunodeficiency virus in seropositive patients with immune thrombocytopenic purpura. Blood 78: 1697-705, 1991. Nieuwenhuis HK and Sixma JJ. Thrombocytopenia and the neglected megakaryocyte (editorial). N ENGL J MED 327: 1812-3, 1992. WASTING SYNDROME Trials, page 203-206 Involuntary weight loss, or wasting, is one of the most common manifestations of HIV infection. It can occur at any stage of infection and is indicative of disease progression. Chronic unintended weight loss is associated with malnutrition, which may contribute to increased immune suppression including reduction of T-lymphocyte helper and suppressor cells, altered phagocytic functions, and decreased killer-cell activity. Weight loss can result from reduced food intake, altered metabolism, or malabsorption and associated diarrhea (see page 135 ). Metabolic abnormalities (i.e., hypogonadism), gastrointestinal disorders, circulating growth factors (i.e., inflammatory cytokines such as IL-1, IL-6, and TNF), and indadequate food intake have all been cited in various reports as: potential causes of moderate to severe wasting. TREATMENT RESULTS APPETITE STIMULATION: Megestrol acetate (Megace) oral suspension has been approved by the FDA for the treatment of anorexia, cachexia, or unexplained significant weight loss in patients with AIDS. The recommended dose is 800 mg/day. This approval was based on data from two twelve-week placebo-controlled studies conducted in patients with AIDS-related wasting. Von Roenn et al. have reported results of megestrol acetate in a twelve-week placebo controlled trial in 271 patients. A total of 270 patients were evaluable for safety data and 195 patients were evaluable for efficacy data. All patients were randomized to receive placebo or megestrol acetate (100 mg, 400 mg, or 800 mg qd). Of the 195 evaluable patients, 64.2% gained 2.27 kg (5 lbs) or more compared with 21.4% of patients in the placebo group (P < 0.001). The most significant weight gain reported was in the 800 mg megestrol acetate group (n = 75) when compared to placebo; 62.3% reporting a median weight gain of 3.54 kg (7.8 lbs) at 12 weeks (P < 0.001). Lean body mass increases were also reported using bioelectrical impedance analysis. The mean change in lean body mass from baseline to last evaluation was 1.14 (2.5 lbs) in the 800 mg megestrol acetate group and -0.14 kg (-0.03 Ibs) in the placebo group (P < 0.001). Results from a second twelve week, randomized, placebo-controlled study of 100 patients with AIDS-related weight loss of 10% or more of ideal body weight were reported by Oster et al. 52 patients received megestrol acetate and 48 received placebo. Body weight in the megestrol acetate group increased by 3.86 kg from baseline to week 8 (P <.001), while body weight decreased in the placebo group 137

Page  138 Opportunistic Infections and Related Disorders 0.46 kg. Body water, lean body mass, and patient survival were not statistically different between the two groups. To determine whether fat mass associated with megestrol acetate administration is caused by the hypogonadic effects of the drug, resulting in lower testosterone production, the AIDS Clinical Trials is currently desiging a study to test this hypothesis. ACTG 330 is enrolling patients with greater than 5% loss in body weight to receive megestrol acetate with or without testosterone. Dronabinol has been approved as an appetite stimulant in AIDS patients with wasting. Side effects associated with dronabinol include dizziness, thinking abnormalities, asthenia and euphoria. Approval of dronabinol for the treatment of AIDS-related weight loss was based on two controlled studies. In a study conducted by Struwe et al., 12 patients were randomized to dronabinol or placebo. The five patients who completed the five-week study showed improvement in symptom distress and increased body fat with minimal increases in appetite scores and weight. No statistically significant differences could be found between those who received dronabinol and those who received placebo. Beal et al. enrolled 139 AIDS patients in a double-blind placebo-controlled trial. All patients were at least 2.3 kg below their ideal body weights and were free from intercurrent illness. Patients were randomized to receive dronabinol 2.5 mg bid or placebo for six weeks, at which time all patients received dronabinol in an open-label extension of the study. After the randomized study, 50/72 dronabinol recipients and 38/67 placebo recipients were evaluable. Appetite (measured on a visual analog scale) was significantly improved in the dronabinol group (P = 0.02). Mean weight change was 0.1 kg in the dronabinol group and -0.4 kg in the placebo group (P = NS). At the end of the first month of the open-label extension study, 7/18 patients who had originally received dronabinol had gained 2 kg, compared to 2/17 patients who had originally received placebo (P = 0.07). Although CNS side effects were common in the dronabinol group, adverse reactions requiring discontinuation of therapy were equally frequent in the two groups (5 on dronabinol and 4 on placebo). NUTRITIONAL SUPPLEMENTATION: Nutritional supplementation has been postulated to be an option for those patients with significant weight loss who are unable to meet caloric demands owing to anorexia or malabsorption. Enteral feeding by percutaneous endoscopic gastostomy (PEG) tubes has been studied by Kotler et al. (1991) in eight patients with advanced HI infection. Amino acids were supplied as small peptides, and 40% of the liped wasin the form of medium chain triglycerides. No statistically significant increases in weight were reported. However, there was a significant increase in body cell mass and serum albumin concentrations. Administration of total parenteral nutrition (TPN) has been studied in a few small uncontrolled clinical trials. Singer et al. reported a restrospective study in 22 patients with a more than 10% loss of body weight (Singer et al, 1992). Fifteen patients gained weight, and nine returned to previous activity. In an earlier study of eight patients with weight loss, all patients gained weight with a solution in which fat comprised 50% nonprotein calories (Singer et al., 1991). There was no associated increase in serum albumin, and in neither study were measurements of body cell mass performed. Kotler et al. (1990) demonstrated weight gain in 12 HIV+ patients receiving intravenous TPN. Patients were administered therapy for a total of 14 weeks. TPN produced increases in body cell mass as well as body fat. Repletion of body cell mass occurred in all patients with an active opportunistic infection (MAC and CMV) and altered nutritional intake. In contrast, the North American Home Parenteral and Enteral Nutrition Registry reported that HIV+ patients with severe and ineffectively treated systemic infection (including CMV and MAC) showed only gains in body fat with no increases in body cell mass after TPN administration. These short-term studies have not established improved survival. ANABOLIC AGENTS: Recombinant human growth hormone (rHGH) has been approved by the Food and Drug Administration (FDA) under its accelerated approval mechanism for HIV+ patients with wasting syndrome. Other anabolic agents in development for the treatment of AIDS-related wasting include testosterone and anabolic steroids. Neither testosterone or any of the anabolic steroids are yet indicated specifically for the treatment of AIDS-related wasting. Results from a twelve-week, multicenter, placebo-controlled trial of recombinant human growth hormone (rHGH) (average dose of 6 mg daily) in 178 patients with AIDS-associated weight loss was presented by Schambelan et al. Patients enrolled in the trial had lost an average of 14% of their normal body weight. Ninety patients were randomized to rHGH 0.1 mg/kg qd; 88 patients received placebo. A median weight gain of 1.6 kg was reported in patients receiving rHGH (P = 0.01). A median lean body mass increase of 3.0 kg was also reported (P < 0.001), accompanied by a median decrease of 1.7 kg in fat mass (P < 0.001). There were five deaths among the participants; three receiving the hormone and two on placebo. No significant differences in the development of opportunistic infections or survival were reported. Results from a second twelve week, multicenter, placebo-controlled trial of recombinant human growth hormone (rHGH) has been reported (Breitmeyer et al.). 138

Page  139 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 r A total of 177 patients were randomized to receive rHGH or placebo for twelve weeks; 115 patients received rHGH (6 mg daily) and 62 received placebo. At baseline, patients had lost an average 10.5 kg of their ideal body weight. Lean body mass and fat mass perameters were not measured. At 6 weeks, the median weight gain in the rHGH group was 2.5 kg above baseline, whereas the median weight gain in the placebo group was 0.7 kg (P < 0.001). At week 12, the median weight gain decreased to 1.6 kg above baseline in the rHGH group and decreased to 0.43 kg in the placebo group. Data at week 12 were not statistically significant. There was not significant difference in the development of opportunistic infections or death in either group (3 deaths in total). Mulligan et al. treated six men with HIV-related weight loss (mean loss of 19%) with a constant metabolic diet and rHGH 0.1 mg/kg/day for seven days. The men were hospitalized, as were six HIV-negative volunteers who served as controls. A mean body weight increase of 2.0 +0.3 kg was observed in the HIV+ men (compared with 1.6 +0.2 kg increase in the control group). Increases in protein anabolism and lipid oxidation were observed. Weight gain data from an open-label study of testosterone cypionate in 29 HIV+ hypogonadic men with sexual dysfunction has been reported (Engelson et al.) The study group was not underweight at baseline. All patients received testosterone cypionate 400 mg biweekly for 12 weeks. Increases in body weight at 12 weeks were not significant when compared to baseline. However, significant increases in lean body mass (fat free) mass (1.2 kg) were reported (P < 0.001). Two studies are currently underway of testosterone transdermal (scrotal) system. The first is a multicenter study examining testosterone transdermal system as a treatment for hypogonadism in HIV+ patients; the second is a small study examining testosterone replacement as a treatment for wasting. A study of testosterone (IM) versus a testosterone transdermal system is being conducted by the Community Research Consortium of the University of California/San Francisco. Results from a randomized, double-blind study of oxandrolone, an anabolic agent, has been reported (Berger et al.) Sixty-seven HIV+ men with > 10% loss of body weight and evidence of generalized or proximal muscle weakness were randomized to receive oxandrolone (5 mg/day or 15 mg/day) or placebo. Fifty patients completed the study. A significant gain in body weight was observed in patients receiving the 15 mg/day dose when compared to placebo. Patients receiving the 5 mg/day dose reported weight maintenance with a trend towards body weight increases. The manufacturer of oxandrolone is currently sponsoring two clinical trials of the drug in patients with HIV and wasting; the first trial is being conducted in HIV+ men, the second is being conducted in HIV+ women. Nandrolone decanoate, an anabolic steroid, has thus far been studied in one placebo-controlled study. Butcher et al. recently reported results for a randomized trial of nandrolone decanoate in HIV+ patients without significant weight loss. A total of 73 patients received either nandrolone decanoate 100 mg IM or placebo for 12 weeks. At weeks 6 and 12, significant differences in body weight increases, as well as lean body mass increases were reported in patients who received nandrolone decanoate in comparison to those who received placebo. Nandrolone was not reported to have a significant impact on either levels of HIV RNA or CD4+ cells. Two trials of nandrolone decanoate are currently enrolling HIV+ patients with wasting. A study at the University of California/San Francisco is currently studying nandrolone (100 mg IM qw in women, 200 mg IM qw in men) to placebo in 40 patients. A second study, being conducted by the ACTG (ACTG 229) is currently enrolling HIV+ women with wasting to receive either nandrolone (100 mg q2w) or placebo. A recent study completed by Hengge et al. of oxymethalone in combination with ketotifen has been completed. A total of 30 patients were treated in an open-label fashion and were divided evenly to receive either oxymethalone monotherapy or a combination of oxymethalone and ketotifen. A group of 30 matching controls were also evaluated. No additive benefit of ketotifen was reported. The mean body weight increase between the two groups was 7/15 kg at approximately 20 weeks of therapy. NIH is currently developing a clinical trial (ACTG 329) to study the effects of nandrolone, an anabolic steroid, in HIV+ women with greater than 5% loss in body weight. IMMUNOMODULATORS: Landman et al. treated five patients with AIDS-related wasting with pentoxifylline 400 mg three times daily. The rationale for the treatment was based on pentoxifylline's anti-TNF-a activity; TNF-ao may play a role in the pathogenesis of AIDS wasting. 3/5 patients had elevated serum TNF-o levels. No significant weight gain was observed in any of the patients. The two patients without elevetaed TNF-cc, continued to lose weight and also developed bacterial pneumonia within 3 weeks of starting therapy. Thalidomide is being investigated as a possible treatment for AIDS-related wasting, due to its anti-TNF-a activity. In a study presented by Reyes-Teran et al., 139

Page  140 Opportunistic Infections and Related Disorders 23 patients receiving antiretroviral therapy, without active opportunistic infections, and with 10% or greater weight loss in the previous six months were included into a randomized, double-blind, placebo-controlled efficacy trial. 18 patients have finished the treatment protocol. Stabalization or weight gain occured in 8/9 patients from the thalidomide group and in 2/9 from the placebo group (P = 0.008). Mild and transient somnolence and erythematous macular lesions were only observed in the thalidomide group. A randomized, placebo-controlled study of thalidomide for the treatment of wasting syndrome is currently underway. For patients who do not qualify for the randomized trial, an expanded access program has been set up by the manufacturer. REFERENCES: Beal JE et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10(2): 89-97, 1995. Berger JR et al. Oxandrolone in AIDS wasting/myopathy. J NeuroVirology 2: 32, 1996. Breitmeyer J et al. Data from the Metabolic and Endocrinology/Antiviral Advisory Committee of the Food and Drug Administration's approval hearing for recombinant human growth hormone. Silver Spring, MD, 1996. Butcher G et al. A prospective study on the safety and effect of nandrolone decanoate in HIV-positve patients. Abstract Mo.B.423, XI International Conference on AIDS, Vancouver, 1996. Couderc L et al. Thalidomide in wasting syndrome in AIDS. Abstract P321, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection. Milan, 1994. Engelson ES et al. Effects of testosterone upon body composition. J AIDS (In print), 1996. Hengge UR et al. Oxymethalone promotes significant weight gain in patients with advanced HIV-1 infection. Abstract #394, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996. Jekot WF and Purdy DW. Treating HIV/AIDS patients with anabolic steroids. A retrospective study. AIDS Pat Care, 68-74, April, 1993. Kotler DP et al. Effect of home TPN on body composition in patients with AIDS. J Parenteral Enteral Nutr 14:454-58, 1990. Kotler DP et al. Effect of enteral alimentation of body cell mass in patients with acquired immunodeficiency syndrome. Am J Clin Nutr 53:149-54, 1991. Landman D et al. Use of pentoxifylline therapy for patients with AIDS-related wasting: pilot study Clin Inf Disease 18:97-9, 1994. Mulligan CK et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrin Metab 77:956-62, 1993 North American Home Parenteral and Enteral Nutrition Registry. Annual report. The Oley Foudnation, 1-20, 1993. Oster et al. Megestrol acetate in patients with AIDS and cachexia. Ann Int Med 121:400-408, 1994. Von Roenn J et al. Megestrol acetate in patients with AIDS-related cachexia. Ann Int Med 121:393-99, 1994. Reyes-Teran G et al. Effects of thalidomide on wasting syndrome in patients with AIDS, A randomized double-blind, placebo-controlled clinical trial. Abstract #536B, X Intl Conf AIDS, Yokohama, 1994 Schambelan M et al. Recombinant human growth hormone increases lean body mass and improves fuctional performance in patients with HIV-associated wasting. 2nd Human Retrovirus Confer<%-2>ence, Abstract #LB-15, Washington, DC, 1995. Singer P et al. Risks and benefits at home parenteral nutrition in the acquired immuneodeficiency syndrome. J Parenteral Enteral Nutr 15:75-9, 1991. Singer P et al. Clinical and immunologic effects of lipid-based parenteral nutrition in AIDS. J Parenteral Enteral Nutr 16:165-7, 1992. Struwe W et al. Effect of dronabinol of nutritional stauts in HIV-infected patients. Ann Pharmacol 27:827-31, 1993. Von Roenn JH et al. Megastrol acetate in patients with AIDS-related cachexia. Ann Intern Med 121: 393-399, 1994. OTHER REPORTS: Graham KK et al. Steady-state pharmacokinetic and pharmacodynamic evaluation of megestrol acetate oral suspension in cachectic AIDS patients. 31st ICAAC, abstract 550, 1991. Grunfeld C et al. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N ENGL J MED 327: 329-37, 1992. Hickey M et al. Nutritional management of patients with ARC or AIDS. Gastro Cl N Amer 17: 546-61, 1988. Kotler D et al. Malnutrition in HIV infection and AIDS. AIDS 3(supp.1): 175-80, 1989. Koster F et al. A randomized, double blind, placebo-controlled Phase II trial of growth hormone and insulin-like growth factor-I for AIDS wasting. Abstract #110, ICAAC, Orlando, 1994. 140

Page  141 Opportunistic Infections Prophylaxis Guidelines AmFAR's AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 USPHS I IDSA GUIDELINES PROPHYLAXIS FOR FIRST EPISODE OF OPPORTUNISTIC DISEASE IN HIV+ ADULTS PATHOGEN INDICATION FIRST CHOICE ALTERNATIVE Strongly recommended as standard of care CD4+ <200 cells/mm3 Dapsone + pyrimethamine + Pneumocystis carinii pneumonia unexplained fever for 2 two weeks TMP/SMX leucovorin; oropharyngeal canidiasis Aerosolized pentamidine TST reaction of _ 5 mm or prior Mycobacterium tuberculosis (MTb) p ositive TST result without treatment Isoniazid + pyridoxine Rifampin Isoniazid-sensitive positive TST result without treatment or contact with case of active Tb MTb Isoniazid-reistant Same as above + exposure to MTb Rifampin Rifabutin MTb Multiple drug resistant Same as above Consult public health authorities None IgG antibody to Toxoplasma and Dapsone + pyrimethamine + Toxoplasma gondii CD4+ < 100 cells/mm3 TMP/SMX leucovorin Recommended for consideration in all patients Streptococcus pneumoniae All patients Pneumococcal vaccine None Mycobactertium avium complex CD4+ < 75 cells/mm3 Clarithromycin (MAC) Recommended only in selected patients Bacteria Neutropenia G-CSF or GM-CSF None Candida species CD4+ < 50 cells/mm3 Fluconazole Ketaconazole Crytococcus neoformans CD4+ < 50 cells/mm3 Fluconazole Itaconazole CD4+ < 50 cells/mm3, endemic Histoplasma capsulatum CD4+ < 50 cells/mm, endemic Itraconazole Fluconazole geographic area CD4+ < 50 cells/mm3, endemic Coccidioides immitis Fluconazole Itraconazole geographic area CMV CD4+ < 200 cells/mm3 Oral ganciclovir None Recommended for consideration Hepititis B virus All susceptible (anti-Hbc-negative) Energix-B or Recombivax HB None Influenza virus All patients (annually, before flu Whole or split virus Rimantadine or amantadine season) 141

Page  142 Trials for HIV Infection: Antiretroviral Therapy TRIALS FOR HIV INFECTION: ANTIRETROVIRAL THERAPY This section is intended to provide a listing of HIV clinical trials open for enrollment nationwide. This is not a comprehensive list of all trials open to enrollment. We encou you to use your local or regional clinical trial directory, your local AIDS organization's newletter for more information on HIV/AIDS clinical trials in your area. For informs on clinical trials underway, but no longer recruiting participants, call the AIDS Clinical Trial Information Service (ACTIS), 1-800-TRIALS-A. 1rage ation REVERSE TRANSCRIPTASE INHIBITORS NUCLEOSIDE ANALOGUES Descriptive text / Trial results, page 19 ACTG:249 DDI00020 ddl: HIV Pregnant Women/Neonatal Transmission Phase I Pharmacokinetics, Safety and Toxicity Trial CD4 Range: 50 to 350 / Viral Load: Unspecified DDA0000 I f-ddA: HIV Infection Symptomatic / AIDS Phase I Open Label Dose Escalating Pharmacokinetics & Safety Trial CD4 Range: 100 to 400 / Viral Load: Unspecified Agent f-ddA Route Dose/Frequency IV 0.2 mg/kg bid once then PO 0.4 mg/kg,.8 mg/kg, 1.6 mg/kg 3.2 mg/kg, 5.3 mg/kg, 8.0 mg/kg 11.2 mg/kg bid Agent ddl ddl Route Dose/Frequency IV 1.6 mg/kg infused x 1 hour PO 200 mg (125 mg if <60kg) Number of Subjects: 12 Start Date: January 1996 Time on Drug(s): 48 weeks Trial Duration: REQUIR Neutrophils: Platelets: greater than 75,000 Hemoglobin: 9.0 males 8.8 females or greater Hematocrit: 50,000 or greater Number of Subjects: 48 Start Date: April 1996 ED BLOOD VALUES: SGOT/PT: less than 2x ULN Creatinine: less than 1.5 Granulocyte: greater than 1,000 Bilirubin: less than 2x ULN Time on Drug(s):3-5 months Trial Duration: REQUIRED BLOOD VALUES: less than 1.2 Creatinine: INCLUSION CRITERIA Age: 13 years or older Sex: Females AZT intolerant or resistant EXCLUSION CRITERIA History of maternal medical conditions Antiretrovirals other than ddl (IV AZT allowed during labor) Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) IINCLUSION CRITERIA Age: 18 years or older Sex: Male/Female EXCLUSION CRITERIA History or evidence of CHF History of pancreatitis or peripheral neruopathy grade 2 or greater Severe malabsorption Evidence of KS or other tumor requring chemotherapy Current use of foscarnet or ganciclovir Site National Cancer Institute, Bethesda, MD Trial Information (301) 496-9054 x 607 Doctor Yarchoan 1-800-TRIALS-A (874-2572) 142

Page  143 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1 997 COMBINATIONS OF NUCLEOSIDE ANALOGUES Descriptive text / Trial results, page 23 Sponsor ID: CNAA2003 CNAA2003 1592U89 + Specified Nucleoside:Analogs HIV Infection I AIDS / Nucleoside Analog Experienced Phase II Open Label Trial CD4 Range:100 / Viral Load: 30,000 copies or greater Descriptive text / Trial results, page 19 ACTG: 274 DI&R1002 ddl + Ribavirin: Pediatric HIV Infection Phase I Safety, Toxicity and Tolerance Trial CD4 Range: see inclusion criteria I Viral Load: Unspecified Agent 1592U89 specified antiretrovirals Route PO PO DoselFrequency 300 mg bid PDN Number of Subjects: 40 Start Date: August 1996 Agent ddl Ribavirin (cohort 1) Ribavirin (cohort 2) Time on Drug(s): 28 weeks Trial Duration: RE Neutrophils: Platelets: greater than 50,000 Hemoglobin: greater than 7.0 Hematocrit: Bilirubin: less than 3 x ULN Route PO PO PO DoselFrequency 120 mg/m q 12h x 24 weeks 6 or 10 mg/kg qd x 20 weeks 6 or 10 mg/kg qd x 24 weeks Number of Subjects: 20 Start Date: August 1995 Time on Drug(s): 24 weeks Trial Duration: 4 wk after tx end QUIRED BLOOD VALUES: SGOT/PT: less than 10.0 x ULN Creatinine: see below Granulocyte: WBC: REQUIRED BLOOD VALUES: Neutrophils: greater than 1,000 Hemoglobin:greater than 10.0 Platelets: greater than 75,000 Creatinine: greater than 50mg/mn EXCLUSION CRITERIA Sex: Male/Female Prior protocol-specified antiretroviral therapy Practiciing adequate contraceptive method EXCLUSION CRITERIA Prior antiretroviral therapy other than protocol-specified Investigational vaccine within prior three months Immunomodulator treatment within prior thirty days Site Trial Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) INCLUSION CRITERIA Age: 12 mos - 12 years Sex: Male/Female Creatinine: less than 1.2 (less than 2 years old) less than 1.7 (2-12 years old) CD4+ cell count range: less than 1,500 (less than 12 months old) less than 1000 (1-5 years old) less than 500 (6-12 years old) Maternal immunomodulators or antiretroviral therapy EXCLUSION CRITERIA Prior ddl or oral ribavirin Antiretroviral or immunomodulator therapy within one week of entry Active serious bacterial infection Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 143

Page  144 Trials for HIV Infection: Antiretroviral Therapy Descriptive text / Trial results, pages 15, 19 LEVAM001 Levamisole + AZT + ddl: PediatriclAdolescent HIV Infection Phase I Drug Safety and Immunology Trial CD4 Range: Unspecified / Viral Load: Unspecified Descriptive text / Trial results, page24 Sponsor ID: GS-96-408 PMEA0008 PMEA (bisPOM, Adefovir Dipivoxil): HIV Infection/AIDS Phase II/111 Randomized Double Blind Placebo Controlled Trial CD4 Range:200 or higher I Viral Load: 2,500 copies or greater Agent levamisole AZT ddl Route Dose/Frequency PO 2.5, 5.0, 7.5, 10.0 mg/kg q MWF for at least 24 weeks PO 120 mg/m2 q6h x 8 weeks PO 135 mg/m2 q12h x 8 weeks Number of Subjects: Start Date: Agent PMEA Route Dose/Frequency PO 120 mg qd x 48 weeks along with antiretroviral therapy (24 weeks blinded/24 weeks open) Time on Drug(s): 32 weeks Trial Duration: Neutrophils: Platelets: Hemoglobin: INCLUSION CRITERIA Age: 2-21 years Sex: Male/Female REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: Site National Cancer Institute, Bethesda, MD Trial Information (301) 402-1391 Doctor Pizzo Time on Drug(s): 24 weeks Number of Subjects: 400 Trial Duration: 24 weeks Start Date: May 1996 REQUIRED BLOOD VALUES: Neutrophils: 750 or greater SGOT/PT: Platelets: 50,000 or greater Creatinine: 1.5 x ULN or less Hemoglobin: 8.0 or greater Granulocyte: Hematocrit: 50,000 or greater WBC: Bilirubin: INCLUSION CRITERIA Age: 13 years or older Sex: Male/Female Karnofsky score: 80% or greater Tolerating current antiretroviral treatment for at least 8 weeks Minimum life expectancy of one year Use of effective contraception EXCLUSION CRITERIA New AIDS-defining diagnosis within 2 months prior to study entry Active serious infections requiring parenteral antibiotic or antiviral therapy Patients recieving treatment or treated four weeks prior to study entry with immunomodulating agent such as systemic corticosteriods, IL-2, or interferons Malabsorption syndrome Pregnant or nursing women Alcohol or drug abuse 144

Page  145 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 Site Albany Medical College, Albany, NY Carolina Medical Center, Charlotte, NC Dallas VA Medical Center, Dallas, TX East Bay AIDS Center, Berkeley, CA Harbor UCLA Medical Center, Torrance, CA Houston Clinical Research Network, Houston, TX Independent Investigator: Chicago, IL Kraus Medical Partners, Los Angeles, CA Massachusetts General Hospital, Boston, MA Mount Zion Medical Center, San Francisco, CA Pacific Oaks Medical Group, Pacific Oaks, CA San Francisco General Hospital, San Francisco, CA San Mateo County General Hospital, San Mateo, CA Santa Clara Valley Medical Center, San Jose, CA Tulane University School of Medicine, New Orleans, LA U Alabama Medical Center, Birmingham, AL U South Florida Health Sciences Center, Tampa, FL U Texas HSC/Galveston, Galveston, TX U Utah School of Medicine, Salt Lake City, UT VA Medical Center / Washington, DC,, Wayne State University, Detroit, MI Trial Information (518) 262- 6323 (704) 355-5292 x3165 (214) 648-3877 (510) 204-1291 (310) 222-3848 (713) 520-2018 (312) 494-2206 (213) 930-2324 (617) 726-5598 (415) 476-6356 (818) 906-6279 (415) 476-4082x84098 (415) 364-6563 (408) 885-4316 (504) 587-7316 (205) 975-7925 (813) 974-3163 (409) 747-0241 (801) 581-4878 (202) 745-8000x 5007 (313) 993-092634 Doctor Stein Weinrib Keiser Brosgart Beall Gathe, Jr. Pottage Jr. Cooper Basgoz Drew Hardy Kahn Israelski Kemper Mushatt Squires Nadler Pollard Pavia Gordin Mac Arthur, D.O COMPARING COMBINATIONS OF NUCLEOSIDE ANALOGUES Descriptive text / Trial results, pages 15, 19, 25 ACTG:276 AZ/D1005 AZT vs ddl vs AZT/ddl: Combinations Effects Of Viral Burden HIV Infection Asymptomatic Phase II Randomized Double Blind Placebo-Controlled Pilot Study CD4 Range:550 or higher I Viral Load: Unspecified PMEA (BisPOM) + AZT Sponsor ID: 405 PMEA0007 PMEA (BisPOM) + AZT: HIV Infection Phase 1/11 Safety & Efficacy Trial CD4 Range: 100 to 400 / Viral Load: Unspecified Agent AZT ddl Route PO PO Dose/Frequency 200 mg tid 200 mg bid Number of Subjects: 85 Start Date: Time on Drug(s): 16-32 weeks Trial Duration: 38 weeks Agent Level 1: PMEA AZT Level 2: PMEA AZT Route PO PO PO PO Dose/Frequency 125 mg qd 500 mg qd 250 mg qd 500 mg qd Number of Subjects: 25 Start Date:January 1995 Time on Drug(s): 12 weeks Trial Duration: Open REQUII Bilirubin:1.5 or less Platelets: greater than 75,000 Hemoglobin: greater than 9.0 Site National Cancer Institute, Bethesda, MD REQUIRED BLOOD VALUES: Neutrophils: 1000 or greater SGOT/PT: less than 5x ULN Platelets: greater than 75,000 Creatinine: less than 1.5 Bilirubin: less than 2.5 Hemoglobin:greater than 12 INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Karnofsky score: 80 or greater No prior antiretroviral therapy Asymptomatic disease EXCLUSION CRITERIA Antiretrovirals other than study drugs Biologic response modifiers Systemic corticosteroids or Immunomodulators within 3 months of study entry Site Information For trial sites call the AIDS Clinical Trial InformationService (ACTIS) 1-800-TRIALS-A (874-2572) RED BLOOD VALUES: Neutrophils: greater than 1,500 Creatinine: 1.5 or less Granulocyte: Trial Information (800) 762-5464 Doctor Yarchoan 145

Page  146 Trials for HIV Infection: Antiretroviral Therapy Descriptive text / Trial results, pages 22, 23, 27 D43TDI d4T + 3TC vs AZT+ 3TC vs d4T + 3TC + ddl: HIV Infection / Nucleoside Analogue Naive Randomized Double Blind Virologic and Immunologic Effects Trial CD4 Range: 20 to 300 / Viral Load: Unspecified Descriptive text / Trial results, page 19, 25, 27 ACTG:300 3TC00010 3TC & AZT vs. AZT & ddl vs. ddl: Pediatric HIV Infection Phase II/III Double-Blind Placebo-Controlled Trial CD4 Range: Unspecified / Viral Load: Unspecified Agent Group 1: AZT 3TC Group 2: d4T 3TC Group 3: d4T 3TC ddl Route PO PO PO PO PO PO PO Dose/Frequency 200 mg tid 150 mg bid 40 mg bid 150 mg bid 40 mg bid 150 mg bid 200 mg bid Number of Subjects: Start Date: Agent 3TC / placebo AZT / placebo ddl / placebo Time on Drug(s): 24 months Trial Duration: R Neutrophils: Platelets: 50,000 or more Hemoglobin: 7.0 or more Route PO PO PO Dose/Frequency 4 mg/kg ql2h 160 mg/m2 tid 120 mg/m2 ql2h Number of Subjects: 740 Start Date: May 1995 EQUIRED BLOOD VALUES: SGOT/PT: 10x normal Creatinine: Age dependent Bilirubin: less than 3x normal Time on Drug(s): 24 weeks Trial Duration: 24 weeks Neutrophils: Platelets: Hemoglobin: Hematocrit: Bilirubin: REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: WBC: INCLUSION CRITERIA Age: 90 days - 15 years Sex: Male/Female Less than 56 days prior antiretroviral therapy IVIG or HIVIG allowed EXCLUSION CRITERIA Current diagnosis of malignancy Current therapy with any other anti-HIV therapy Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) INCLUSION CRITERIA Sex: Male/Female Less than two weeks prior antiretroviral therapy Site Harbor/UCLA Medical Center, Torrance, CA Trial Information (310) 222-3848 Doctor Beall 146

Page  147 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1 997 Descriptive text / Trial results, page 22, 27 ACTG: 327 d4T/D183 d4T + ddl VS d4T: Pediatric HIV Infection d4T-Experienced I AZT Monontherapy Phase II Double Blind Randomized / Open Label Trial CD4 Range: Unspecified I Viral Load: Unspecified Descriptive text / Trial results, pages22, 25, 27 ACTG:290 D4T/ZOIO D4T VS AZT + D4T VS AZT + DDI: HIV Infection I AZT Experienced Phase II Randomized Partially Blinded Drug Tolerance Trial CD4 Range:300 to 600 / Viral Load: Unspecified Agent Arm 1: ddl Arm 2: ddl d4T Route PO PO PO Dose/Frequency 90 mg/m2 bid 90 mg/m2 bid 1 mg/kg bid Number of Subjects: 143 Start Date: August 1996 Agent Arm 1: d4T Arm 3: ddl AZT Arm 4: d4T Route PO PO PO PO Dose/Frequency 40 mg bid 200 mg bid 200 mg tid 40 mg bid x 8 weeks Time on Drug(s): 48 weeks Trial Duration: Note: Arm 2 closed, Arm 4 open to individuals originally in arm 2 (ddl+d4T) Neutrophils: Platelets: Hemoglobin: Hematocrit: Bilirubin: REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: WBC: Time on Drug(s): 48 weeks Trial Duration: Open Number of Subjects: 200 Start Date: March 1995 INCLUSION CRITERIA Age: 6 months - 10 Sex: Male/Female Children on long-term d4T monotherapy Children on AZT monotherapy Rollover protocol for ACTG 240 EXCLUSION CRITERIA Children on ACTG 240 who have reached protocol endpoint Current 01 at time of enrollment Grade 3 or greater toxicities Malignancy Intractable diarrhea or vomiting Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) REQUIRED BLOOD VALUES: Neutrophils: greater than 1000 SGOT/PT: less than 3x ULN Platelets: Creatinine: less than 1.5 x ULN Hemoglobin: greater than 9.0 males greater than 8.5 female Granulocyte: INCLUSION CRITERIA Age: 12 years or older Sex: Male/Female No active 01 Enrollment of subjects from correctional facilities approved No prior or current AIDS diagnosis EXCLUSION CRITERIA Unexplained temperature greater than 38.5 c for 7 days Chronic diarrhea or chronic pancreatitis History of grade 2 or higher peripheral neuropathy More than 2 weeks total prior use of ddl or d4T NNRTI or protease inhibitors 30 days prior to study IL2 or interferon within 30 days prior to study Foscarnet Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 147

Page  148 Trials for HIV Infection: Antiretroviral Therapy Descriptive text / Trial results, page 15, 22, 27 ACTG: 298 D4T/Z011 d4T vs AZT vs d4T + AZT: HIV Infection in Women Phase II Randomized Double Blind Drug Efficacy and Tolerance Trial CD4 Range: 300 to 600 / Viral Load: Descriptive text / Trial results, pages 15, 25 ACTG: 239 DI&Z0007 ddl + AZT vs AZT: HIV Exposed Infants I Pediatrics Phase 1/11 Randomized Tolerance, Pharmacokinetics & Safety Trial CD4 Range: see inclusion criteria / Viral Load: Unspecified Agent Arm 1: AZT Arm 2: d4T Arm 3: d4T AZT Route PO PO PO PO Dose/Frequency 200 mg tid 40 mg bid 40 mg bid 200 mg tid Number of Subjects: 105 Start Date: July 1995 Time on Drug(s): at least 48 weeks Trial Duration: 48 weeks Agent Part I AZT ddl Part II for 1st 6 wk AZT ddl Time on Drug(s): 12 months Trial Duration: 3 years RE( Neutrophils: 500 or less Platelets: 75,000 or less Hemoglobin: 8.0 or less Hematocrit: less than 24% Bilirubin: 2.6x normal or less PO PO 2.0 mg/kg x 6 wks then 120 mg/kg q6 25, 50, 75 mg/m2 q12h REQUIRED BLOOD VALUES Neutrophils: greater than 1000 SGOT/PT: greater than 3x ULN Platelets: Creatinine: greater than 1.5 Hemoglobin: greater than 9.0 males greater than 8.5 females Granulocyte: Hematocrit: WBC: Bilirubin: INCLUSION CRITERIA Age: 12 years or older Sex: Male/Female Karnofsky score: greater than 80% Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Route Dose/Frequency PO 2 mg/kg q6 x 6wks, then increasing to 120 mg m2 q6 PO 50, 75, or 90 mg q12h Number of Subjects: 180 Start Date: April 1994 QUIRED BLOOD VALUES: SGOT/PT: 10x normal or less Creatinine: 1.5 or less Granulocyte: WBC: 1,500 or less INCLUSION CRITERIA Age: 0-90 days Sex: Male/Female If asymptomatic CD4+ count must be less than 1750 mm3 or 30% EXCLUSION CRITERIA History of pancreatitis Vaccine therapy Antiretroviral or immunomodulator therapy for more than 6 weeks clinically unstable Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 148

Page  149 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) AND NUCLEOSIDE ANALOGUE COMBINATIONS Descriptive text for NNRTI, page 30 Descriptive text / Trial results, pages 27, 34 Sponsor ID: M3331/0021 U90/Z002 Delavirdine (U-90) + AZT + 3TC vs U-90 + AZT vs AZT + 3TC: HIV Infection Phase II/111 Double-Blind Placebo-Controlled Safety & Efficacy Trial CD4 Range:200 to 500 / Viral Load: Unspecified INCLUSION CRITERIA Age: 18 years or older EXCLUSION CRITERIA Greater than 6 months previous AZT therapy or AZT intolerance Previous non-nucleoside RTI therapy or use of ddl, ddC, d4T or 3TC Pregnant or nursing women Significant peripheral neuropathy Pancreatitis within previous 2 years Agent Arm 1: DLV AZT placebo Arm 2: DLV 3TC AZT Arm 4: Placebo AZT 3TC Route PO PO PO PO PO PO PO PO PO Dose/Frequency 400 mg tid 200 mg tid bid 400 mg tid 150 mg bid 200 mg tid tid 200 mg tid 150 mg bid Site AIDS Community Research Consortium, Redwood City, CA AIDS Research Consortium of Atlanta, Atlanta, GA Albany Medical College, Albany, NY Baltimore Community Research Initiative, Baltimore, MD Baystate Medical Center, Springfield, MA Beth Israel Medical Center, New York, NY Brigham and Women's Hospital, Boston, MA Carolina Medical Center, Charlotte, NC Community Health Network, Rochester, NY Cornell Clinical Trials Unit, New York, NY CRIA, New York, NY Dallas VA Medical Center, Dallas, TX Davies Medical Center, San Francisco, CA Detroit Medical Center, Detroit, MI Duke U Medical Center, Durham, NC East Bay AIDS Center, Berkeley, CA Erie County Medical Center, Buffalo, NY George Washington U Medical Center, Washington, DC Georgetown U, Washington, DC Goodgame and Hopkins, Maitland, FL Graduate Hospital, Philadelphia, PA Harbor UCLA Medical Center, Torrance, CA Harlem AIDS Treatment Group, New York, NY Harper Hospital, Detroit, MI Harvard Medical School, Boston, MA Hennepin County Medical Center, Minneapolis, MN Henry Ford Hospital, Detroit, MI Hines VA Medical Center, Hines, IL HIV Study Group, Austin, TX HIVCare, San Francisco, CA Houston VA Medical Center, Houston, TX Indiana University School of Medicine, Indianapolis, IN Jersey Shore Medical Center, Neptune, NY Kansas City AIDS Research Consortium, Kansas City, MO Maine Medical Center, Portland, MN Massachusetts General Hospital, Boston, MA Medical College of Virginia, Richmond, VA Medical University of South Carolina, Charleston, SC Milton S. Hershey Medical Center, Hershey, PA Mount Sinai School of Medicine, New York, NY Nelson-Tebedo Community Clinic, Dallas, TX New England Deaconess Hospital, Boston, MA New York Medical College, Valhalla, NY Trial Information (415) 364-6563 (415) 364-6563 (518) 262-6759 (410) 328-1216 (413) 784-3689 (212) 420-4519 (617) 732-6807 (704) 355-5292 (716) 244-9000 x 36 (212) 746-4166 (212) 924-3934 (214) 376-5451 x5667 (415) 565-6649 (313) 993-092634 (919) 681-6060 (510) 204-1291 (716) 898-4119 (202) 994-2417 (202) 687-1079 (407) 647-6000 (215) 893-7541 (310) 222-3848 (212) 939-3949 (313) 993-0934 (617) 726-3819 (612) 373-1810 (313) 876-2666 (708) 343-7200 x4511 (512) 450-1866 (415) 353-6215 (713) 791-1414 (317) 274-8456 (908) 776-4700 (816) 756-5116 (207) 871-2995 (617) 726-3819 (804) 371-6471 (803) 792-6174 (717) 531-7488 (212) 241-3932 (214) 528-2336 (617) 632-0785 (914) 285-1561 Doctor Deresinski Thompson Remick Beiser Sands Mildvan Kazanjian Horton Rhoades Giordano Sonnabend Keiser Follansbee Crane Heald Brosgart Hewitt Parenti Pierce Goodgame Henry Beall EI-Sadr Crane Basgoz Schut Mateo Pachucki Wright Leoung Hamill Goldman Frank Stanford Smith Basgoz Kerkering Sanders Eyster Cheung Daly Allan Wormser Time on Drug(s) 2 years Trial Duration: Open Number of Subjects: 1250 Start Date: February 1994 REQUIRED BLOOD VALUES: Neutrophils: 1,000 or more SGOT/PT: 1.5x normal or less Platelets: 75,000 or more Creatinine: 1.5x normal or less Hemoglobin: 8.0 or more Bilirubin: 1.5x normal or less 149

Page  150 Trials for HIV Infection: Antiretroviral Therapy Park Plaza Hospital, Houston, TX Research & Education Group, Portland, OR Rush-Presbyterian/St. Luke's Med Center, Chicago, IL San Mateo County General Hospital, San Mateo, CA Santa Clara Valley Medical Center, San Jose, CA Shared Medical Research Foundation, Tarzana, CA St. Luke's/Roosevelt Hospital at 59th, New York, NY St. Paul Ramsey Medical Center, St. Paul, MN St. Vincent's Medical Center, New York, NY Stratogen of Rhode Island, Providence, RI SUNY Health Science Center/Stony Brook, Stony Brook, NY Tulane University School of Medicine, New Orleans, LA U Alabama Medical Center, Birmingham, AL U California Irvine Medical Center, Orange, CA U California Los Angeles, Los Angeles, CA U Cincinnati, Cincinnati, OH U Colorado, Denver, CO U Illinois, Chicago, IL U Iowa Hospital and Clinics, Iowa City, IA U Kansas School of Medicine, Wichita, KS U Kentucky Medical School, Lexington, KY U Massachusetts Medical School, Worcester, MA U Miami Medical Center, Miami, FL U Nebraska Medical Center, Omaha, NE U North Carolina at Chapel Hill, Chapel Hill, NC U Pennsylvania Medical Center, Philadelphia, PA U Pittsburgh Medical Center, Pittsburgh, PA U Puerto Rico School of Medicine, San Juan, PR U Rochester Medical Center, Rochester, NY U Southern California, Los Angeles, CA U Southern California, Los Angeles, CA U Texas HSC/Galveston, Galveston, TX U Texas HSC/Houston, Houston, TX U Texas HSC/San Antonio, San Antonio, TX U Vermont Medical Center, Burlington, VT U Washington Medical Center, Seattle, WA Vanderbilt U Medical Center, Nashville, TN ViRx Inc., San Francisco, CA Washington U School of Medicine, St. Louis, MO Yale University, New Haven, CT (713) 527-5410 (503) 229-8428 (312) 942-5865 (913) 588-6035 (408) 885-4316 (818) 345-2172 (212) 523-5818 (612) 221-1280 (212) 790-7625 (401) 781-2400 (516) 444-1658 (504) 584-3605 (205) 934-3690 (714) 456-7612 (310) 206-6414 (513) 558-6977 (303) 270-8551 (312) 996-6300 (319) 353-8441 (913) 588-6035 (606) 257-5473 (508) 856-2456 (305) 243-3840 (402) 559-8621 (919) 966-6712 (215) 662-2196 (412) 647-8125 (809) 754-3730 (716) 275-0526 (213) 343-8288 (213) 343-8288 (409) 747-0241 (713) 792-4929 (210) 567-4823 (802) 656-2176 (206) 731-3184 (615) 936-1174 (415) 474-2233 (314) 454-0058 (203) 737-4148 Gathe, Jr Sampson Kessler Israelski Deresinski Galpin McKinley Henry Torres Fisher Steigbigel Hyslop Saag See Mitsuyasu Frame Kuritzkes Novak Stapelton Sweet Greenberg Cheeseman Fischl Swindells van der Horst Frank McMahon Vasquez Reichman Currie Currier Pollard Johnson Sharkey-Mathis Grace Collier Pierce Lang Powderly Friedland Descriptive text / Trial results, page 32 Sponsor ID: DMP 266 05 DMP26605 DMP 266 + AZT + 3TC: HIV Infection / AIDS / Antiretroviral naive Phase II Double Blind Placebo Controlled Dose Ranging Trial CD4 Range: 50 to 500 / Viral Load: 10,000 or greater Agent Arm 1: DMP 266 AZT 3TC Arm 2: DMP266 AZT 3TC Arm 3: DMP 266 AZT 3TC Arm 4: placebo DMP 266 AZT/3TC Route PO PO PO PO PO PO PO PO PO PO PO PO Dose/Frequency 200 mg qd (morning) 300 mg bid 150 mg bid 400 mg qd (morning) 300 mg qd 150 mg qd 600 mg qd (morning) 300 mg qd 150 mg bid qd (morning) x 12 weeks then switch 200,400,600 mg qd 13-24 wks 300 mg/ 150 mg bid Number of Subjects: 120 Start Date: November 1996 Time on Drug(s): 24 weeks Trial Duration: 28 weeks REQUIR Neutrophils: 750 or greater Bilirubin:less than 1.5 x ULN Hemoglobin: less than 10.0 (males) less than 9.0 (females) ED BLOOD VALUES: SGOT/PT: less than 3.0 x ULN Creatinine: less than 2.0 INCLUSION CRITERIA Age: 13 - 60 years Sex: Male/Female Karnofsky score: less than 70% Asymptomatic with HIV infection Mildly symptomatic with history fever, chills, night sweats, or weight loss EXCLUSION CRITERIA Prior treatment with any retroviral therapy Prior treatment within 30 days of initiating study drug with any other experimental tx Concomitant systemic therapy for acute OI or malignancy Recurrent episodes of moderate or severe diarrhea or vomiting 150

Page  151 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1 997 Site AIDS Research Alliance, Chicago, IL Birgham and Women's Hospital, Boston, MA Brown University/Miriam Hospital, Providence, RI Duke University Medical Center, Durham, NC Infectious Disease Associates, Tampa, FL John Hopkins Hospital, Baltimore, MD Krauss Medical Group, Los Angeles, CA Northwestern U Medical School, Chicago, IL San Francisco General Hospital, San Francisco, CA SUNY/Stonybrook, Stonybrook, NY University of Texas, Galveston, TX Vanderbilt University Medical Center, Nashville, TN Trial Information (312) 244-5804 (617) 732-0850 (401) 331-8500 (919) 681-6060 (813) 875-4373 (410) 614-4487 (213) 930-2324 (312) 908-0946 (415) 476-9296 (516) 444-1283 (409) 747-0241 (615) 936-1173 Doctor Luskin-Hawk Sax Carpenter Hicks Yangco Gallant Cooper Murphy Kahn Steigbigel Pollard Haas INCLUSION CRITERIA Age: 13-60 years old Sex: Male/Female Weight greater than 40 kg Minimum 8 weeks treatment with AZT + 3TC prior to entry EXCLUSION CRITERIA Less than 12 months life expectancy Prior treatment with DMP266, other NNRTI or protease inhibitors Concomitant treatment with an antiretroviral agent other than AZT/3TC Concomitant systemic therapy for acute 01 or malignancy Concomitant use of rifampin, rifabutin, fluconazole, ketoconazole, itraconazole, or macrolide antibiotics or vitamin C at doses > 1g/day Recurrent episodes of moderate to severe diarrhea Difficulty swallowing capsules Sponsor ID: DMP266-004 DMP2660 DMP-266 + AZT + 3TC: HIV Infection / Nucleoside Analog Experienced Phase II Double Blind Placebo Controlled Safety, Tolerable & Activity Trial CD4 Range: 100 to 500 / Viral Load: 5,000 or greater Agent DMP-266/placebo AZT 3TC DMP-266/placebo AZT 3TC placebo AZT 3TC Route PO PO PO PO PO PO PO PO PO DoselFrequency 400 mg qd 300 mg bid 150 mg bid 600 mg qd 300 mg bid 150 mg bid 300 mg bid 150 mg bid Site AIDS Research Consortium, Atlanta, GA Brigham and Women's Hospital, Boston, MA Brown University/Miriam Hospital, Providence, RI Deaconess Hospital, Boston, MA Duke University Medical Center, Durham, NC George Washington U Medical Center, Washington, DC Henry M. Jackson Foundation, Bethesda, MD Independent Investigator, Bradenton, FL John Hopkins Medical Center, Baltimore, MD Kraus Medical Group, Los Angeles, CA Medical Center of Delaware, Wilmington, DE Milton S. Hershey Medical Center, Hershey, PA Nalle Clinic, Charlotte, NC San Francisco General Hospital, San Francisco, CA SUNY/Stony Brook, Stony Brook, NY University of South Florida, Tampa FL Walter Reed Medical Center, Washington, DC Trial Information (404) 876-2317 (617) 732-8100 (401) 876-3217 (617) 632-0785 (919) 681-8474 (202) 994-2417 (301) 897-3290 (941) 746-2711 (410) 614-4487 (213) 930-2324 (302) 428-2538 (717) 531-5999 (704) 342-8000 (415) 476-9296 (516) 444-1660 (813) 974-3164 (202) 782-8707 Doctor Thompson Sax Carpenter Albrecht Hicks Simon Mayer Bach Gallant Cooper Holloway Eyster Jemsek Kahn Steigbigel Nadler Hawkes Time on Drug(s): 12 weeks w/ extension Number of Subjects: 330 Trial Duration: Open Start Date: July 1996 REQUIRED BLOOD VALUES: Neutrophils: 750 or greater SGOT/PT: Platelets: Creatinine: less than 2.0 Hemoglobin: 10.0 or greater (males) Bilirubin: 1.5 x ULN or less 9.0 or greater (females) Granulocyte: 151

Page  152 Trials for HIV Infection: Antiretroviral Therapy Sponsor ID: HBY0972001 HYB09701 HBY 097 vs HBY 097 + AZT vs AZT: HIV Infection Asymptomatic I Mildly Symptomatic Phase I Double Blind Placebo Controlled Dose Escalating Trial CD4 Range: 200 to 500 / Viral Load: greater than 10,000 copies Descriptive text / Trial results, page 33 Sponsor ID: 1100-1090 BIRG0082 Nevirapine + 3TC + Stable Nucleoside Analogue Therapy: HIV Infection / AIDS I Nucleoside Analog Experienced Phase Ill Randomized Double Blind Comparative Safety & Efficacy Trial CD4 Range: 200 Or Lower I Viral Load: Unspecified Agent HBY 097 or placebo AZT or placebo Route PO PO Dose/Frequency 250 or 750 mg tid 200 mg tid Agent Nevirapine 3TC Nevirapine placebo Route PO PO PO Dose/Frequency 200 mg qd x 2 weeks, then bid 150 mg bid 200 mg qd x 2 weeks, then bid Number of Subjects: 2000 Start Date: December 1995 Time on Drug(s): 14 wee Trial Duration: 14 week Neutrophils: Platelets: 75,000 or greate Hemoglobin: greater than greater than Bilirubin: 2.5 or less k Number of Subjects: 144 Start Date: November 1995 REQUIRED BLOOD VALUES: SGOT/PT: less than 5x ULN r Creatinine: 2.0 or less Time on Drug(s): 18-24 months Trial Duration: up to 24 months 9.5 (males) 9.0 (females) Granulocyte: 1,000 or greater Neutrophils: Platelets: Hemoglobin: Hematocrit: Bilirubin: REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: WBC: INCLUSION CRITERIA Age: greater than 13 Sex: Male/Female Antiretroviral naive EXCLUSION CRITERIA AIDS-defining 01 Immunomodulating agents within 30 days Immunotherapeutic vaccines with the past 6 months Radiation therapy within 30 days Cytotoxic chemotherapy within 30 days Any investigational drugs within 30 days Oral contraceptives Specified concomitant medical conditions INCLUSION CRITERIA Age: 13 years or older Sex: Male/Female Karnofsky score: 70% or greater Stable nucleoside therapy for at least one month Life expectancty greater than 3 months EXCLUSION CRITERIA Prior therapy with nevirapine or other NNRTI Therapy with antiretroviral agents other than AZT, d4T, ddl, ddC or 3TC Recurring acute therapy for AIDS or non-AIDS condition Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Site Georgetown U, Washington, DC Houston Clinical Research Network, Houston, TX LAC+USC Medical Center, Los Angeles, CA Medical College of Georgia, Augusta, GA NYU Medical Center, New York, NY Stanford University Medical Center, Stanford, CA Trial Information (202) 687-1079 (713) 520-2018 (213) 343-8283 (706) 721-9685 (212) 263-8707 (415) 723-2805 Doctor Kumar Schrader Leedom Newman Gulick Merigan 152

Page  153 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1 997 PROTEASE INHIBITORS Descriptive text, page 36 COMBINATION PROTEASE INHIBITORS AND NUCLEOSIDE ANALOGUES Descriptive text / Trial results, page 41 Sponsor ID: PROA2002 PROA2002 141W94 in combination with AZT + 3TC: HIV Infection/AIDS Phase II Randomized Partially Blinded Placebo Controlled Safety & Efficacy CD4 Range: 150 / Viral Load: 10,000 copies or greater EXCLUSION CRITERIA Prior treatment with protease inhibitor or 3TC Prior treatment greater than one year with ddl or ddC ( alone or in combination with AZT) Current or active AIDS-defining OI History of malabsorption History of clinical pancreatitis Treatment with terfenadine, astemizole, cisapride, triazolam, midazolam in past 21 days Foscarnet treatment or others with document anti-HIV activity Use of immunomodulating agents within four weeks of study entry Using other investigational agents Radiation or cytotoxic chemotherapeutic agents Site AIDS Research Consortium, Atlanta, GA ViRX, Inc. San Francisco, CA Trial Information (404) 876-2317 (415) 353-5623 Doctor Thompson Lang Descriptive text / Trial results, page 42 Agent 141W94 AZT 3TC placebo AZT 3TC Route PO PO PO PO PO PO Dose/Frequency 900 mg, 1050 mg, 1200 mg bid 300 mg bid 150 mg bid bid matched to 1050 mg dose 300 mg bid 150 mg bid Number of Subjects: 80 Start Date: October 1996 L7350010 Indinavir (Crixivan, MK-0639) + AZT + 3TC: Pediatric HIV Infection Phase I/II Safety and Tolerance Trial CD4 Range: Unspecified / Viral Load: Unspecified Route Dose/Frequency PO 250, 350, 500 mg/m2 q8h Time on Drug(s): 12 weeks Trial Duration: 4 weeks after Tx Agent Phase II MK-639 Phase III MK-639 AZT 3TC MK-639 REQUIRED BLOOD VALUES: Neutrophils: greater than 1000 SGOT/PT: Platelets: greater than 75,000 Creatinine: 1.5 x or less ULN Hemoglobin: greater than 11.0 (males) greater than 10.0 (females) Granulocyte: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female PO PO PO PO same dose as in phase II 120 mg/m2 q8h 4 mg/kg bid continue on dose from phase II Number of Subjects: Start Date: Februray 1996 Time on Drug(s): 14 weeks Trial Duration: Open INCLUSION CRITERIA Age: Sex: Male/Female Site National Cancer Institute, Bethesda, MD Trial Information (301) 402-1391 Doctor Pizzo 153

Page  154 Trials for HIV Infection: Antiretroviral Therapy Descriptive text / Trial results, page 27, 42 ACTG: 320 L7350009 Indinavir (Crixivan, MK-639) + 3TC + AZT vs 3TC + AZT: AIDS Phase III Randomized Placebo Controlled Drug Efficacy + Safety Trial CD4 Range: 200 / Viral Load: Unspecified Agent Route Dose/Frequency Arm 1: AZT PO 200 mg tid 3TC PO 150 mg bid Inidinavir PO 800 mg tid Arm 2: AZT PO 200 mg tid 3TC PO 150 mg bid placebo PO tid Note: Patients experiencing intolerance to AZT or disease progression after 24 weeks may switch to d4T Descriptive text / Trial results, page 42 Sponsor ID: Merck 054 054 Indinavir + AZT + 3TC: HIV Infection/AIDS Phase II Open Label Randomized Safety & Efficacy Trial CD4 Range:150 to 500 / Viral Load: 20,000 copies or greater Agent Arm 1: Indinavir AZT/3TC Arm 2: Indinavir AZT/3TC Arm 3: Indinavir AZT/3TC Arm 4: Indinavir AZT/3TC Arm 5: Indinavir AZT/3TC Time on Drug(s): 36 weeks Trial Duration: RE Neutrophils: 850 or greater Platelets: 75,000 or greater Hemoglobin: greater than 8.0 Route PO PO PO PO PO PO PO PO PO PO Dose/Frequency 800 mg q8h 300 mg/150 mg q12h 1000 mg q12h 300 mg/150 mg q12h 800 mg q12h plus placebo 300 mg/150 mg q12h 1200 mg q12h 300 mg/150 mg q12h 800 mg q12h plus placebo 300 mg/150 mg q12h Number of Subjects: 100 Start Date:October 1996 Time on Drug(s): 48 weeks Trial Duration: Open REQUIRED Neutrophils: Platelets: 65,000 or greater Hemoglobin: greater than 9.0 males greater than 8.9 females Number of Subjects: 1750 Start Date: February 1995 BLOOD VALUES: SGOT/PT: 5.0 x ULN or less Creatinine: 2.0 x ULN or less Bilirubin:1.5 x ULN or less QUIRED BLOOD VALUES: SGOT/PT: less than 5x ULN Creatinine: less than 2.0 Granulocyte: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Karnofsky score: 70 or greater At least six months prior use of AZT EXCLUSION CRITERIA Dose limiting intolerance to AZT at 600 mg qd Greater than one week prior 3TC use Any prior protease inhibitior use Antiretrovirals other than study drugs Specified medications Pregnant or nursing women Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Must have chest x-ray without signs of active pulmonary disease within 21 days of enrollment EXCLUSION CRITERIA Prior use of protease inhibitors or 3TC Use of antiretroviral agents other than study protocol drugs Use of investigational agents, including unapproved antiviral agents, mmunomodulatory agents, EPO within 30 days of study entry Use of immunosuppressive therapy for malignancy during study treatment period Active 01, hepatitis or malignancy Any drugs with potential to inhibit metabolism of indinavir 154

Page  155 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1 997 Site AIDS Research Consortium of Atlanta, Atlanta, GA Baylor College of Medicine, Houston, TX John Hopkins Hospital, Baltimore, MD LAC/USC Medical Center, Los Angeles, CA San Juan VA Medical Center, San Juan, PR U Texas/Galveston, Galveston, TX U Washington Medical Center, Seattle, WA Vanderbilt University Medical Center, Nashville, TN Trial Information (404) 876-2317 (713) 798-5246 (410) 955-7473 (213) 343-8288 (787) 766-6513 (409) 747-0243 (206) 731-3293 (615) 936-1174 Doctor Thompson White Gallant Currier Ramirez-Rhonda Paar Collier Haas EXCLUSION CRITERIA Prior use of protease inhibitors Acute 01 infections at baseline Significant fever or diarrhea Acute hepatitis or pancreatitis Clinicially significant malabsorption Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Descriptive text / Trial results, page 38 Descriptive text / Trial results, page 38 For trial ofnelvinavir effects on clinical outcome of CMV Retinitis treatment, see page 196 For trial of nelvinavir effects on clinical outcome of MAC treatment, see page 174 Sponsor ID: 525 AG134304 Nelfinavir (AG-1343): AIDS Phase III Double Blind Randomized Efficacy & Safety CD4 Range: 100 Or Lower / Viral Load: 50,000 or less 13435343 Nelfinavir + d4T + 3TC HIV Infection in Women Randomized Double-Blind Placebo-Controlled Trial CD4 Range: 400 or less I Viral Load: Unspecified Agent Nelfinavir Standard of care Time on Drug(s): One year Trial Duration: 6 months RE Neutrophils: Platelets: less than 50,000 Hemoglobin: less than 8.0 Hematocrit: Bilirubin: 2.5 x ULN Route Dose/Frequency PO 750 mg tid Number of Subjects: 500 Start Date: June 1996 Agent Arm 1: Nelfinavir d4T 3TC Arm 2: Placebo d4T 3TC Route PO PO PO PO PO PO Dose/Frequency 750 mg tid 20 or 40 mg bid 150 mg bid tid 20 or 40 mg bid 150 mg bid EQUIRED BLOOD VALUES: SGOT/PT: 5x normal or greater Creatinine: 1.5 or greater Granulocyte: WBC: All patients will be offered 6 months open label treatment with nelfinavir INCLUSION CRITERIA Age: 13 years or older Sex: Male/Female Stable approved antiretroviral therapy for at least one month prior to entry Stable prophylactic treatment and no new ones begun within past month Must be on PCP prophylaxis Time on Drug(s): 12 months Trial Duration: 1 year RE( Neutrophils: 750 or greater Platelets: 50,000 or greater Hemoglobin: greater than 8.0 Bilirubin: less than 2.5x ULN QUIRED BLOOD VALUES: SGOT/PT: Creatinine: less than 2.5 Granulocyte: Number of Subjects: 60 Start Date: November 1996 INCLUSION CRITERIA Age: older than 13 Sex: Women only Karnofsky score: 70 or greater Less than one month cumulative lifetime exposure to d4T and/or 3TC 155

Page  156 Trials for HIV Infection: Antiretroviral Therapy EXCLUSION CRITERIA Prior treatment with protease inhibitiors Vaccine or immunomodulator use within one month of study entry Neoplastic disease requiring systemic cytotoxic chemotherapy History of using or now requiring vincristine Acute pancreatitis or hepatitis Severe intercurrent medical conditions Clinically significant malabsorption syndrome Site Baylor University Medical Center, Houston, TX LSU Medical Center, New Orleans, LA U Alabama Medical Center, Birmingham, AL U Southern California, Los Angeles, CA INCLUSION CRITERIA Age: 6 months - 18 Sex: Male/Female Site National Cancer Institute, Bethesda, MD Trial Information (301) 402-1391 Doctor Pizzo Trial Information (713) 793-4020 (504) 568-4732 (205) 975-7925 (213) 343-8250 Doctor Miller Clark Squires Currier Descriptive text / Trial results, page 40 Sponsor ID: NV15355B NV15355B Saquinavir (soft vs hard) + Other Retroviral Drugs: HIV Infection/AIDS Phase II Randomized Open Label Safety & Comparative Crossover Trial CD4 Range:Unspecified I Viral Load: see below Descriptive text / Trial results, page 39, 43 Sponsor ID: M95-310 ABT53803 Ritonavir (ABT-538) vs Ritonavir + AZT vs Ritonavir + ddl: Pediatric HIV Infection Phase 1/11 Safety Tolerance and Pharmacokinetics Trial CD4 Range: see / Viral Load: Unspecified Agent Saquinavir (hard) antiviral regimen Saquinavir (soft) anitviral regimen Route PO PO PO PO Dose/Frequency 600 mg tid PRN 1200 mg tid PRN Number of Subjects: 140 Start Date: November 1996 Time on Drug(s): 16 wks then open Trial Duration: 48 weeks Agent Monotherapy ABT-538 Combination ABT-538 AZT ddl Route DoselFrequency PO 250, 300, 350, 400 mg/m2 bid x 12w' PO PO PO continue on assigned dose 90 mg/m2 90 mg/m2 bid Number of Subjects: 36-70 Start Date: October 1995 Time on Drug(s): 24 weeks Trial Duration: 24 weeks REQUIRED BLOOD VALUES: Neutrophils: greater than 750 Hemoglobin: greater than 8.0: Platelets: greater than 50,000 Bilirubin: less than 1.5 INCLUSION CRITERIA Sex: Male/Female Viral load randomization: greater than 20,000; less than 20,000 At day 1 patient must be able to start treatment with at least one nucleoside analog with which they have been taking for one month or less No more than 2 weeks treatment with one or more protease inhibitiors EXCLUSION CRITERIA Active 01 Malignancy requiring chemotherapy and/or radiation therapy Malabsorption or pts who have inadequate oral intake Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) REQUIRED BLOOD VALUES: Neutrophils: greater than 750 SGOT/PT: Platelets: greater than 50,000 Creatinine: less than 2x ULN Hemoglobin: greater than 8.0 Granulocyte: Hematocrit: WBC: greater than 1.5 Bilirubin: less than 1.5 156

Page  157 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 Comparing Protease Inhibitors Descriptive text / Trial results, page 37, 40 ACIG: 333 333 Saquinavir hard to soft capsule vs Indinvair: HIV Infection Antiviral Effect Of Switching Squinavir Formulations vs Switching Protease Inhibitor CD4 Range:Unspecified I Viral Load: Unspecified CPCRA: 042 043 Nelfinavir vs Ritonavir: AIDS Radonomized Efficacy and Safety Comparison Study of two protease inhbitors added to background antiretroviral therapy CD4 Range: 100 or less / Viral Load: Unspecified Agent Arm 1: Nelfinavir Arm 2: Ritonavir Route Dose/Frequency PO 750 mg tid along with antiretroviral tx PO 600 mg bid along with antiretroviral tx Agent Group 1: Saquinavir (hard) indinavir Group 2: Saquinavir (soft) Group 3: Indinavir Route Dose/Frequency Time on Drug(s): 12 months Trial Duration: 18 months Number of Subjects: Start Date: January 1997 PO PO 9 capsules qd x 8 weeks then 12 capsules qd x 16 wks PO 18 capsules x 24 weeks PO 12 capsules x 24 weeks 24 weeks Number of Subjects: Start Date: Neutrophils: Platelets: Hemoglobin: REQUIRED BLOOD VALUES: SGOT/PT: less than 5x ULN Creatinine: Granulocyte: Time on Drug(s): Trial Duration: 24 weeks INCLUSION CRITERIA Sex: Male/Female Must have taken saquinavir (hard capsules) for at least one year Use of approved antiretroviral agents or combination Any CD4+ cell count and viral load EXCLUSION CRITERIA Use of any other protease inhibitiors in past including soft shell saquinavir or indinavir Use of rifampin, rifabutin, seldane or Hismanal in past 14 days Change of other antiretroviral therapy or doses within 8 weeks prior to entry Site Information For trial sites call the AIDS Clinical Trial InformationService (ACTIS) 1-800-TRIALS-A (874-2572) INCLUSION CRITERIA Sex: Male/Female Age: 13-99 years CD4+ cell count under 100 for at least 3 months Saquinavir allowed No use of antiretroviral therapy may be considered "background therapy" EXCLUSION CRITERIA Prior use of protease inhibitors except for saquinavir Pregnant or nursing women Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 157

Page  158 Trials for HIV Infection: Antiretroviral Therapy INTEGRASE INHIBITORS Descriptive text, page 46 Descriptive text / Trial results, page 46 INTER002 AR177 (Zintevir): HIV Infection Phase I Multiple Dose Virologic/lmmunologic Activity Pharmacokentics CD4 Range:200 Or Higher I Viral Load: 10,000 or greater Agent Route Dose/Frequency AR177 IV 1.5 or 3.0 mg/kg every other day for a total of 7 doses Time on Drug(s): 2 hours Number of Subjects: 11 Trial Duration: 18 days Start Date: May 1996 REQUIRED BLOOD VALUES: Neutrophils: 1,250 or greater SGOT/PT: less than 3x ULN Platelets: 100,000 or more Creatinine: 1.5 or less Hemoglobin: 9.0 or more Granulocyte: Hematocrit: 18 days WBC: Bilirubin: INCLUSION CRITERIA Age: 18 years or older Hospitalization reguired: 18 days: Systolic BP betweem 90 and 100 Diastolic BP 90 or less No antiretroviral therapy within 2 weeks EXCLUSION CRITERIA All medications within 48 hours MAO inhibitor or other enzyme inducers within 2 weeks Nicotine products within 3 months Marijuana or opiate use AIDS-defining illness Investigational drugs within 30 days: INTER001 AR177 (Zintevir): HIV Infection Phase I Pharmacokioentic and Safety Trial CD4 Range:200 Or Higher/ Viral Load: Unspecified Route Dose/Frequency IV 0.75 mg/kg to 12 mg/kg single dose Agent AR177 Time on Drug(s): 2 hours Trial Duration: 14 days R Neutrophils: 1,250 or more Platelets: 100,000 or more Hemoglobin: 9.0 or more Hematocrit: Bilirubin: Number of Subjects: 4/dose Start Date: September 1995 tEQUIRED BLOOD VALUES: SGOT/PT: less than 3x ULN Creatinine: 1.5 or less Granulocyte: WBC: INCLUSION CRITERIA Age: 18 years or older Systolic BP betweem 90 and 100 Diastolic BP 90 or less No antiretroviral therapy within 2 weeks EXCLUSION CRITERIA Nicotine products within 3 months Marijuana or opiate use AIDS-defining illness Alcohol within 7 days Site San Francisco General Hospital, San Francisco, CA Trial Information (415) 476-9296 Doctor Kahn Site Harris Laboratories, Phoenix, AZ Trial Information (602) 437-0097 Doctor Raschke 158

Page  159 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 19 997 ZINC FINGER INHIBITORS Sponsor ID: NIAID 97 1-032 Zinc 971032 CI-1012 Phase I Multiple Dose Escalating Pharmacokinetics and Efficacy Trial CD4 Range: 200 to 500 / Viral Load: Unspecified OTHER ANTIRETROVIRAL COMPOUNDS Descriptive text, page 47 ACTG: 273; HIVIG273 HIVIG: Pediatric HIV Infection Phase 1/11 Radnomized Dose Ranging Pharmacokinetics Trial CD4 Range: see inclusion criteria / Viral Load: Unspecified Agent CI-1012 Route Dose/Frequency PO 25 mg qd Time on Drug(s): 13 days Trial Duration: 6 weeks Number of Subjects: 24 Start Date: January 1997 Agent HIVIG HIVIG HIVIG Route Dose/Frequency IV 200 mg/kg every 28 days IV 400 mg/kg every 28 days IV 800 mg/kg every 28 days Number of Subjects: 30-45 Start Date: June 1995 Neutrophils: Platelets: Hemoglobin: Hematocrit: Bilirubin: REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: WBC: Time on Drug(s): 6 months Trial Duration: 9 months INCLUSION CRITERIA Age: 18 years to 60 years Sex: Male/Female See protocol for blood values EXCLUSION CRITERIA History of allergies to sulfa drugs Treatment with prophylactic systemic antibacterial, antifungal or antiviral agents during the study No antiretroviral treatment or willing to discontinue antiretroviral therapy 4 weeks prior to study entry. Must also remain off antiretroviral therapy for 1 week after study. (7 weeks total) Systemic steroids or anticancer agents for 4 weeks prior to study Active substance abuse INCLUSION CRITERIA Age: 2-12 years Sex: Male/Female CD4+ cell count greater than 200 if between ages 2-5 CD4+ cell count greater than 100 if greater than 5 years old Body weight less than 45 kg Antiretroviral therapy for at least 6 months with no change in treatment for past 3 months ICD p24 greater than 70 pg/ml EXCLUSION CRITERIA Protein wasting state Acute illness to temperature 100 deg. F or greater Use of specified medications Hypersensitivity to IVIG Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Site National Institute of Health (NIH), Bethesda, MD Trial Information 1-800-772-5464 x 312 159

Page  160 Trials for HIV Infection: Antiretroviral Therapy Sponsor ID: 95-310-01 PEPTI012 Peptide T: HIV Infection/AIDS Phase Il/Ill Double Blind Placebo Controlled Safety & Efficacy Trial CD4 Range:100 to 400 / Viral Load: Unspecified Sponsor ID: S-96-701 PMPA701 PMPA: HIV Infection Phase I/ll Randomized Double Blind Placebo Controlled Pharmokinetics & Safety Trial CD4 Range:200 or greater / Viral Load: 2,500 or greater Agent Peptide T placebo Peptide T placebo Route Dose/Frequency IV 3 mg qd continious infusion IV qd continious infusion IV 3 mg qd divided doses IV qd divided doses Time on Drug(s): 6 months Trial Duration: Open RE Neutrophils: 750 or greater Platelets: 25,000 or greater Hemoglobin: 8.0 or greater Hematocrit: Bilirubin: 2.5 x ULN or less INCLUSION CRITERIA Age: 18-75 years old Sex: Male/Female Number of Subjects: 210 Start Date: January 1996 Agent Part A: PMPA or placebo Part B: PMPA or placebo Time on Drug(s):2 weeks Trial Duration: 6 weeks RE Neutrophils: 1000 or greater Platelets: 75,000 or greater Hemoglobin: 9.0 or greater Bilirubin: 1.5 or less Route Dose/Frequency Day 1 IV 1.3.6.10 mg/kg 1 infusion / hr followed by 1 week observation 8 pts each dose level / 2 placebo Days 8-14 IV daily infusion at part A dose x 7 d Number of Subjects:80 Start Date: October 1996 EQUIRED BLOOD VALUES: SGOT/PT: Creatinine: 1.5 or less Granulocyte: EQUIRED BLOOD VALUES: SGOT/PT: 5x ULN or less Creatinine: 1.5 or less Granulocyte: WBC: Site Shared Medical Research Foundation, Tarzana, CA Trial Information (818) 345-2172 Doctor Galpin INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Karnofsky score: 80% or greater Negative pregnancy test Minimum life expectancy of 12 months EXCLUSION CRITERIA Ongoing therapy at time of enrollment with any antiretroviral therapy, interferon, interleukin, aminoglycoside antibiotics, ampho B, cidofovir, foscarnet, ganciclovir, diuretics, itraconaole, fluconazole, ketoconazole, clarithromycin, azithromyicin, isoniazid, rifampin, or rifabutin Systemic corticosteroids or any agent with nephrotoxic potential All above medications must be discontinued at least 2 weeks prior to enrollment Systemic chemotherapeutic agents Site John Hopkin's Medical Center, Baltimore, MD San Francisco General Hospital, San Francisco, CA Trial Information (410) 955-3150 (415) 476-9296 Doctor Flexner Deeks 160

Page  161 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 I SPC3 I SPC30001 SPC3: HIV Infection/AIDS Phase 1/11 Randomized Study of 2 doses CD4 Range:100 or greater / Viral Load: 10,000 or greater Route Dose/Frequency IV 20 mg or 40 mg qd x 21 days TRANS001 Viral Activation Tranfusion Study (VATS): HIV Infection Multicenter Randomized Trial CD4 Range: Unspecified I Viral Load: Unspecified Agent SPC3 Time on Drug(s): 21 days Trial Duration: 2 months RI Granulocyte: Neutrophils: Platelets: Hemoglobin: 10.0 or greater Number of Subjects: 20 Start Date: August 1996 Agent Arm 1: Leukocyte Reduced Red Blood Cells Arm 2: Non-leukcyte Reduced Red Blood Cells Time on Drug(s): 1 to 2 years Trial Duration: Route Dose/Frequency infusion infusion Number of Subjects: 400 Start Date: EQUIRED BLOOD VALUES: SGOT/PT:3x ULN or less Creatinine: 1.6 or less WBC: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Karnofsky score: greater than 70% Stable antiretroviral therapy for at least eight weeks EXCLUSION CRITERIA Women of child-bearing potential Neutrophils: Platelets: Hemoglobin: Hematocrit: Bilirubin: REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: WBC: Site Brown University AIDS Program, Providence, RI Trial Information (401) 456-2437 Doctor Skowron INCLUSION CRITERIA Age: 14 years or older Sex: Male/Female Site Case Western Reserve Medical School, Cleveland, OH Georgetown U, Washington, DC Miriam Hospital, Providence, RI Mount Sinai School of Medicine, New York, NY U California San Diego, San Diego, CA U California San Francisco, San Francisco, CA U North Carolina at Chapel Hill, Chapel Hill, NC U Pittsburgh Medical Center, Pittsburgh, PA U Texas HSC/Galveston, Galveston, TX U Washington Medical Center, Seattle, WA Trial Information (216) 844-5383 (202) 687-5378 (401) 331-8500 x4028 (212) 241-7856 (619) 294-6137 (415) 476-9296 (919) 966-2536 (412) 647-8116 (206) 772-1661 (206) 292-6548 Doctor Lederman Kumar Flanigan Sacks Lane Murphy van der Horst Mellors Pollard Collier 161

Page  162 Trials for HIV Infection: Antiretroviral Therapy COMBINATIONS OF OTHER ANTIRETROVIRAL COMPOUNDS AND NUCLEOSIDE ANALOGUES Descriptive text, Trial results, pages 15, 73 ACTG: 185 IVIG/Z01 HIVIG + AZT vs IVIG + AZT: HIV Pregnant Women/Neonatal Transmission Phase Ill Randomired Double-Blind Comparative Trial CD4 Range:500 Or Lower I Viral Load: Unspecified Descriptive text / Trial results, page 49 Sponsor ID: CBCT 07 HYDREA03 Hydroxyurea + ddl: HIV Infection/AIDS Phase 1/11 Randomized Open-Label Trial CD4 Range:50 to 600 / Viral Load: 10,000 or greater Agent Arm 1: Hydroxyurea ddl Arm 2: ddl Hydroxyurea Route PO PO PO PO DoselFrequency 500 mg bid 200 mg bid 200 mg bid 500 mg bid weeks 13-24 Number of Subjects: 80 Start Date: January 1996 Agent Women Arm 1: HIVIG Arm 2: IVIG llntrapartum: AZT Newborns: Arm 1: HIVIG AZT Arm 2: IVIG AZT Time on Drug(s): Open Trial Duration: 3 years Creatinine:1.5 or less INCLUSION CRITERIA Age: 13 years or older Urine protein: 2.0 or less Route Dose/Frequency (20-30 weeks gestation): IV 200 mg/kg q28d IV 200 mg/kg q28d IV 2.0 mg/kg for 1st hour followed by 1.0 mg/kg until delivery Time on Drug(s): 24 weeks Trial Duration: 9-12 months IV PO IV PO 200 mg/kg within 12 hours of birth 2.0 mg/kg qid x 6 weeks 200 mg/kg within 12 hours of birth 2.0 mg/kg qid x 6 weeks Number of Subjects: 800 Start Date: November 1993 REQUIRED BLOOD VALUES: Neutrophils: greater than 1,000 SGOT/PT: less than 2.5 x ULN Platelets: greater than 75,000 Creatinine: less than 1.5 x ULN Hemoglobin: less than 10.0 Granulocyte: Bilirubin: less than 2.5 x ULN INCLUSION CRITERIA Age: 13 years or older Sex: Male/Female EXCLUSION CRITERIA Greater than one week prior use of ddl, ddC or 3TC Use of cytokines including G-CSF, EPO, GM-CSF, or IL-2 within one month of study entry Any vaccination within 45 days Active AIDS-defining 01 REQUIRED BLOOD VALUES: Hemoglobin: 8.0 or more Pregnant women 20-30 weeks into gestation period EXCLUSION CRITERIA Pre-exisiting fetal anomalies by sonograph Prior CVS or PUBS in this pregnancy Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Site AIDS Research Consortium of Atlanta, Atlanta, GA Brown University AIDS Program, Providence, RI Clinical Directors Network of Region II, New York, NY Cornell Clinical Trials Unit, New York, NY CRI of New England, Brookline, MA CRI of S. Florida, Coral Gables, FL Houston Clinical Research Network, Houston, TX Kansas City AIDS Research Consortium, Kansas City, MO North Jersey CRI, Newark, NJ Philadelphia FIGHT, Philadelphia, PA Research & Education Group, Portland, OR Trial Information (404) 876-2317 (401) 456-2437 (212) 255-3841 (212) 746-4177 (617) 566-4004 (305) 667-9296 (713) 520-2018 (816) 756-5116 (201) 483-3444 (215) 557-8265 (503) 229-8428 Doctor Thompson Skowron Torres Giordano Cohen Stein Shader Stanford Perez Smith Ward 162

Page  163 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 Descriptive text / Trial results, page49 HYDREAO2 Hydroxyurea vs Hydroxyurea + ddl vs Hydroxyurea + ddl + d4T: HIV Infection I AIDS Phase 1/11 Open Label Safety & Efficacy Trial CD4 Range:100 to 500 / Viral Load: 13,500 or greater Agent Route Dose/Frequency Hydroxyurea PO 500 mg bid Hydroxyurea PO 500 mg bid ddl PO 200 mg bid Hydroxyurea PO 500 mg bid ddl PO 200 mg bid d4T PO 40 mg bid Time on Drug(s): 6 months Number of Subjects: 45 Trial Duration: One year Start Date: September 1995 REQUIRED BLOOD VALUES: Neutrophils: 1,500 or greater SGOT/PT: less than 5x ULN Platelets: 35,000 or greater Creatinine: 1.6 or less Hemoglobin: 10.0 or greater Granulocyte: Bilirubin: less than 2.5 INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Site Trial Information Doctor Shared Medical Research Foundation, Tarzana, CA (818) 345-2172 Galpin 163

Page  164 Actively Recruiting Trials for Immune-Based Therapies I TRIALS FOR HIV INFECTION IMMUNE-BASED THERAPIES CYTOKINES Descriptive text, page 51 Descriptive text / Trial results, page 67 Sponsor ID: 022 A1000082 Alpha Interferon (Oral low dose): HIV Infection Symptomatic Multicenter Prospective Randomized Double Blind Placebo Controlled Trial CD4 Range:50 to 350 / Viral Load: Unspecified Harlem Hospital Center, New York, NY Henry Ford Hospital, Detroit, MI Howard University Hospital, Washington, DC Independent Investigator, New York, NY, King-Drew Medical Center, Los Angeles, CA Medical Center of Delaware, Wilmington, DE Meharry Medical College, Nashville, TN New York Medical College, Valhalla, NY SUNY Health Science Center/Brooklyn, Brooklyn, NY U Minnesota Hospitals and Clinics, Minneapolis, MN U Pennsylvania Medical Center, Philadelphia, PA (212) 939-4170 (313) 876-2798 (202) 806-4700 (212) 926-8557 (310) 668-4213 (302) 428-2538 (615) 327-5830 (914) 285-7400 (718) 270-3372 (612) 625-1462 (215) 662-2473 EI-Sadr Kumi Delapenha Justice Jordan Holloway Shu Horowitz Chirgwin Balfour MacGregor Sponsor ID: C92-271 A 1000013 Alpha Interferon (low-dose): HIV Infection Asymptomatic Phase I Randomized Dose-Ranging Open-Label Trial CD4 Range:300 or higher / Viral Load: Unspecified Agent Arm 1: Alpha IFN placebo (veldona) placebo(ferimmune) Arm 2: placebo(IFN) veldona placebo(ferimmune) Arm 3: placebo(IFN placebo(veldona) ferimmune Arm 4: placebo placebo placebo Time on Drug(s): 6 months Trial Duration: 18 months INCLUSION CRITERIA Age: 13 years or older Sex: Male/Female Route PO PO PO PO PO PO PO PO PO PO PO PO Dose/Frequency 500 IU/ml qd qd qd qd 150 IU qd qd qd qd 200 IU qd qd qd qd Number of Subjects: 560 Start Date: May 1996 Agent Arml:Alpha Interferon Arm2:Alpha Interferon Arm3:Observation Route SC SC NA Dose/Frequency 0.2 MU tiw 2.0 MU tiw NA Time on Drug(s): 12 weeks Trial Duration: 12 weeks Number of Subjects: 75 Start Date: September 1993 REQUIRED BLOOD VALUES: SGOT/PT:2.5x normal or less Bilirubin: 2x ULN or less Platelets: 100,000 or more Creatinine: 2.5x normal or less Hemoglobin: 11.0 or more Granulocyte: 2,000 or more WBC:4,000 or more INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female EXCLUSION CRITERIA Concurrent or previous treatment with any antiretroviral or immunomodulating agent such as IL-2, alpha, beta or gamma interferon Participant in other clinical trials within 30 days prior to study entry Site Trial Information Abundant Life Clinic Foundation, Washington, DC (202) 397-4000 AIDS Community Research Consortium, Redwood City, CA (415) 364-6563 Georgetown U, Washington, DC (202) 687-1079 Doctor Muhammad Bubp, Pharm D Kumar 164

Page  165 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 07 Hypersensitive to alpha interferon or any component of the injectable formula Pregnant or nursing women Site Duke U Medical Center, Durham, NC San Francisco General Hospital, San Francisco, CA U Colorado, Denver, CO Trial Information (919) 684-8748 (415) 476-9296x84099 Closed at this site Doctor Bartlett Volberding Kuritzkes Descriptive text / Trial results, page 51 Sponsor ID: C942-18 I L 120003 IL-12: HIV Infection Phase II/Ill Randomized Double Blind Placebo Controlled Dose Escalating Trial CD4 Range:100 to 500 / Viral Load: Unspecified IL1 SC 200 L100002 IL-10 (SCH 5200): HIV Infection Asymptomatic Open Label Dose Escalating Efficacy Trial CD4 Range:200 Or Higher / Viral Load: Unspecified Agent IL-12 Route Dose/Frequency SC 30, 100, 300, 500 ng/kg biw Agent Arm 1: IL-10 Arm 2: IL-10 Route Dose/Frequency IV 1.0, 10, or 25 [g/kg IV 1.0, 10, or 25 pg/kg x 4 injection 12 hours apart Time on Drug(s): 12 weeks Trial Duration: 1 year RI Neutrophils: Platelets: 100,000 or greater Hemoglobin: 9.0 or greater WBC:greater than 1,500 Number of Subjects: 72 Start Date: December 1995 EQUIRED BLOOD VALUES: SGOT/PT: less than 3x ULN Creatinine: 1.8 or less Granulocyte: Bilirubin: 2x ULN or less Time on Drug(s): 21 days Trial Duration: 21 days Number of Subjects: 18 Start Date: REQUIRED BLOOD VALUES: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Site National Institutes of Health, Bethesda, MD INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Must have at least 8 weeks stable antiretroviral theapy prior to entry EXCLUSION CRITERIA AIDS-defining 01 except PCP Cardiac history, abnormal EKG Pulmonary disease GI disorders Prior vaccine use Neuropathy Use of immunomodulators, systemic corticosteroids, anticoagulants, or any investigational drug within 8 weeks of entry Trial Information (800) 243-7644 Doctor Weissman Site New England Medical Center, Boston, MA St. Luke's/Roosevelt Hospital at 59th, New York, NY San Francisco General Hospital, San Francisco, CA Trial Information (617) 636-8642 (212) 523-5818 (415) 476-9296 Doctor Skolnik McKinley Jacobson 165

Page  166 Actively Recruiting Trials for Immune-Based Therapies IL-2 I Descriptive text / Trial results, page 52 Sponsor ID: C-183 IL200014 IL-2 Pilot Study CD4 Range: Unspecified I Viral Load: Unspecified Route Dose/Frequency SC 1.0 or 4.5 MU/m q12h for 5 days bimonthly for first 8 weeks alone then added to IL-2 PO 120 mg/m2 q6h for at least 40 wks PO 135 mg/m2 q12h for at least 40 wks Sponsor ID: 1-133 IL200011 IL-2 with or without TNF antagonist: HIV Infection 3-Arm Randomized Open Label Drug Combination And Tolerance Trial CD4 Range:200 to 500 / Viral Load: Unspecified Agent IL-2 AZT ddl Time on Drug(s): 32 weeks Trial Duration: Number of Subjects: 34 Start Date: April 1996 Agent Arm 1: IL-2 Arm 2: IL-2 anti-TNF monoclonal antibody Arm 3: IL-2 thalidomide Time on Drug(s): 1 year Trial Duration: 2 years REC Neutrophils: Platelets: greater than 75,000 Hemoglobin: greater than 10 Hematocrit: Bilirubin: less than 2 mg Route Dose/Frequency IV continous infusion for 5 days every 8 weeks for one year IV continous infusion for 5 days every 8 weeks for one year administered concurrently with 1L-2 IV continous infusion for 5 days every 8 weeks for one year administered concurrently with IL-2 Number of Subjects: 90 Start Date: March 1995 WUIRED BLOOD VALUES: SGOT/PT: less than 150 unit/I Creatinine: less than 2.0 Granulocyte: greater than 1000 WBC: REQUIRED BLOOD VALUES: INCLUSION CRITERIA Age: 2-21 years Sex: Male/Female Site National Cancer Institute, Bethesda, MD Trial Information (301) 402-1391 Doctor Pizzo INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Site National Cancer Institute, Bethesda, MD Trial Information (301) 402-1391 Doctor Pizzo 166

Page  167 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 07 CYTOKINES AND ANTIRETROVIRALS COMBINATIONS *IL] *gn(OW DOS:)+ tiAov soviral Descriptive text / Trial results, page 52 ACTG: 248 IL200008 IL-2 (low dose) + Antiretroviral vs Antiretroviral: HIV Infection Randomized Safety & Efficacy Pilot Study CD4 Range: 300 to 700 / Viral Load: Unspecified Sponsor ID: 96 I 46 96 I 46 IL-2 + Antiretroviral: HIV Infection / Asymptomatic Phase I Dose-Escalating Tolerance & Safety Trial CD4 Range: 200 Or 500 / Viral Load: Unspecified Agent Arm 1: IL-2 AZT Arm 2: IL-2 AZT Route IM PO IM IM Dose/Frequency weeks 1-24 200 mg tid weeks 1-44 weeks 25-44 200 mg tid weeks 1-44 Number of Subjects: 104 Start Date: October 1995 Agent Arm 1: IL-2 antiretroviral therapy Arm 2: placebo (IL-2) antiretroviral therapy Time on Drug(s): 14 months Trial Duration: 14 months RE Neutrophils: Platelets: greater than 75,000 Hemoglobin: greater than 9.0 Hematocrit: Bilirubin: 2.0 x ULN or less Route Dose/Frequency SC q 8 weeks PO as directed SC q 8 weeks PO as directed Number of Subjects: Start Date: 4QUIRED BLOOD VALUES: SGOT/PT: 5x normal or less Creatinine: 2.0 or less Granulocyte: 1000 cells or greater WBC: Time on Drug(s): 56 weeks Trial Duration: 56 weeks REQUIRED BLOOD VALUES: Neutrophils: greater than 1,000 SGOT/PT: less than 5x ULN Platelets: greater than 75,000 Creatinine: less than 1.5 x ULN Hemoglobin: greater than 9.1 (males) greater than 8.8 (females) INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Karnofsky score: 70 or greater Stable approved antiretroviral therapy for at least 3 months EXCLUSION CRITERIA Other immunomodulators History of autoimmune disease including inflammatory bowel disease and psoriasis Pregnant or nursing women Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Patients must receive concomitant standard of care antiretroviral therapy with either approved or experimental drugs available through compassionate use protocol for at least 2 weeks prior to entry Patients initally randomized to receive antiretroviral therapy alone are eligible to receive IL-2 at end of one year EXCLUSION CRITERIA History of AIDS defining condition History of psoraiasis, Crohn's disease or other autoimmune disease Signficiant cardiac, renal, pulmonary, gastrointestinal or CNS disesase Hypertension Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 167

Page  168 Actively Recruiting Trials for Immune-Based Therapies GENE THERAPY Descriptive text, page 54 Sponsor ID: A-9501 A-9501 Autologous CD4-Zeta Gene Modified T Cells: HIV Infection Phase II Activity and Safety Trial CD4 Range: 50 to 500 / Viral Load: 1,000 to 10,000 TUMOR NECROSIS FACTOR INHIBITORS Descriptive text, page 55 Descriptive text / Trial results, page 55 Sponsor ID: 22-95-02 OPC00002 OPC-8212 + AZT: HIV Infection Phase II Randomized Open Label Safety & Efficacy Trial CD4 Range:501 Or Lower / Viral Load: Unspecified Agent Pilot phase:Modified T-cells antiretroviral therapy Randomized phase Arm 1: Modified T-cells antiretroviral therapy Arm 2: antiretroviral therapy Repeat Treatment phase Modified T-cells Time on Drug(s): Trial Duration: 1 year Route Dose/Frequency IV 3 infusions PO IV PO PO 3 infusions Agent OPC-8212 AZT Route PO PO Dose/Frequency 120 mg qd 200 mg tid Number of Subjects: 81 Start Date: December 1995 IV 1 infusion Number of Subjects: 10 (pilot) Start Date: Time on Drug(s): 42 days Trial Duration: 6 months REQUIRED BLOOD VALUES: Neutrophils: greater than 1,000 Bilirubin: less than 2X ULN Platelets: greater than 75,000 Creatinine:less than 1.8 Hemoglobin: greater than 9.0 Granulocyte: Hematocrit: 10,000 or greater WBC: greater than 2.0 INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Karnofsky score: greater than 70 Stable antiretroviral therapy for at least 8 weeks Anticipated survival greater than 6 months EXCLUSION CRITERIA KS requiring systemic therapy Pregnant or nursing women Treatment with other investigational drugs within 8 weeks of enrollment Interleukin therapy within past 6 months REQUIRED BLOOD VALUES: Neutrophils: greater than 1,500 SGOT/PT: Platelets: greater than 75,000 Creatinine: Hemoglobin: greater than 8.5 Granulocyte: Hematocrit: 10,000 or greater WBC: Bilirubin: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Site Oak Lawn Physicians, Dallas, TX Trial Information (214) 520-1810 Doctor Brand Site San Francisco GeneralHospital,San Francisco, CA Trial Information (415) 475-9296 Doctor Deeks 168

Page  169 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199 7 THERAPEUTIC VACCINES Descriptive text, page 58 Sponsor ID: 010 VACCINOI HIV-1 C4-V3 Polyvalent Peptide Vaccine: HIV Infection Phase I Randomized Double Blind Dose Comparison Immunuology Trial CD4 Range: 500 Or Lower / Viral Load: Unspecified Descriptive text / Trial results, page 61 Sponsor ID: 806 HIVI1M007 HIV-Immunogen: HIV Infection Symptomatic Phase III Double Blind Dose Ranging Safety & Efficacy Trial CD4 Range:300 to 549 / Viral Load: Unspecified Agent HIV-lmmunogen HIV Immunogen IFA alone Time on Drug(s): Trial Duration: 3 years RE Neutrophils: Platelets: 75,000 or greater Hemoglobin: greater than 9.0 Route IM IM IM Dose/Frequency 40U q 12 weeks 10U q 12 weeks q 12 weeks Number of Subjects: 2500 Start Date: November 1995 Agent Arm 1: HIV-1 C4-V3 placebo Arm 2: HIV-1 C4-V3 placebo Time on Drug(s): 24 weeks Trial Duration: 52 weeks Route Dose/Frequency SC 2.0 mg at day 0 and at weeks 4,8,12, and 24 SC at day 0 and at weeks 4,8,12,24 SC 8.0 mg at day 0 and at weeks 4,8,12, and 24 SC at day 0 and at weeks 4,8,12,24 Number of Subjects: 30 Start Date: September 1995 QUIRED BLOOD VALUES: SGOT/PT: less than 5x ULN Creatinine: less than 2x ULN Granulocyte: REQUIREE Neutrophils: Platelets: 50,000 or greater Hemoglobin: greater than 12 males greater than 11 females Hematocrit: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Site Duke U Medical Center, Durham, NC ) BLOOD VALUES: SGOT/PT: Creatinine: 1.5 x ULN or less INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Use of approved or experimental drugs must be with same agents and dose for past 30 days Must have stopped any investigational vaccine or immune-based therapy 3 months prior to study EXCLUSION CRITERIA AIDS-defining condition KS requiring systemic chemotherapy Acute infection requiring prescription treatment within one month of study except for genital or oral and oral or vaginal candidiasis Current systemic treatment for malignancy, except basal cell or squamous cell carcinoma of skin or carcinoma in situ of the cervix Previous participation in HIV-1 Immunogen study Granulocyte: Trial Information (919) 684-8216 Doctor Bartlett Site Cedars Sinai Medical Center, Los Angeles, CA George Washington U Medical Center, Washington, DC Goodgame and Hopkins, Maitland, FL Research & Education Group, Portland, OR San Francisco General Hospital, San Francisco, CA Trial Information (310) 855-3755 (202) 994-2417 (407) 647-6000 (503) 229-8428 (415) 476-9296 Doctor Daar Parenti Goodgame Antoniskis Kahn 169

Page  170 Actively Recruiting Trials for Immune-Based Therapies NC195C 172 HIV Immunogen: Pediatric HIV Infection Phase I Safety and Tolerance Dose Ranging Trial CD4 Range: 200 or greater I Viral Load: Unspecified Agent Route Dose/Frequency Arm 1: Antiretroviral-naive IM 2.5 U or 10.0 U at 0, 3, 6, 9, 12 mos Arm 2: Antiretroviral-experienced IM 2.5 U or 10.0 U at 0, 3, 6, 9, 12 mos Sponsor ID: T904-0051 VACIN005 Syntheic HIV Envelope Peptides (PCLUS) Vaccine: HIV Infection Phase I Open Label Non-Randomized Comparative Trial CD4 Range:500 Or Higher I Viral Load: Unspecified Time on Drug(s): 12 months Trial Duration: 12 months Number of Subjects: Start Date: Agent PCLUS Route Dose/Frequency SC day 0 and months 1,3,6,9 and 12 Time on Drug(s): 12 months Trial Duration: Open Number of Subjects: Start Date: REQUIRED BLOOD VALUES: Neutrophils: 750 or greater SGOT/PT: 5x ULN or less Platelets: 10,000 or greater Creatinine: 2x ULN or less Hemoglobin: 8.0 or greater Granulocyte: Hematocrit: WBC: 15,000 or more Bilirubin: 3x ULN or less INCLUSION CRITERIA Age: 3 months - 18 years Sex: Male/Female Arm 1: Children with mild or no symptoms and not requring antiretroviral therapy Arm 2: Children with mild to moderate symptoms and currently recieving antiretroviral therapy for 6 weeks or more EXCLUSION CRITERIA Presence of activeinfection requiring acute intervention other than a single episode of bacterial pneumonia Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) REQUIRED BLOOD VALUES: Neutrophils: greater than 1000 SGOT/PT: less than 75 IU/ml Platelets: greater than 100,000 Creatinine: less than 1.5 Hemoglobin: less than 12 Granulocyte: Hematocrit: WBC: Bilirubin: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Site National Cancer Institute, Bethesda, MD Trial Information (301) 496-9054 x 562 Doctor Yarchoan 170

Page  171 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199d 7 OTHER IMMUNE BASED THERAPIES Descriptive text, page 62 001 0012 GM-CSF: HIV Infection Asymptomatic Phase III Randomized, Double Blind Placebo Controlled Trial CD4 Range: 100 / Viral Load: 30,000 copies or greater Central Florida Research Initiative, Maitland, FL Central Texas Medical Foundation, Austin,TX Clinical Research of South Florida, Coral Gables,FL Comprehensive Immunology, Prarie Village,KS CRI/New England, Brookline, MA Dartmouth-Hitchcock, Medical Center, Dartmouth, NH Davies Medical Center, San Francisco, CA Future Scripts, Spokane, WA Independent Investigator, Washington, DC Independent Investigator, Houston, TX Independent Investigator, Ft. Lauderdale, FL Indiana U Medical Center, Indianapolis, IN Infectious Disease Associates, Kansas City, MO Infectious Disease Associates, Tampa, FL Hershey Medical Center, Hershey, PA New England Medical Center, Boston, MA North Broward Hospital, Ft. Lauderdale, FL Oak Lawn Physicians, Dallas, TX Omega Medical Research, Providence, RI Ochsner Clinic, New Orleans, LA Remington-Davis, Inc, Columbus, OH Research and Education Group, Portland, OR Southern Illinois University, Springfield, IL Therafirst Medical Center, Ft. Lauderdale, FL U Alabama, Birmingham, AL UCSD Medical Center, San Diego, CA U Cincinnati, Cincinnati, OH U Illinois, Louisville, KY U Kentucky, Lexington, KY U South Florida, Tampa, FL UT-Southwestern Medical Center, Dallas, TX ViRx, Inc. San Francisco, CA Washington Univ. School of Medicine, St. Louis, MO Wayne State University, Detroit, MI (407) 647-6000 (512) 450-1866 (305) 445-5637 (913) 384-7307 (617) 424-0240 (603) 650-5438 (415) 565-6153 (509) 458-0444 (202) 331-3888 (713) 526-9821 (954) 524-2250 (317) 274-8456 (816) 276-4038 (813) 875-4374 (717) 531-7488 (617) 636-8186 (954) 467-3006 (214) 520-1810 (401) 467-7760 (504) 842-3000 (614) 487-2560 (503) 413-7446 (217) 524-3926 (954) 564-4222 (205) 934-1917 (619) 294-6484 (513) 558-6362 (502) 852-1149 (606) 323-6326 (813) 974-3163 (214) 648-3246 (415) 474-4440 (314) 454-0058 (313) 993-0921 Goodgame Wright Rosen Nemechek Cohen von Reyn Follansbee Coffin Mustafa Gathe Richmond Wheat McKinsey Yangco Ehmann Skolnik Sension Brand Mikolich Pankey Baird Sampson Khardori LaMarca Squires Mathews Feinberg Huang Greenberg Toney Peterson Lang Powderly MacArthur Agent GM-CSF Route Dose/Frequency SC 250 pg tiw x 24 weeks Time on Drug(s): 6-12 months Trial Duration: 13 months REQL Neutrophils: greater than 750 Platelets: greater than 50,000 Hemoglobin: greater than 6.0 Number of Subjects: Start Date: November 1996 JIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: INCLUSION CRITERIA Sex: Male/Female Must be on stable antiretroviral regimen (approved/experimental) for at least 28 days prior to entry EXCLUSION CRITERIA AIDS-defining illness Concurrent use of other colony stimulating factors Concurrent radiation or systemic cancer chemotherapy within 2 weeks History of allergy to yeast-derived GM-CSF Site Abbott Northwestern Hospital, Minneapolis, MN AIDS Community Research Consort.,Redwood City, CA Alexis Medical Center, Toledo, OH Antibiotics Research Associates, Kansas City, MO Arizona Clinical Research Center, Inc., Tucson, AZ Associates in Medical & Mental Health, Tulsa, OK Beer Medical Group, Los Angeles, CA Beth Israel/Deaconess Hospital, Boston, MA Bowman Gray School of Medicine, Winston-Salem, NC Carolinas Medical Center, Charlotte, NC Trial Information (612) 863-5336 (415) 364-6563 (419) 474-0571 (816) 822-1633 (520) 290-2510 (918) 743-1000 (213) 937-5151 (617) 632-0785 (910) 716-2942 (704) 355-5292 Doctor Rhame Deresinski Grossman McKinsey Carmichael Beal McNamara Hammer High Horton 171

Page  172 Actively Recruiting Trials for Immune-Based Therapies Descriptive text / Trials Results, page 64 PASIM008 Passive Hyperimmune Therapy (Immupath): HIV Infection Phase III Double-Blind Placebo-Controlled Trial CD4 Range:50 to 400 / Viral Load: Unspecified Sponsor ID: # 110-101 110-101 Tucaresol (589C80): HIV Infection Open Label Dose Escalating Safety and Efficacy Pilot Study CD4 Range:300 to 500 / Viral Load: Unspecified Agent Arm 1: Immupath Arm 2: Placebo Route Dose/Frequency IV 500 ml qm IV qm Agent Tucaresol Tucaresol Tucaresol Tucaresol Tuc aresol Route PO PO PO PO PO Time on Drug(s):24 months Trial Duration: 24 months Number of Subjects:600 Start Date: January 1994 Dose/Frequency 25 mg q week 25 mg biw 25 mg tiw 50 mg biw 50 mg tiw Number of Subjects: 40 Start Date: January 1996 Neutrophils: Platelets: Hemoglobin: Hematocrit: Bilirubin: REQUIRED BLOOD VALUES: SGOT/PT: Creatinine: Granulocyte: WBC: Time on Drug(s): 4 weeks Trial Duration: 12 weeks INCLUSION CRITERIA Age: Sex: Male/Female Site HemaCare Corp., Sherman Oaks, CA Trial Information (213) 654-0565 Doctor Levy REQUIRED BLOOD VALUES: Neutrophils: 1,000 or greater SGOT/PT: Platelets: 75,000 or greater Creatinine: 1.5 X ULN or less Hemoglobin: 10.0 or greater Granulocyte: INCLUSION CRITERIA Age: 18 years or older Sex: Male/Female Concurrent use of liscensed antiretroviral therapy if tolerated for at least 3 months EXCLUSION CRITERIA Greater than one year use of currently liscensed antiretroviral nucleoside analog History of significant cardiovascular disease, respiratory disease or suspected autoimmune or chronic inflammatory disorders Abnormal EKG History of AIDS-defining 01 Use of experimental anti-HIV drugs Previous investigatioinal immunotherapy including HIV vaccine or IL-2, IFNs, G-CSF, and GM-CSF Serological evidence of hep B or hep C Radiation therapy or cytotoxic chemotherapy within six months Drugs known to have a marked effect on cytochrome P450 enzymes Pregnant or nursing women Site Atlanta AIDS Research Consortium, Atlanta, GA Trial Information (404) 876-2317 Doctor Thompson 172

Page  173 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 199 7 TRIALS FOR OPPORTUNISTIC INFECTIONS AND RELATED DISORDERS BACTERIAL / MYCOBACTERIAL INFECTIONS BACTERIAL PROPHYLAXIS TRIALS Treatment Results, page 80 ACTG: 292 BACT0010 Pneumococcal Vaccine: Presumed HIV-infected infants Phase 1/11 Randomized Double Blind Placebo Controlled Trial MYCOBACTERIUM AVIUM COMPLEX (MAC) TREATMENT TRIALS Treatment Results, page 81 Drug descriptions, pages 69, 70, 77 ACTG: 223 MYCOB072 CLARITHROMYCIN + ETHAMBUTOL + RIFABUTIN VS CLARITHROMYCIN + ETHAMBUTOL VS CLARITHROMYCIN + RIFABUTIN Disseminated MAC Phase 1/ll Randomized Safety & Efficacy Trial Agent Pneumococcal vaccine Heptavalent vaccine Route IM/SC IM Dose/Frequency 0.5ml at 24 months 0.5ml at 0,2,4,15 months Number of Subjects: 60 Start Date: January 1996 Time on Drug(s): 24 months Trial Duration: 24 months Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Agent Arm 1:Clarithromycin Ethambutol Arm 2:Clarithromycin Rifabutin Arm 3:Clarithromycin Ethambutol Rifabutin Route PO PO PO PO PO PO PO Dose/Frequency 500 mg bid 15 mg/kg qd 500 mg bid 450 mg qd 500 mg bid 15 mg/kg qd 450 mg qd Time on Drug(s): 48 weeks Trial Duration: Open Number of Subjects: 246 Start Date: November 1994 Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 173

Page  174 Actively Recruiting Trails for Opportunistic Infections Drug descriptions / HIV trial results, page 38 Sponsor ID: AG1343-518 1343518 Nelfinavir Effects on Clinical Outcome of Standard Treatment for MAC: Disseminated MAC A Pilot, Phase II Randomized Placebo-Controlled Trial Sponsor ID: OYPR0018 MYCOB082 Rifapentine alone or in combination therapy: AIDS Phase II Open Label Randomized Tolerance Trial Agent MAC Treatment Azithromycin ethambutol nelfinavir / placebo Time on Drug(s): 3 months Trial Duration: 12 months Site Baylor University Medical Center, Housto Boston VA Medical Center, Boston, MA Harbor UCLA Medical Center, Los Angele Rush Presbyterian Medical Center, Chica UCSD, San Diego, CA Route Dose/Frequency PO 600 mg qd PO 800 mg qd along with optimal nucleoside therapy and PO 750 mg tid Number of Subjects: 20 Start Date: November 1996 Agent Route Rifapentine PO Cohort 1 Rifapentine PO Azithromycin PO Clarithromycin PO Ethambutol PO Cohort 2 Rifapentine PO Azithromycin PO Clarithromycin PO Ethambutol PO Cohort 3 Rifapentine PO Time on Drug(s): 42 days Trial Duration: 49 days Site NY, Philadelphia, Pittsburgh Washington, DC sites Dose/Frequency 300 mg qd (monotherapy cohorts 1-3) 300 mg qd with 250 mg qd or 500 mg bid or 15 mg/kg qd 300 mg qd with 250 mg qd or 500 mg bid or 15 mg/kg qd dose to be 150 mg or 600 mg TBD based on safety profiles from 1 & 2 Number of Subjects: 450 Start Date: May 1996 Trial Information Doctor 1-800-711-5878 Anderson CI. Res. Trial Information (713) 793-4020 (617) 478-5584 (310) 222-3848 (312) 942-5865 (619) 543-8080 Doctor White Maslow Witt Benson Torriani Drug descriptions, page 77 MYCOB065 Rifabutin Oral Suspension: Pediatric HIV Infection Phase 1/11 Randomized Safety, Efficacy & Pharmacokinetics Trial RIFAPENTINE + ISONIAZID VS RIFAMPIN + ISONIAZID Sponsor ID: 1427 1427TB22 Rifapentine + Isoniazid vs Rifampin + Isoniazid: Active MTB Phase IIl Randomized Open Label Safety & Efficacy Trial Agent Arm 1: Rifabutin Arm 2: Rifabutin Arm 3: Rifabutin Route PO PO PO Dose/Frequency 5 mg/kg qd 10 mg/kg qd 15 mg/kg Number of Subjects: 100 Start Date: November 1993 Agent Rifapentine Isoniazid Vitamin B Rifampin Isoniazid Vitamin B Route PO PO PO PO PO PO Time on Drug(s): Open Trial Duration: Open Site National Cancer Institute, Bethesda, MD Dose/Frequency.600 mg qw 900 mg qw 50-100 mg each dose 600 mg biw 900 mg biw 50-100 mg each dose Number of Subjects: 1100 Start Date: April 1995 Trial Information (415) 221-4810 Trial Information (301) 402-1391 Doctor Pizzo Time on Drug(s): 4 months Trial Duration: 2 years Site VA Medical Center, San Francisco, CA Doctor Jensen 174

Page  175 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 1 997 MAC PROPHYLAXIS TRIALS Treatment Results, page 81 Drug descriptions, pages 68, 78 254 BACT0005 Atovaquone & Azithromycin vs. TMP/SMX: PediatriclAdolescent HIV Infection Phase II/111 Safety & Efficacy Study TUBERCULOSIS TREATMENT TRIALS Treatment Results, page 88 Drug descriptions, pages 70, 71, 73, 77 TUBTX006 Gamma IFN + Isoniazid + Rifampin + Ethambutol Pyrazinamide + Vitamin B6 Phase I Randomized Double-Blind Placebo-Controlled Trial Agent Arm 1: Atovaquone Azithromycin Arm 2: TMP/SMX Route PO PO PO Dose/Frequency 30 mg/kg qd 5 mg/kg qd 5 mg/kg qd Agent Gamma IFN Isoniazid Rifampin Ethambutol Pyrazinamide Vitamin B6 Route IN PO PO PO PO PO Time on Drug(s): 2 -4 years Trial Duration: 2 years Number of Subjects: 690 Start Date: Dose/Frequency 1,000 pg qd x 4 weeks 300 mg qd 600 mg qd 800 mg qd 1,000 mg qd Number of Subjects: 30 Start Date: August 1994 Trial Information A (408) 885-4316 Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Drug descriptions, pages 69, 70, 71, 77, 78 ACTG: 283 MYCOB 100 Fluconazole, Clarithromycin, Rifabutin effects on TMP/SMX & Dapsone: Concurrent Prophylaxis Interactions Phase I Pharmacokinetics and Pharmacodynamics Trial Time on Drug(s): 9 months Trial Duration: 9 months Site Santa Clara Valley Medical Center, San Jose, C Doctor Deresinski Agent Clarithromycin TMP/SMX Dapsone Rifabutin Fluconazole Time on Drug(s): 8 weeks Trial Duration:12 weeks Route PO PO PO PO PO Dose/Frequency 500 mg bid 1 DSqd 100 mg qd 300 mg qd 200 mg qd Number of Subjects: 48 Start Date: January 1996 Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 175

Page  176 Actively Recruiting Trails for Opportunistic Infections Drug descriptions, pages 70, 77 ACTG: 309 TUBTX010 Isoniazid, Rifampin, Ethambutol, Pyrazinamide: AIDSITB Pharmacokinetics Of Combination Antituberculosis Agents TUBERCULOSIS PROPHYLAXIS TRIALS Treatment Results, page 88 Drug descriptions, page 77 Sponsor ID: 91 IALM013 TUBPR008 Isoniazed vs Rifabutin: HIV Infection/AIDS Phase III Double Blind Placebo Controlled Trial Agent Isoniazid Pyridoxine HCL Rifampin Ethambutol Pyrazinamide Route PO PO PO PO PO Dose/Frequency 300 mg daily phase 50 mg concurrently with isoniazid 600 mg daily phase 20 mg/kg daily phase 2.0 g daily phase Number of Subjects: 50 Start Date: January 1996 Agent Rifabutin Isonized Route PO PO Time on Drug(s): Up to 8 weeks Trial Duration: Dos 300 300 e/Frequency mg qd x 3 months mg qd x 12 months iber of Subjects: 1880 t Date: September 1995 Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Time on Drug(s): 1 year Num Trial Duration: 36 months Star Site Goodgame and Hopkins, Maitland, FL Long Island Jewish Medical Center, New Hyde Park, NY Maricopa Medical Center/McDowell Clinic, Phoenix, AZ San Francisco VA Medical Center, San Francisco, CA U Kentucky Medical School, Lexington, KY U South Florida Health Sciences Center, Tampa, FL VA Medical Center, San Francisco, CA Trial Information (407) 647-6000 (718) 470-8930 (602) 257-0606 (415) 221-4810 x4798 (606) 323-6327 (813) 974-3163 (415) 221-4810 Doctor Goodgame Siegal Post Sullam Greenberg Bergen Sullam 176

Page  177 AIDS/HIV Treatment Directory; Vol 8, No. 3; January n1 )97 FUNGAL INFECTIONS CANDIDIASIS TREATMENT Treatment Results, page 91 Drug descriptions, page 67 CAND1025 Amphotericin B Lipid Complex: Pediatric HIV Infection Phase 1/11 Open-Label Trial ------------------------------ Drug descriptions, pages 67, 71 Sponsor ID: 056-188 CANDI022 Fluconazole vs Amphotericin B: Pediatric HIV Infection Phase ////// Randomized Pharmacokinetics, Safety & Efficacy Trial Agent Arm 1: Fluconazole Arm 2: AmphotericinB Time on Drug(s): up to 6 months Trial Duration: 96 days Site LAC+USC Medical Center, Los Angeles, Route DoselFrequency PO/IV 12 mg/kg bid IV 1 mg/kg qd Number of Subjects: 128 Start Date: September 1993 Agent ABLC Route Dose/Frequency IV Weight dependent Time on Drug(s): 6 months Trial Duration: Open Site National Cancer Institute, Bethesda, MD Number of Subjects: Open Start Date: September 1994 Trial Information (213) 226-5068 Doctor Kovacs Trial Information (301) 402-3527 Doctor Walsh Drug descriptions, page 71 CANDIO16 Fluconazole: HIV Infection in Women Phase 1/11 Open-Label Trial Drug descriptions, pages 67, 72 Sponsor ID: 001.0010 001 0010 GM-CSF + Amphotericin B Vs Amphotericin B: HIV Infection I AIDS I Refractory Oral Candidiasis Phase II Open Label Randomized Trial Agent Arm 1: Fluconazole Arm 2: Fluconazole Route PO PO Dose/Frequency 200 mg qw 100 mg qd Agent GM-CSF Amphotericin B Route Dose/Frequency SC 250 pg qd IV 200-250 mg 10-14 days Time on Drug(s): Subjects: 70 Trial Duration: 3 months 1 day or 1 week Number of Time on Drug(s): 10-14 days Trial Duration: Site Infectious Disease Associates, Sommerville, NJ Number of Subjects: 48 Start Date: September 1996 Start Date: De< Site Trial Information AIDS Community Research Consortium, Redwood City, CA (415) 364-6563 Santa Clara Valley Medical Center, San Jose, CA (408) 885-4316 U California Irvine Medical Center, Orange, CA (714) 456-7612 U California San Diego, San Diego, CA (619) 543-8080 U Southern California, Los Angeles, CA (310) 358-2429 cember 1992 Doctor Deresinski Kemper Tilles Havlir Leedom Trial Information (609) 497-1068 Doctor Nahass 177

Page  178 Actively Recruiting Trails for Opportunistic Infections - 9-3-- 1~-- -- - ------ ---p Drug descriptions, pages 71, 72 CANDIO82 GM-CSF + Fluconazole vs Fluconazole: Fluconazole-Resistant Candidiasis Phase II Open-Label Safety & Efficacy Trial CANDIDIASIS PROPHYLAXIS TRIALS TREATMENT RESULTS, PAGE 91 Drug descriptions, page 71 CANDI017 Fluconazole: HIV Infection in Women Phase I Randomized Open-Label Trial Agent GM-CSF Fluconazole Route SC PO D 21 41 loselFrequency 50 pg qd 00 mg qd umber of Subjects: 48 tart Date: April 1996 Agent Arm 1: Fluconazole Arm 2: Fluconazole Route PO PO Dose/Frequency 200 mg qw 50 mg qd Time on Drug(s): 14 days N Trial Duration: 16 weeks S Site NY, Philadephia, Pittsburgh, Washington DC sites U Nebraska Medical Center, Omaha, NE Trial Information 1-800-711-5878 (402) 559-4219 Doctor Anderson CR Swindells Time on Drug(s): 6 months Trial Duration: 1 year Number of Subjects: 50 Start Date: March 1993 Site Trial Information AIDS Community Research Consortium, Redwood City, CA (415) 364-6563 Santa Clara Valley Medical Center, San Jose, CA (408) 885-4316 U California Irvine Medical Center, Orange, CA (714) 456-7612 U California San Diego, San Diego, CA (619) 543-8080 U Southern California, Los Angeles, CA Closed at this site Doctor Deresinski Kemper Tilles Havlir Leedom Sponsor ID: SFS253E00 CAND1036 Terbinafine: Fluconazole-Resistant Candidiasis Phase 11/111 Double Blind Randomized Safety & Efficacy Trial Agent Arm 1: Terbinafine Arm 2: Terbinainfe Fluconazole Route PO PO PO Dose/Frequency to be determined to be determined 200 mg qd Number of Subjects: Start Date: April 1996 Time on Drug(s): 4 weeks Trial Duration: 4 weeks Site George Washington U, Washington, DC U Texas HSC/Galveston, Galveston, TX Trial Information (202) 994-2417 (409) 772-0361 Doctor Simon Pollard 178

Page  179 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 1i 997 COCCIDIOIDOMYCOSIS PROPHYLAXIS TRIALS Treatment Results, page 95 Drug descriptions, page 71 Sponsor ID: R-0266 COCC1004 Fluconazole: HIV Infection Phase II Randomized Double-Blind Placebo-Controlled Trial CRYPTOCOCCAL MENINGITIS TREATMENT TRIALS Treatment Results, page 95 Drug descriptions, page 67 Sponsor ID: 94-0-013 CRYPC030 Ambisome (Lipsomal Amphotericin B) Vs Ampho B Followed by Fluconazole: AIDS Phase II Double Blind Dose-Ranging Safety & Efficacy Trial Agent Arm 1: Fluconazole Arm 2: Placebo Route PO PO Do, 200 qd se/Frequency ) mg qd nber of Subjects: 190 rt Date: July 1993 Time on Drug(s): up to 24 months Nur Trial Duration: 24 months Sta Site Audie Murphy VA Hospital, San Antonio, TX Maricopa Medical Center/McDowell Clinic, Phoenix, AZ Probst Professional Building, Rancho Mirage, CA Agent Liposomal ampho B fluconazole Lipsomal ampho B fluconazole Amphotericin B fluconazole Route IV IV/PO IV IV/PO IV IV/PO Dos< 3.0 40C 6.0 40C 0.7 40C e/Frequency mg/kg qd x 14 days followed by ) mg qd weeks 3-10 mg/kg qd x 14 days followed by ) mg qd weeks 3-10 mg/kg qd x 14 days followed by ) mg qd weeks 3-10 iber of Subjects: 370 t Date: June 1995 Trial Information (210) 617-5111 Closed at this site (619) 346-5688 Doctor Graybill Cone Time on Drug(s): 8 weeks Num Trial Duration: 10 weeks Start Site Audie Murphy VA Hospital, San Antonio, TX Baylor College of Medicine, Houston, TX Beer Medical Group, Los Angeles, CA Bowman Gray School of Medicine, Winstom-Salem, NC Cabrini Medical Center, New York, NY Center for Special Immunology - Irvine, Irvine, CA Community Hospital, Indianapolis, IN Davies Medical Center, San Francisco, CA Harlem Hospital Center, New York, NY Indiana University School of Medicine, Indianapolis, IN Kaiser Permanente of San Francisco, San Francisco, CA Manatee Memorial Hospital, Bradenton, FL Medical College of Virginia, Richmond, VA Medical College of Virginia, Richmond, VA Methodist Hospital / Life Core Clinic, Indianapolis, IN NYU/Bellevue Hospital Center, New York, NY Ohio State U Hospitals, Columbus, OH San Francisco General Hospital, San Francisco, CA St. Michael's Hospital, Newark, NJ St. Vincent's Medical Center, New York, NY U Southern Alabama, Mobile, AL U Texas HSC/Houston, Houston, TX Vanderbilt U Medical Center, Nashville, TN Trial Information (210) 614-6197 (713) 794-7385 (213) 937-5151 (910) 716-4507 (212) 725-7305 (714) 753-0670 (317) 355-4833 (415) 565-6660 (212) 939-2936 (317) 274-8456 (415) 202-2854 (813) 753-2949 (804) 828-6471 (803) 792-6173 (317) 929-2700 (212) 562-3906 (614) 293-8745 (415) 476-9296 (201) 877-5690 (212) 604-1576 (205) 460-7220 (713) 792-4929 (615) 936-1174 Doctor Graybill Hamill Beer Peacock, Jr. Mullen Cimoch Baker, Follansbee EI-Sadr Wheat Fessel Bach Kerkering Kerkering Black Javaly Koletar Stansell Johnson Klein Dill Johnson Haas 179

Page  180 Actively Recruiting Trails for Opportunistic Infections ------- - -- --------- ----- Drug descriptions, page 71 CRYPC027 Fluconazole + Flucytosine Phase 1I Safety & Effiacy Trial Drug descriptions, pages 67, 73 Sponsor ID: ITR-USA-11 HIST0007 Itraconazole (IV) vs Amphotericin B followed with oral itraconazole maintenance HIV Infection Symptomatic Phase III Randomized Open Label Comparative Trial Agent Fluconazole Flucytosine Route Dose/Frequency PO 800 mg qd x 10 weeks PO 100 mg qd x 4 weeks Time on Drug(s): 10 weeks N Trial Duration: 1 year S Site Harbor UCLA Medical Center, Torrance, CA Santa Clara Valley Medical Center, San Jose, CA umber of Subjects: 40 tart Date: August 1994 Agent Itraconazole Itraconazole Amphotericin B Itraconazole Route Dose/Frequency IV 200 mg bid x 2 days, then 200 mg IV qd x 5 days followed by PO 200 mg qd or bid for up to one year IV 0.5 - 1.0 mg/kg x 7 days followed PO 200 mg qd or bid for up to one year Trial Information Closed at this site (408) 885-4316 Doctor Witt Kemper HISTOPLASMOSIS TREATMENT TRIALS Treatment Results, page 98 Drug descriptions, page 67 HIST0006 Liposomal Amphotericin B vs Amphotericin: AIDS Phase II/111 Double Blind Safety & Efficacy Trial Time on Drug(s): 1 year Nu Trial Duration: 1 year Sta Site Ann Arbor VA Medical Center, Ann Arbor, MI Indiana University School of Medicine, Indianapolis, IN Infectious Disease Assoc. of Kansas City, Kansas City, MO U Arkansas for Medical Sciences, Little Rock, AR mber of Subjects: 60 art Date: Trial Information (313) 761-7984 (317) 274-8456 (816) 276-4522 (501) 686-5585 Doctor Kauffman Wheat McKinsey Martin Agent AmBisome Itraconazole Amphotericin B Itraconazole Route IV IV IV IV ( 4 0 4 DoselFrequency 3.0 mg/kg qd 7-14 days with 400 mg qd weeks 2-12 ).7 mg/kg qd 7-14 days with 400 mg qd weeks 2-12 lumber of Subjects: 75 Start Date: September 1995 Time on Drug(s): 12 weeks Trial Duration: 12 weeks C Site Baylor College of Medicine, Houston, TX San Francisco General Hospital, San Francisco, CA U Texas HSC/Houston, Houston, TX Trial Information (713) 794-7385 (415)476-9296 (713) 792-4929 Doctor Hamill Stansell Johnson 180

Page  181 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 1n )97 MALIGNANCIES KAPOSI'S SARCOMA TREATMENT TRIALS Treatment Results, page 99 Drug descriptions, page 74 Sponsor ID: AR 94-0101 KAPOS070 AR-623 (Liposomal Tretinoin): KS Phase II//Il Open-Label Dose-Ranging Safety & Efficacy Trial Drug descriptions, page 70 Sponsor ID: 30-38 30-38 Doxorubicin vs Daunorubicin: Prior Systemic Chemotherapy Phase 1/11 Randomized Double Blind Efficacy Trial Route Dose/Frequency IV Agent Doxorubicin Daunorubicir n IV Agent AR-623 Route Dose/Frequency IV 60-120 mg/m2 qw to tiw Time on Drug(s): 12 weeks Trial Duration: until progression Site Boston Medical Center, Boston, MA Graduate Hospital, Philadelphia, PA Kaiser Permanente, San Francisco, CA Rosewell Park Cancer Center, Buffalo, NY Thomas Street Clinic, Houston, TX Tulane University Medical Center: New Orleans, LA University of Miami, Miami, FL Trial Information (617) 638-7537 (215) 893-7520 (415) 202-2859 (716) 845-8075 (713) 793-4020 (504) 588-5482 (305) 243-3838 Number of Subjects: 80 Start Date: July 1996 Doctor Cooley Henry Mass Bernstein Miller Mudad Fischl Time on Drug(s): Open Nur Trial Duration: Open Stai Site George Washington U Medical Center, Washington, DC New England Deaconess Hospital, Boston, MA Oncol Medical Associates, Houston, TX U Miami Medical Center, Miami, FL U Southern California, Los Angeles, CA nber of Subjects: 120 rt Date: September 1994 Trial Information (202) 994-2417 Closed at this site (713) 995-6866 (305) 547-3838 (213) 224-6668 Doctor Parenti Scadden Rios Fischl Gill Drug descriptions, page 71 ACTG: 269 KAPOS072 Etoposide (low-dose): KS Phase II Open-Label Safety & Tolerance Trial Agent Etoposide Route Dose/Frequency PO 50 mg qd days 1-7 q2w with escalation to 100 mg qd after 2 cycles if patient achieves partial or complete remission Time on Drug(s): minimum 4 weeks Trial Duration: Open Number of Subjects: 41 Start Date: October 1994 Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 181

Page  182 Actively Recruiting Trails for Opportunistic Infections Actively -R----ruitingTralsforOprt Drug descriptions, page 72 Sponsor ID: 17K-94-3 KAPOS071 Human Chorionic Gonadotropin (HCG): KS Open-Label Dose-Ranging Pilot Study Route Dose/Frequency IL 500, 1,000, or 2,000 USP loading dose / 4 wk observation/500, 1,000, or 2,000 USP qw x 4wk Sponsor ID: Janssen LIA-USA34 LIAUSA34 Liarozole: AIDS Open Label Non-Randomized Dose Escalation Two-Arm Pilot Trial Agent HCG Agent Arm 1:Liarozole Arm 2:Liarozole wk Route PO PO Dose/Frequency 150 mg bid x 12wks 150 mg bid x 2 wks /300 mg bid x 10 Number of Subjects: 30 Start Date: July 1996 Time on Drug(s): 9 weeks Trial Duration: 2 months Number of Subjects: 18 Start Date:\ October 1994 Time on Drug(s): 12 weeks Trial Duration: 48 weeks Site San Francisco General Hospital, San Francisco, C Site Trial Information Kenneth Norris Jr. Cancer Hospital/USC, Los Angeles, CA (213) 224-6668 Doctor Gill A Trial Information (415) 476-9296 Doctor Kahn 1C'II ~----L I~sr;tligl~PI~IBIIII~IP~ Drug description, page 51 ILI2KS Interleukin 12 (IL-12): KS Dose Escalating Safety & Efficacy Pilot Study Route Dose/Frequency SC 100, 300, 500 ng/kg biw Drug descriptions, page 75 KAPOS061 OPC 8212 (Vesnarinone, Arkin-Z): KS Phase 1/11 Open-Label Dose-Ranging Safety Trial Agent IL-12 Time on Drug(s): 12 weeks Trial Duration: 2 months Site National Cancer Institute, Bethesda, MD Number of Subjects: 37 Start Date: November 1996 Agent Arm 1: OPC 8212 Arm 2: OPC 8212 Arm 3: OPC 8212 Arm 4: OPC 8212 Route PO PO PO PO Dose/Frequency 60 mg qd 120 mg qd 180 mg qd 240 mg qd Number of Subjects: Open Start Date: March 1994 Trial Information (301) 496-9054 Doctor Pluda Time on Drug(s): at least 16 weeks Trial Duration: Open Site Northwestern U Medical Center, Chicago, IL U California Los Angeles, Los Angeles, CA Trial Information Closed at this site (310) 206-6414 Doctor VonRoenn Mitsuyasu 182

Page  183 __AIDS/HIV Treatment Directory; Vol 8, No. 3; January 19 997 Drug Description, page 75 KAPOS082 Paclitaxel (taxol): Advanced KS Phase II Open Label Trial ~"' "_ '"" ' '""" "__ '"?L '"'"'" __ Sponsor ID: C92-007-02 KAPOS069 Platelet Factor 4 (rPF4): KS Phase 1/11 Open-Label Safety Trial Route Dose/Frequency IV 0.3 mg/kg over 6 hours IV 1.0 mg/kg over 6 hours IV 3.0 mg/kg over 6 hours Agent Paclitaxel Route Dose/Frequency IV 100 mg/m q 2 weeks Agent Arm 1: rPF4 Arm 2: rPF4 Arm 3: rPF4 Time on Drug(s): at least 2 cycles Trial Duration: up to 10 cycles Site New England Deaconness Hospital, Boston, MA Number of Subjects: 40-80 Start Date: January 1996 Note: drug is delivered day 1 of week 1 days 1,2,3 of week 2 and days 1,2,3,4,5 of subsequent weeks up to 12 weeks Trial Information (617) 845-8965 Doctor Bernstien Drug descriptions, page 76 Sponsor ID: VERSN 1 KAPOS039 Platelet Factor 4 (PF4): HIV Infection Symptomatic Phase I Randomized Dose-Tolerance Safety & Efficacy Trial Time on Drug(s): 12 weeks Trial Duration: 2 months Site ViRx Inc., San Francisco, CA Number of Subjects: 18 Start Date: August 1994 Trial Information (415) 474-2233 Doctor Lang Drug descriptions, page 75 Sponsor ID: AMC002 KAPOS084 Retinoic Acid (9-cis): AIDS Phase II Open Label Dose Escalating Trial Agent Arm 1: PF4 x 3 weeks Route Dose/Frequency IL 0.10, 0.50, 1.50, or 2..50 mg qd loading dose x 1 week followed by tiw Time on Drug(s): 28 days I Trial Duration: Open Site San Francisco General Hospital, San Francisco, CA Agent 9-cis RA Route Dose/Frequency PO 60-140 mg/m2 qd Number of Subjects: 12 Start Date: July 1992 Time on Drug(s): 16 weeks or longer Trial Duration: Number of Subjects: 29 Start Date: July 1996 Trial Information (415) 476-9296x84093 Doctor Kahn Site Trial Information Rosewell Park Cancer Institute, Buffalo, NY (716) 845-3221 Mount Sinai School of Medicine, New York, NY (212) 241-3932 U Miami Medical Center, Miami, FL (305) 547-3838 Georgetown U, Washington, DC (202) 687-3064 NYU, New York, NY (212) 263-6485 Memorial Sloan-Kettering Cancer Center, New York, NY (212) 639-7163 Kenneth Norris Jr. Cancer Hospital/USC, Los Angeles, CA (213) 342-2448 U California Los Angeles, Los Angeles, CA (310) 206-6414 Massachusetts General Hospital, Boston, MA (617) 724-9190 Northwestern U Medical Center, Chicago, IL (312) 908-8358 John Hopkins Hospital, Baltimore, MD (410) 614-4487 San Francisco General Hospital, San Francisco, CA (415) 476-9296 Washington U Medical Center, St. Louis, MO (314) 362-8836 Doctor Bernstein Cheung Fischl Freter Friedman Krown Levine Mitsuyasu Scadden VonRoenn Ambinder Kaplan Ratner 183 II

Page  184 Actively Recruiting Trails for Opportunistic Infections Sponsor ID: L1057T-31 KAPOS086 Retinoic acid (9-cis), ALRT-1057 topical gel: KS Phase Ill Randomized Double Blind Placebo Controlled Safety & Efficacy Trial Agent Route DoselFrequency ALRT1057 topical 0.10% tid or qid x 12 weeks placebo tid or qid x 12 weeks Drug descriptions, page 67 Sponsor ID: AMC002 KAPOS066 ALRT 1057: KS Phase II Open-Label Trial Time on Drug(s): up to 16 weeks NL Trial Duration: open St Site Anderson Clinical Research, Pittsburgh, PA Baltimore Trials, Inc, Baltimore, MD Beth Israel Hospital, Boston, MA Center for Special Immunology - Irvine, Irvine, CA Center for Special Immunology - San Diego, San Diego, Center Special Immunology - Chicago,, Coleman Institute, North Miami, FL Conant Medical Group, San Francisco, CA Desert AIDS Project, Palm Springs, CA East Bay AIDS Center, Berkeley, CA Henry Ford Hospital, Detroit, MI HIVCare, San Francisco, CA Independent Investigator Kraus Medical Partners, Los Angeles, CA Massachusetts General Hospital, Boston, MA Medical College of Wisconsin, Charleston, SC Medical University of South Carolina, Charleston, SC Mount Sinai School of Medicine, New York, NY New England Deaconess Hospital, Boston, MA NYU Medical Center, New York, NY Rosewell Park Cancer Institute, Buffalo, NY So. California Permanente Medical Group, Los Angeles, U California Los Angeles, Los Angeles, CA U California Los Angeles, Los Angeles, CA U Southern California, Los Angeles, CA U Texas / Houston, Houston, TX U Texas HSC/Dallas, Dallas, TX U. Hospitals Cleveland, Cleveland, OH ViRx Inc., San Francisco, CA imber of Subjects: 230 art Date: April 1996 Trial Information (412) 371-7768 (410) 328-3588 (617) 632-0833 (714) 753-0670 CA (619) 291-1122 (312) 296-2400 (305) 651-3076 (415) 759-4127 (619) 323-2118 (510) 204-1291 (313) 876-1984 (415) 353-6295 (602) 834-6632 (213) 930-2324 (617) 724-9190 (414) 454-5312 (308) 792-9155 (212) 241-3932 (617) 632-0833 (212) 263-5244 (716) 845-3221 CA (213) 667-8172 (310) 825-9611 (310) 206-6414 (213) 342-2448 (713) 794-5232 (214) 648-3877 (216) 844-7164 (415) 474-2233 Doctor Anderson Wolde-Rufael Groopman Cimoch Pearce Berger Johnson Conant Northfelt Brosgart Fivenson Leoung Payne Sandier Scadden Crosby Thiers Cheung Groopman Freidman-Kien Bernstein Turner Miles Miles Gill Duvic Cockerell Elmets Wagner Agent Route Dos Arm 1:LGD 1057 PO 60 rr by twc Time on Drug(s): Open Nun Trial Duration: 4-6 weeks Star Site Desert Hospital Comp Cancer Center Independent Investigator: Washington, DC Massachusetts General Hospital, Boston, MA Memorial Sloan-Kettering Cancer Center, New York, NY Milton S. Hershey Medical Center, Hershey, PA New England Deaconess Hospital, Boston, MA Northwestern U Medical Center, Chicago, IL NYU Medical Center, New York, NY Shared Medical Research Foundation, Tarzana, CA Tulane University School of Medicine, New Orleans, LA U California Los Angeles, Los Angeles, CA U California San Diego, San Diego, CA U Texas HSC/Houston, Houston, TX e/Frequency ng/m2/qd. Dose will escalate 40 mg/m2 at intervals of every Sweeks, to maximum 140 mg/m2 iber of Subjects: 36 tDate: July 1996 Trial Information (619) 323-6585 (202) 331-3888 (617) 726-8166 (212) 639-7169 (717) 531-7488 Closed at this site Closed at this site (212) 263-6565 (818) 345-2172 (504) 588-5135 (310) 825-1301 (619) 552-8585 (713) 794-5232 Doctor Lemon Mustafa Scadden Myskowsky Eyster Groopman VonRoenn Valentine Galpin Millikan Miles Looney Duvic 184

Page  185 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 19 097 Drug descriptions, page 75 Sponsor ID: L1069-21 L1069-21................D i---------l------------- 1 9 LGD1069: AIDS-Related KS Phase II Open Label Safety & Efficacy Trial Route Dose/Frequency PO 650 mg/m qd. Dose reductions to 500 mg/m2, 400mg/m2, or 300 mg/m2 KAPOS083 Ritonavir + d4T + Alpha IFN: KS Phase 1/11 Open Label Dose Escalating Efficacy Trial Route Dose/Frequency SC 1,5,10,15 MU Agent Alpha IFN Agent LGD1069 Time on Drug(s): Open Trial Duration: Open Number of Subjects: 20-36 Start Date: July 1996 Time on Drug(s): 16 weeks Trial Duration: Open Site National Cancer Institute, Bethesda, MD Number of Subjects: 40 Start Date: July 1996 Trial Information (301) 496-9054 Doctor Pluda Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) ---- ----- -- ----- ----... Drug descriptions, page 67 Sponsor ID: T92-0032 KAPOS034 Retinoic Acid (all-trans) + Alpha Interferon: KS Phase I Pharmacokinetics Safety & Efficacy Trial KAPOS077 Soluble TNF Receptors: KS Phase II Open-Label Safety & Efficacy Trial Route Dose/Frequency SC 2.5 mg/m2 loading dose 1.25 mg/m2 biw Agent TNFR:FC Agent All-trans Retinoic Acid Alpha-Interferon Route Dose/Frequency PO 45 mg/m2 qd day 1, 14, 18 50 mg/m2 bid day 2-13, 15-17, 19-42 SC 1, 3, 4.5, 6, or 9 MU qd day 15-42 Time on Drug(s): Open Trial Duration: 2 years Number of Subjects: 20 Start Date: June 1992 Time on Drug(s): 52 weeks Trial Duration: Site U California Los Angeles, Los Angeles, CA Number of Subjects: 40 Start Date: April 1 1995 Trial Information (310) 206-6414 Doctor Miles Site Trial Information Memorial Sloan-Kettering Cancer Center, New York, NY (212) 639-7163 Doctor Krown 185

Page  186 Actively Recruiting Trails for Opportunistic Infections JI KAPOS050 Tecogalen (SP-PG, DS-4152): KS Phase I Dose-Escalating Pharmacokinetics & Safety Trial Route Dose/Frequency IV 390 mg/m 24 hours qw x 21 days Drug descriptions, page 78 KAPOS040 TNP-470: KS Randomized Open-Label Dose-Escalating Pharmacokinetics & Safety Pilot Agent SP-PG Agent TNP-470 Route Dose/Frequency IV 4.6, 9.3, 15.4, 23.2 32.4,43.1, 57.4 or 76.3 mg/m qod Time on Drug(s): Open Trial Duration: Open Number of Subjects: Open Start Date: April 1993 Site Trial Information Kenneth Norris Jr. Cancer Hospital/USC, Los Angeles, CA (213) 343-8271 U Texas HSC/San Antonio, San Antonio, TX (210) 616-5798 Doctor Gill Eckhardt Time on Drug(s): 8-18 weeks Trial Duration: 2 weeks Site National Cancer Institute, Bethesda, MD Number of Subjects: 48 Start Date: September 1992 Trial Information (301) 496-9054 x 607 Doctor Yarchoan Drug descriptions, page 78 Sponsor ID: NC196C0004 KAPOS087 Thalidomide: KS Phase II Open Label Pharmacokinetics Safety & Efficacy Trial Agent Route Dose/Frequency Thalidomide PO 200 mg increasing to 1000 mg qd Sponsor ID: 064 KAPOS081 Topotecan: KS Phase II Open Label Non-comparative 21 day continous infusion Trial Agent Topotecan Route Dose/Frequency IV 21 day continous infusion Time on Drug(s): 6 months Trial Duration: One year Site National Cancer Institute, Bethesda, MD Number of Subjects: 15-32 Start Date: April 1996 Trial Information (800) 7762-5464x 507 Doctor Yarchoan Time on Drug(s): 21 days Number of Subjects: 40 Trial Duration: Open Start Date: August 1995 Site Trial Information San Francisco General Hospital, San Francisco, CA (415) 476-9296 U California Los Angeles, Los Angeles, CA (310) 206-6414 Doctor Kaplan Mitsuyasu 186 II

Page  187 AIDS/HIV Treatment Directory; Vol 8, No 3; January 1 997 LYMPHOMA TREATMENT TRIALS Treatment Results, page 103 Sponsor ID: AMC 001 LYMPHO85 5-azacytdine: EBV-Associated Malignancies Open Label Safety & Efficacy Pilot Study Site Trial Information Kenneth Norris Jr. Cancer Hospital/USC, Los Angeles, CA (213) 342-2448 Massachusetts General Hospital, Boston, MA Closed at this site NYU Medical Center, New York, NY (212) 263-6485 Doctor Levine Scadden Wernz Agent 5-azacytidine Route Dose/Frequency IV 75 mg/m2 x 7 days q 28 days Drug descriptions, pages 69, 70 Sponsor ID: DS95-33 DS95-33 Ara-C + Adriamycin + Cisplatin + Decadron + Hydrea + ddl + IL-2: AIDS-Related Lymphoma Open Label Safety & Efficacy Pilot Study Time on Drug(s): 7 days every 28 Trial Duration: at least 2 cycles Number of Subjects: 8 Start Date: August 1996 Site Trial Information Rosewell Park Cancer Institute,Buffalo, NY (716) 845-3221 Mount Sinai School of Medicine, New York, NY (212) 241-3932 U Miami Medical Center, Miami, FL (305) 547-3838 Georgetown U, Washington, DC (202) 687-3064 NYU, New York, NY (212) 263-6485 Memorial Sloan-Kettering Cancer Center, New York, NY (212) 639-7163 Kenneth Norris Jr. Cancer Hospital/USC, Los Angeles, CA (213) 342-2448 U California Los Angeles, Los Angeles, CA (310) 206-6414 Massachusetts General Hospital, Boston, MA (617) 724-9190 Northwestern U Medical Center, Chicago, IL (312) 908-8358 John Hopkins Hospital, Baltimore, MD (410) 614-4487 San Francisco General Hospital, San Francisco, CA (415) 476-9296 Doctor Bernstein Cheung Fischl Freter Friedman Krown Levine Mitsuyasu Scadden VonRoenn Ambinder Kaplan Agent R Hydroxyurea P ARA-C IV Cisplatin IV Dexamethasone IV Adriamycin IV IL-2 IV G-CSF S( ddl PR Time on Drug(s): 6-8 months Trial Duration:until relapse Site Rosewell Park Cancer Institute, Buffalo, NY oute Dose/Frequency O 500 mg q6h days 1-3 2gm/m q 12hr x 4 one-hour infusion S 50mg/m2 q 24hr days 2-3 15mg/m2 q6h x 10 days 1,2,3 S 15mg/m2 x 2-24 hr days 4,5 900,000 units/m2 C 5pg/kg O 125 or 200 mg bid Number of Subjects: 10 Start Date: May 1996 Drug descriptions, page 68 Sponsor ID: NCI 91-0045 LYMPHO17 Anti-B4 Blocked Ricin: Relapes or Refractory Lymphoma Phase 1/11 Open-Label Dose-Escalating Safety & Efficacy Trial Agent Route Dose/Frequency Anti-B4 BR IV 10, 20, 30, 40 ipg/kg qd continous infusion x 28 days (1 cycle) Trial Information (716) 845-8446 Doctor Bernstein Time on Drug(s):1-2 cycles Trial Duration: Open Number of Subjects: 10 Start Date: October 1991 187 II

Page  188 Actively Recruiting Trails for Opportunistic Infections Drug descriptions, pages 70, 72, 74 LYMPH036 Chemotherapy: Pediatric HIV Infection Open-Label Pilot Study ACTG: 252 LYMPHO40 Chemotherapy and Radiotherapy: CNS Lymphoma Phase II Efficacy Tolerance Trial Agent Cyclophosphamide Methotrexate G-CSF Note:1 cycle=3 weeks Route IV IV SC DoselFrequency variable x 3 cycles variable x 3 cycles variable as determined by ANC Number of Subjects: Open Start Date: August 1993 Time on Drug(s): 10 weeks Trial Duration: Open Site National Cancer Institute, Bethesda, MD Agent R Cyclophasphamide IV Doxorubicin IV Vincristine IV Dexamethasone IV G-CSF S( Cytarabine- IT Radiotherapy Time on Drug(s): Up to 10 months Trial Duration: oute DoselFrequency 750 mg/m day 1 S 50 mg/m2 day 1 1.4 mg/m2 (max 2.0) day 1 IPO 16 mg IV day 1, then 16 mg PO or IV daily with tapering as tolerated C 5 pg/kg qd beginning day 2 for a minimum of 10 days and until granulocytes are >500 x 2 days S 50 mg bid until CSF is negative, then weekly x 6 weeks/ qmonthly x 10 2.5 Gy qd x 5 days for 4 weeks Number of Subjects: 60 Start Date: Trial Information (301) 496-2321 Doctor Shad Drug descriptions, pages 70, 71, 72, 79 LYMPH023 Chemotherapy + ddl + G-CSF: CNS Lymphoma Phase //// Open-Label Dose-Escalating Safety Tolerance & Efficacy Trial Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Agent Cyclophosphamide Doxorubicin Vincristine Etoposide ddl G-CSF Route IV IV IV IV PO SC DoselFrequency 400 mg/m day 1 every 21 days 8 mg/m2 qd days 1-4 every 21 days 0.4 mg/m qd days 1-4 every 21 days 30 mg/m2 qd days 1-4 every 21 days 200 mg bid days 8-21 every 21 days 5pg/kg qd days 6-19 every 21 days Number of Subjects: 50 Start Date: June 1992 Time on Drug(s): 18 weeks Trial Duration: Open Site National Institutes of Health, Bethesda, MD Trial Information (301) 402-0586 Doctor Kaufman 188

Page  189 __AIDS/HIV Treatment Directory; Vol 8, No. 3; January 11 997 Drug descriptions, pages 68, 70, 74, 79 Sponsor ID: AMC 005 LYMPHO84 Chemotherapy and Triple Combination Antiretroviral: AIDS Open Label Pilot Study Site Kenneth Norris Jr. Cancer Hospital /USC, Los Angeles, CA Montefiore Hospital, Bronx, NY U Texas HSC/San Antonio, San Antonio, TX Trial Information (213) 226-7622 (718) 920-6706 (210) 616-5920 Doctor Levine Sparano Von Hoff Agent Indinavir AZT 3TC Chemotherapy Route Dose/Frequency PO 800 mg q8h PO 200 mg q8h PO 150mgq12h (bleomycin doxorubicin cyclophosphamide vincristine, folinic acid, methrotrexate)) Drug descriptions, page 71 Sponsor ID: US BIOSCIENCE DS95-05 Hexamethylamine + VP-16: AIDS Phase 11/11 Multiple Dose Safety & Efficacy Trial Time on Drug(s): 6 months Numi Trial Duration: Indefinite Start Site Rosewell Park Cancer Institute, Buffalo, NY Mount Sinai School of Medicine, New York, NY U Miami Medical Center, Miami, FL Georgetown U, Washington, DC NYU Medical Center, New York, NY Memorial Sloan-Kettering Cancer Center, New York, NY Kenneth Norris Jr. Cancer Hospital/USC, Los Angeles, CA U California Los Angeles, Los Angeles, CA Massachusetts General Hospital, Boston, MA Northwestern U Medical Center, Chicago, IL John Hopkins Hospital, Baltimore, MD San Francisco General Hospital, San Francisco, CA ber of Subjects: 10 Date: May 1996 Agent VP16 Hexamethylamine Route PO PO Dose/Frequency 50 mg/ml qd x 7 days 50 mg/ml qd Number of Subjects: Start Date: June 1996 Trial Information (716) 845-3221 (212) 241-3932 (305) 547-3838 (202) 687-3064 (212) 263-6485 (212) 639-7163 (213) 342-2448 (310) 206-6414 (617) 724-9190 (312) 908-8358 (410) 614-4487 (415) 476-9296 Doctor Bernstein Cheung Fischl Freter Friedman Krown Levine Mitsuyasu Scadden VonRoenn Ambinder Kaplan Time on Drug(s): Trial Duration: Site Rosewell Park Cancer Institute, Buffalo, NY Trial Information (716) 845-8075 Doctor Bemstein Drug Description, page 68 LYMPH02 I IgG-RFB4-dGA (Ricin A-Chain Conjugated Anti-CD22): AIDS Phase 1/11 Open-Label Dose-Ranging Safety & Efficacy Trial Sponsor ID: T94-0043 LYMPH035 Gallium Nitrate (NSC 15200): No Prior Treatment for Lymphoma Phase II Open-Label Pharmacokinetics, Safety & Efficacy Trial Agent RFB4-dgA Route Dose/Frequency IV 5 mg/m2 q48h x 4 9 mg/m2 q48h x 4 18 mg/m2 q48h x 4 36 mg/m2 q48h x 4 Agent Gallium Nitrate Route Dose/Frequency IV 300 mg/m for 7 days q3w Time on Drug(s): Open Trial Duration: Open Site San Francisco General Hospital, San Francisco, CA Number of Subjects: 25 Start Date: November 1991 Time on Drug(s): Open Trial Duration: Open Number of Subjects: 20 Start Date: June 1993 Trial Information (415) 476-4082x84100 Doctor Kaplan 189

Page  190 Actively Recruiting Trails for Opportunistic Infections Actively eruiin Trails for pportunisti Infection Drug description, page 52 LYMPH027 IL-2 (ultra low-dose): Non-Hodgkin's Lymphoma Phase II Open-Label Trial Route Dose/Frequency SC 400,000 U qd -- ---------- ----------- Sponsor ID: SWOG9320 LYMPH082 ProMACE - CytaBOM + TMP/SMX + AZT + G-CSF: AIDS Phase II Dose Escalating Trial Agent IL2 Time on Drug(s): 40-45 days Trial Duration: 1 year Site Rosewell Park Cancer Institute, Buffalo, NY Number of Subjects: 10 Start Date: October 1992 Trial Information (716) 845-8965 Doctor Bernstein Sponsor ID: 92-64 LYMPH024 OK-B7 with Iodine-131: Previously Untreated Non-Hodgkin's Lymphoma Phase 1/II Open-Label Dose-Escalating Safety & Efficacy Trial Agent Rout cyclphosphamide IV doxorubicin IV etoposide IV prednisone PO cytarabine IV bleomycin IV methotrexate IV leucovorin PO vincristine IV G-CSF SC Time on Drug(s): 18 weeks (6 cycles) Trial Duration: Open Site U Texas HSC/Galveston, Galveston, TX:e Dose/Frequency 490 mg/m day 1 21 day cycle 19 mg/m2 day 1 21 day cycle 90 mg/m2 day 1 21 day cycle 60 mg/m2 days 1-14 21 day cycle 225 mg/m2 day 8 21 day cycle 5 U/m day 8 21 day cycle 90 mg/m2 day 8 21 day cycle 25 mg/m2 day 9 21 day cycle 1.4 mg/m2 day 8 21 day cycle 5 g/kg days 9-20 21 day cycle Number of Subjects: 50 Start Date: July 1996 Trial Information (409) 772-1164 Doctor Mc Clure Agent OK-B7 with 1-131 Route Dose/Frequency IV 200 pg/kg can be repeated in 12 weeks Time on Drug(s): up to 12 weeks Trial Duration: Open Number of Subjects: 20-25 Start Date: August 1992 ---------- ---------- - ----------- Sponsor ID: SKF 104864 LYMPH08 I Topotecan: Non-Hodgkin's Lymphoma Phase II Open Non-Comparative continous 21-day infusion Trial Site Trial Information Memorial Sloan-Kettering Cancer Center, New York, NY (212) 639-8365 Doctor Straus Agent Topotecan Route DoselFrequency IV 1.5 mg/m2 qd cont infusion Time on Drug(s): every 28 days P Trial Duration: Open Site San Francisco General Hospital, San Francisco, CA Number of Subjects: 40 Start Date: November 1995 Trial Information (415) 476-9296 Doctor Kaplan 190

Page  191 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 11 997 PROTOZOAL INFECTIONS CRYPTOSPORIDIOSIS TREATMENT TRIALS Treatment Results, page 106 GG1009 Bovine immunoglobulin concentrate C. Parvum: AIDS Phase II11/I Randomized Double Blind Placebo Controlled Trial MICROSPORIDIOSIS TREATMENT TRIALS Treatment Results, page 108 Drug descriptions, page 78 THAL3 Thalidomide: AIDS Phase II Double Blind Placebo Controlled Trial Agent Thalidomide Route Dose/Frequency PO 100mg qd (at bedtime) Agent BIC-C.parvum Route Dose/Frequency PO 10 gm 4x qd Time on Drug(s): 4 weeks Trial Duration: 6 weeks Site St. Luke's Roosevelt Hospital, New York, NY Number of Subjects: Start Date: Time on Drug(s): 28 days Trial Duration: open label arm S Site Oak Lawn Physicians, Dallas, TX San Francisco General Hospital, San Francisco, CA Conant Medical Group, San Francisco, CA Independent Investigator, San Francisco, CA NYU Medical Center, New York, NY The Miriam Hospital, Providence,RI Independent Investigator, New York, NY Georgia Research Associates, Atlanta, GA UCLA Care Center, Los Angeles, CA Infectious Disease Associates, Bellemead, NJ Gulf Coast Clinical Services, Mobile, AL Center for Quality Care, Tampa, FL U Texas/Houston, Houston, TX Infectious Disease, Vero Beach, FL CCCR, Chicago, IL Novum, Washington, DC Tower I.D. Medical Associates, Los Angeles, CA Albert Einstein College of Medicine, Bronx, NY Novum, Seattle, WA Mayo Clinic, Rochester, NY UAB, Birmingham, AL Number of Subjects: 90 Start Date: February 1996 Trial Information (212) 523-3670 Doctor Kotler Trial Information (214) 520-1810 (415) 206-4746 (415) 436-0100 (415) 923-3320 (212) 986-3330 (401) 331-8500 (212) 929-2629 (404) 257-0076 (310) 206-6414 (908) 725-2522 (334) 443-9179 (813) 875-4048 (713) 792-4929 (407) 770-2664 (312) 494-2200 (202) 466-8042 (310) 358-2300 (718) 918-5650 (206) 223-0086 (507) 255-7763 (205) 934-7332 Doctor Brand Cello Conant Conlin Dieterich Flanigan Grossman Kagan Moe Nahass Nolan Norris Okhuysen Pierone Pottage Rashbaum Ruane Simon Smith Temesgen Wilcox PNEUMOCYSTIS CARINII PNEUMONIA TREATMENT TRIALS Treatment Results, page 110 urug descriptions, pages 6o, 7o Sponsor ID: PR/93/0067 PCPPR040 Atovaquone (High vs Low Dose) vs Pentamidine (aerosolized): Intolerant to TMP/SMX Phase 1/111l Randomized Open-Label Efficacy Trial Agent Arm 1: Atovaquone Arm 2: Atovaquone Arm 3: Pentamidine Time on Drug(s):2 years Trial Duration: Open Route Dose/Frequency PO 750 mg qd PO 1,500 mg qd nebulizer300 mg q4w Number of Subjects:615 Start Date: August 1994 191 I~

Page  192 Actively Recruiting Trails for Opportunistic Infections Site ComBAT Group, Los Angeles, CA CRI of New England, Brookline, MA East Bay AIDS Center, Berkeley, CA Goodgame and Hopkins, Maitland, FL HIVCare, San Francisco, CA Philadelphia FIGHT, Philadelphia, PA St. Vincent's Medical Center, New York, NY U California Los Angeles, Los Angeles, CA U Cincinnati, Cincinnati, OH Trial Information (213) 469-5888 (617) 566-4004 Closed at this site (407) 647-6000 (415) 353-6215 (215) 557-8265 (212) 604-7625 (310) 206-6414 (513) 558-6977 Doctor Akil Cohen Brosgart Goodgame Leoung Turner Torres Hardy Frame Drug descriptions, page 78 Sponsor ID: 06 PCPPR043 TMPISMX (Desensitization vs Direct Rechallenge): HIV Infection/AIDS Multicenter, Randomized, Double-Blind Two Arm Trial METH&TOI Methadone + TMPISMX: HIV+ Injection Drug User Phase I Randomized Double-Blind Placebo-Controlled Safety & Pharmacokinetics Trial Agent Arm 1: TMP/SMX Arm 2: TMP/SMX Time on Drug(s): 6 months Trial Duration: 6 months Route DoselFrequency PO 10 mg TMP / 50 mg SMX increasing to 80 mg TMP / 400 mg SMX over 6 days PO (80 mg / 400 mg) single strength Number of Subjects: 200 Start Date: October 1995 Agent Arm 1: Methadone TMP/SMX Arm 2: Methadone Placebo Route PO PO PO PO Dose/Frequency current tolerated regimen 1DS qd current tolerated regimen qd Number of Subjects: 30 Start Date: April 1994 Site Trial Information AIDS Research Consortium of Atlanta, Atlanta, GA (404) 876-2317 Brown University AIDS Program, Providence, RI (401) 456-2437 Clinical Directors Network of Region II, New York, NY (212) 255-3841 CRI of New England, Brookline, MA (617) 566-4004 CRI of S. Florida, Coral Gables, FL (305) 667-9296 HIVCare, San Francisco, CA (415) 353-6299 Houston Clinical Research Network, Houston, TX (713) 520-2000 Kansas City AIDS Research Consortium, Kansas City, MO(816) 756-5116 North Jersey CRI, Newark, NJ (201) 483-3444 Philadelphia FIGHT, Philadelphia, PA (215) 557-8265 Research & Education Group, Portland, OR (503) 229-8428 Doctor Thompson Skowron Torres Cohen Stein Leoung Shader Stanford Perez Smith Ward Time on Drug(s): 14 days Trial Duration: 16 days Site Trial Information Addiction Research & Treatment Corp., Brooklyn, NY (718) 789-2540 Doctor Brown, Jr. 192

Page  193 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 11 997 TOXOPLASMOSIS TREATMENT TRIALS Treatment Results, page 115 VIRAL INFECTIONS CYTOMEGALOVIRUS (CMV) TREATMENT TRIALS Treatment Results, page 119 263W94A 1263W94: AIDS Phase 1/11 Randomized Double Blind Placebo Controlled Dose Ranging Trial Drug descriptions, pages 68, 77, 78 ACTG: 237 ACTG: 237 ATOVAQUONE + PYRIMETHAMINE VS ATOVAQUONE + SULFADIAZINE Phase /I11 Randomized Open-Label Efficacy Trial Agent Arm 1: Atovaquone pyrimethamine w/ leucovorin Arm 2: Atovaquone sulfadiazine qd Route PO PO Dose/Frequency 1500 mg qd x 6 wks 200 mg day 1 / 50 or 75 mg qd 1500 mg qd x 6 wks 500 mg qd x 6 wks / 1000 or 1500 mg Agent 1263W94 Route Dose/Frequency PO 100 mg tid PO PO Time on Drug(s): 4 weeks Trial Duration: 4 weeks Site San Francisco General Hospital, San Francisco, CA Jumber of Subjects: 56 Start Date: September 1996 Trial Information (415) 746-9296 Doctor Aberg Time on Drug(s): 6 weeks Trial Duration: Open Number of Subjects: Start Date: Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Drug descriptions, page 71 Sponsor ID: 93-FOS-29 CMVTX062 Foscarnet: Gastrointestinal CMV Phase Ill Randomized Open-labe Triall Agent Arm 1: Foscarnet Arm 2: Foscarnet Route IV IV Do 90 90 12( se/Frequency mg/kg bid x 4 weeks mg/kg bid x 4 weeks, then 0 mg/kg qd for up to 22 weeks mber of Subjects: 150 irt Date: March 1994 Time on Drug(s): 4-26 weeks Nu Trial Duration: 26 weeks Sta Site East Bay AIDS Center, Berkeley, CA NYU Medical Center, New York, NY Rush-Presbyterian/St. Luke's Med Center, Chicago, IL Trial Information Closed at this site (212) 263-6485 (312) 908-9636 Doctor Brosgart Dieterich Kessler 193 II

Page  194 Actively Recruiting Trails for Opportunistic Infections Actvel Reritn Tril for Opportunisticrr Infcton Sponsor ID: 93-FOS-31 CMVTX063 Foscarnet + Oral Hydration vs Foscarnet + IV Hydration: AIDS Phase IV Randomized Open-Label Trial Texas Children's Hospital, Houston, TX U Alabama Medical Center, Birmingham, AL U California Los Angeles, Los Angeles, CA U Chicago / Wylers, Chicago, IL U Nebraska Medical Center, Omaha, NE U Rochester Medical Center, Rochester, NY U Southern California, Los Angeles, CA (713) 798-4784 (205) 934-5316 (310) 825-5235 (303) 270-7147 (402) 559-4000 (716) 275-5944 (213) 342-3732 or 3733 Demmler Whitley Bryson Johnson Schaefer Frenkel Levine Agent Arm 1: Foscarnet Arm 2: Foscarnet Route IV IV DoselFrequency 90 mg/kg bid with normal saline 90 mg/kg bid with oral hydration Number of Subjects: 112 Start Date: October 1994 Sponsor ID: GCVI 605 CMVTXO57 Ganciclovir (Intravitreal Pellet): Sight-Threatening CMV, Unable To Receive Standard Treatment Phase III Open-Label Trial Time on Drug(s): 2-3 weeks Trial Duration: 3 weeks Site Trial Information AIDS Community Research Consortium, Redwood City, CA (408) 885-7970 Austin Infectious Disease Consultants, P.A., Austin, TX (512) 459-0301 Community Health Network, Rochester, NY (716) 244-9000 x 36 HIV Research Group, San Diego, CA (619) 291-1122 Independent Investigator: Beverly Hills, CA (310) 246-6550 Independent Investigator: Los Angeles, CA (310) 556-7991 Independent Investigator: New York, NY (212) 818-0853 Independent Investigator: Berley, MI (810) 544-9300 Independent Investigator: Indianapolis, IN (317) 638-1851 Independent Investigator: Atlanta, GA (404) 325-4677 Infectious Diseases Associates, Somerville, NJ (609) 497-1068 Northwestern U Medical Center, Chicago, IL (312) 908-8358 U California Los Angeles, Los Angeles, CA (310) 206-6392 Doctor Deresinski Bagwell Rhoades Pearce Hansen Wool Grossman Benson Karedes Rosenstock Nahass Murphy Fiala Agent Ganciclovir Route Dose/Frequency implant 1 ulg qh continuous release Time on Drug(s): 8 months Trial Duration: Open Site U California Irvine Medical Center, Orange, CA Number of Subjects: 150 Start Date: September 1993 Trial Information (714) 856-6256 Doctor Kuppermann Sponsor ID: GAN 2226 CMVTX058 Ganciclovir (Oral vs IV): AIDS Phase Ill Randomized Open-Label Safety & Efficacy Trial 11 II------------ -- -------qllSI Drug descriptions, page 72 CMVTX032 Ganciclovir: Pediatric HIV Infection Open-Label Pharmacokinetics & Safety Trial Route DoselFrequency IV 5 mg bid Agent Oral Ganciclovir IV Ganciclovir Route Dose/Frequency PO 1,000, 1500, 2,000 mg tid IV 5 mg/kg qd Agent Ganciclovir Time on Drug(s): Open N Trial Duration: Open S Site Children's Hospital of Los Angeles, Los Angeles, CA LAC+USC Medical Center, Los Angeles, CA lumber of Subjects: 20 tart Date: August 1990 Time on Drug(s): 26 weeks Nui Trial Duration: Open Sta Site Audie Murphy VA Hospital, San Antonio, TX Austin Infectious Disease Consultants, P.A., Austin, TX Cornell Clinical Trials Unit, New York, NY CRI of S. Florida, Coral Gables, FL Davies Medical Center, San Francisco, CA Independent Investigator Independent Investigator Nalle Clinic, Charlotte, NC Trial Information (210) 614-6197 (512) 459-0301 (212) 746-4177 (305) 667-9296 (415) 565-6058 (817) 877-3442 (918) 743-1000 (704) 344-2280 mber of Subjects: 280 rt Date: December 1993 Doctor Graybill Bagwell Heinemann Stein Follansbee Barbaro Beal Jemsek Trial Information (213) 669-2546 (213) 224-2662 Doctor Lenarsky Kovacs 194

Page  195 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 1 )97 Oak Lawn Physicians, Dallas, TX Ochsner Medical Foundation, New Orleans, LA Pennsylvania Hospital, Philadelphia, PA Texas Tech U School of Medicine, El Paso, TX U Alabama Medical Center, Birmingham, AL U California San Diego, San Diego, CA U Hawaii at Manoa - Hawaii ACTU, Honolulu, HI VA Medical Center of Portland, Portland, OR (214) 520-1810 (504) 842-4005 (215) 925-8010 (915) 545-6624 (205) 975-9127 (619) 543-8080 (808) 737-0036 (503) 220-8262 x7140 Andruczk Pankey Braffman Nabhau Saag Freeman Heath-Chiozzi Chou Drug descriptions, page 73 Sponsor ID: 2922-CS2 CMVTXO73 ISIS 2922 (Immediate vs Delayed Treatment): HIV Infection/AIDS Phase III Randomized Open-Label Trial Drug descriptions, page 69 Sponsor ID: 501 CMVTX074 HPMPC: AIDS / Relapsed CMV Retinitis Phase II Dose-Ranging Trial Agent HPMPC Route Dose/Frequency 5,10,15 gig monthly Agent Route Do Arm 1:Immediate treatment ISIS 2922 implant 3 Maintenance 3 Arm 2: Delayed treatment. Time on Drug(s): 20 weeks plus Nu Trial Duration: Open Sta Site Community Eye Medical, Pasadena, CA Independent Investigator: San Juan, PR Independent Investigator: Atlanta,GA Independent Investigator: Washngton, DC Indiana University School of Medicine, Indianapolis, IN New England Medical Center, Boston, MA Retina-Vitreous Associates Medical Group, Los Angeles, CA Santa Clara Valley Medical Center, San Jose, CA U Colorado, Denver, CO Vitreo-Retinal Consultants, New York, NY se/Frequency 00 pg qw x 3 weeks 00 hg qow x 20 weeks or endpoirnt mber of Subjects: 200 art Date: December 1994 Time on Drug(s): Open N Trial Duration: 1-2 years S Site Independent Investigator: Washington, DC St. Luke's/Roosevelt Hospital at 59th, New York, NY U California Irvine Medical Center, Orange, CA U Miami Medical Center, Miami, FL lumber of Subjects: 90 tart Date: Sept. 1 1995 Trial Information (202) 833-1668 (212) 523-5818 (714) 824-6256 (305) 326-6348 Doctor Palestine McKinley Kuppermann Davis Trial Information (818) 584-1200 (954) 763-3993 (404) 351-9668 (202) 833-1668 (317) 274-3970 (617) 523-7900 (213) 483-8810 (408) 885-7970 (303) 372-1750 (212) 737-7400 Doctor Terry Perez Lampert Palestine Danis Duker Boyer Mansour Johnson Lieberman Sponsor ID: GS-93-108 CMVTX083 HPMPC (Cidofivir): Early CMV Retinitis Phase I///// Open Label Trial Agent HPMPC Route Dose/Frequency IV 5.0 mg/kg every 2 weeks Time on Drug(s): Open Trial Duration: Open Site Santa Clara Valley Medical Center, San Jose, CA Number of Subjects: 30 Start Date: October 1995 Trial Information (408) 885-4316 Doctor Kemper 195

Page  196 Actively Recruiting Trails for Opportunistic Infections Drug descriptions, pages 72, 73 Sponsor ID: 2922-CS3 CMVTX072 ISIS 2922 + Ganciclovir vs Ganciclovir (IVIPO): AIDS / Relapsed CMV Retinitis Phase llM Randomized Safety & Efficacy Trial Drug descriptions, page 69 Sponsor ID: SOCA CMVTX 100 Lobucavir: AIDS Phase 11/111 Randomized Double Blind Safety & Efficacy Trial Agent Lobucavir Route DoselFrequency PO TBD qid Agent Arm 1: Induction ISIS 29221 Maintenance ISIS 2922 Arm 2: Induction Ganciclovir Maintenance Time on Drug(s): 20 weeks plus Trial Duration: Open Route Dose/Frequency 150 ig q 7 days 150 lg q 14 days IV PO 5mg/kg q 12h x 14 days 1 gram q 8h Number of Subjects: 200 Start Date: December 1994 Time on Drug(s): Open Trial Duration: minimum 2 years Site Baylor College of Medicine, Houston, TX John Hopkins Medical Center, Baltimore, MD Number of Subjects: 325 Start Date: November 1996 Trial Information (713) 798-3030 (410) 955-3150 Doctor Lewis Meinert Site Trial Information Associated Retinal Consultants, Philadelphia, PA (215) 928-3092 Baylor College of Medicine, Houston, TX (713) 798-3092 Charlotte Eye Ear Nose & Throat Association, Charlotte, NC (704) 358-4111 Community Eye Medical, Pasadena, CA (818) 584-1200 Hahnemann University Hospital, Philadelphia, PA (215) 762-7171 Independent Investigator (954) 763-3993 Independent Investigator: Atlanta, GA (404) 351-9668 Independent Investigator: Washington, DC (202) 833-1668 Indiana University School of Medicine, Indianapolis, IN (317) 274-3970 Retina-Vitreous Associates Medical Group, Los Angeles, CA (213) 483-8810 Santa Clara Valley Medical Center, San Jose, CA (408) 885-7970 U Illinois, Chicago, IL (312) 996-0615 U Texas HSC/Dallas, Dallas, TX (214) 648-4749 Vitreo-Retinal Consultants, New York, NY (212) 737-7400 Doctor Vrabec Lambert Browning Terry Territo Perez Lampert Palestine Danis Boyer Mansour Goldstein Park Lieberman For descriptive text, HIV trial results, page 38 Sponsor ID: AG1343-517 1343517 Nelfinavir Effects on Clinical Outcome of CMV Retinitis Treatment: AIDS Phase II Randomized Placebo-Controlled Trial CD4 Range: Unspecified I Viral Load: Unspecified Agent Route Dos CMV Induction TX GCV IV 5 mt foli GCV PO 100( Nelfinavir/placebo PO 750 wit Time on Drug(s): 3 mos then open Nun Trial Duration: 12 months Star Site Baylor University Medical Center, Houston, TX George Washington U Medical Center, Washington, DC Harbor UCLA Medical Center, Los Angeles, CA LAC/USC Medical Center, Los Angeles, CA Northwestern U Medical Center, Chicago, IL U California/Irvine, Irvine, CA UCSD, San Diego, CA U Texas, Galveston, TX e/Frequency g/kg bid x 2 wk/5mg/kg qd x 1wk lowed by maintenance therapy of 3 mg tid with the addition of mg tid or placebo tid along:h optimal nucleoside therapy nber of Subjects: rt Date: October 1996 Trial Information (713) 793-4020 (202) 994-0006 (310) 222-3848 (213) 343-8278 (312) 908-9636 (714) 456-7612 (619) 543-8080 (409) 747-0241 Doctor White Parenti Witt Kramer Murphy Forthal Torriani Pollard 196

Page  197 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 19 097 CYTOMEGALOVIRUS (CMV) MAINTENANCE TRIALS Treatment Results, page 119 Drug descriptions, page 72 Sponsor ID: 930310 CMVTX067 Ganciclovir + G-CSF: First Episode CMV Retinitis Phase II Randomized Safety & Efficacy Trial HEPATITIS TREATMENT TRIALS Treatment Results, page 125 Drug descriptions, page 67 HEPAT006 Alpha Interferon: Hepatitis C Open-Label Pilot Study Agent Arm 1: Ganciclovir G-CSF Arm 2: Ganciclovir G-CSF Arm 3: Ganciclovir G-CSF Time on Drug(s): 32 weeks Trial Duration: Open Site Georgetown U, Washington, DC Route Dose/Frequency IV 5 mg/kg induction, followed by 10 mg/kg qd maintenance SC dose to maintain ANC 2,000-10,000 IV 10 mg/kg induction followed by 10 mg/kg qd maintenance SC dose to maintain ANC 2,000-10,000 IV 15 mg/kg induction followed by 15 mg/kg qd maintenance SC dose to maintain ANC 2,000-10,000 Number of Subjects: 50 Start Date: August 1994 Agent Alpha IFN Time on Drug(s): 6 months Trial Duration: 6 months Site NYU Medical Center, New York, NY Route Dose/Frequency SQ 5 MIU tiw Number of Subjects: 20 Start Date: July 1994 Trial Information (212) 263-6485 Doctor Dieterich --------------------------- --- - - - --- -- -- ----p---- - ------- ~PLL- -~l~ HEPAT004 Alpha Interferon: Hepatitis C Open-label Dose-Ranging Safety & Efficacy Pilot Study Trial Information (202) 687-3064 Doctor Kumar Agent Alpha Interferon Route Dose/Frequency SC 3MU qd x 2 weeks, then 5MU qd 10MU qd will be given if incomplete response at month 2 Time on Drug(s): 24 weeks Trial Duration: Open Number of Subjects: 20 Start Date: September 1993 Site Trial Information Center for Special Immunology - Irvine, Irvine, CA (714) 753-0670 Center for Special Immunology - San Diego, San Diego, CA (619) 291-1122 Doctor Cimoch Loss 197

Page  198 Actively Recruiting Trails for Opportunistic Infections HEPAT005 Alpha Interferon: Hepatitis Phase II Randomized Open-Label Safety & Effiacy Trial Agent Route Dose/Frequency Arm 1: Alpha IFN SC 3 million IU tiw Arm 2: Alpha IFN SC 5 million IU tiw Note: Alpha IFN will be delivered at 5 million IU tiw to those patients in arm 1 who are non-responsive - ---- ------------ ---- ---- ------rr C ~ "" '"C ~ " ' I* I Sponsor ID:020B HERPE083 Acyclovir Open Label Pilot Study Route Dose/Frequency PO 200 mg 5x qd x 10 days or resoultion of HSV Agent HSV Time on Drug(s): 6-12 months Trial Duration: Open Site Albany Medical College, Albany, NY Number of Subjects: 50 Start Date: September 1994 Time on Drug(s): 10 days or resoultion Number of Subjects: 15 Trial Duration: 12 weeks Start Date: May 1996 Trial Information (518) 262-4381 Doctor Szebenyi Site Research & Education Group, Portland, OR Trial Information (800) 875-8428 Doctor Sampson HERPES SIMPLEX TREATMENT TRIALS Treatment Results, page 127 Drug descriptions, page 67 HERPEO82 Acyclovir: HIV Infection Asymptomatic A Double Blind Placebo Controlled Pilot Study Drug descriptions, page 71 Sponsor ID: BRL 428100 BRL42810 Famciclovir: HIV Infection I Recurrent Gential Herpes Open Label Trial Agent famciclovir Route Dose/Frequency PO 500 mg bid Agent ACV Route Dose/Frequency PO 400 mg bid Time on Drug(s): 4 Trial Duration: 7 months S Site San Francisco General Hospital, San Francisco, CA St. Luke's Roosevelt Hospital, New York, NY Smonths Number of Subjects: itart Date: June 1996 Trial Information (415) 476-9296 (212) 523-6743 Doctor Sampson McKinley Time on Drug(s): 12 weeks Trial Duration: 12 weeks Site Research & Education Group, Portland, OR Number of Subjects: 30 Start Date: May 1996 Trial Information (800) 875-8428 Doctor Sampson 198

Page  199 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 1i 997 Drug descriptions, page 79 ACTG: 253 253 Valacyclovir: Herpes Simplex or Zoster in Children Phase I Safety and Tolerance Trial HUMAN PAPILLOMA VIRUS TREATMENT TRIALS Treatment Results, page 129 Drug descriptions, page 67 Sponsor ID: SLM 92-02 HPV00002 Alpha Interferon: HIV Infection Open-Label Safety & Efficacy Trial Agent 1st Cohort: Valacyclovir 2nd Cohort: Valacyclovir 3rd Cohort: Valacyclovir Route PO PO PO Dose/Frequency 250 or 500 mg tid 500 or 750 mg tid dose based on results of cohorts 1+ 2 Number of Subjects: Open Start Date: Time on Drug(s): 10 days Trial Duration: 4 wks after last dose Agent Alpha Interferon Route Dose/Frequency IL 1 MU/lesion tiw Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) HERPES ZOSTER TREATMENT TRIALS Treatment Results, page 128 Drug descriptions, page 77 Sponsor ID: A1458-900 HERPEO21 BV-ara-U: Sight-Threatening Varicella-Zoster Disease Phase IlI Open Label Trial Time on Drug(s): 3 weeks N Trial Duration: Open S Site Infectious Diseases Physicians, Inc., Annandale, VA lumber of Subjects: 10 tart Date: March 1994 Trial Information (718) 560-4821 Doctor Poretz Drug descriptions, page 73 ACTG: 293 HPV00005 Isotretinoin vs Observation: HIV Infection in Women Phase 111 Randomized Open Label Safety & Efficacy Trial Agent BV ara U Route Dose/Frequency PO qd Agent Isotretinoin Observation Time on Drug(s): 6 months Trial Duration: 12 months Route Dose/Frequency PO 0.5 mg/kg qd x 6 months Number of Subjects: 50 Start Date: Time on Drug(s): 6 weeks Trial Duration: Open Number of Subjects: Open Start Date: Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Site Trial Information Long Island Jewish Medical Center, New Hyde Park, NY (718) 470-8930 Doctor Siegal 199 I~

Page  200 Actively Recruiting Trails for Opportunistic Infections NEUROLOGICAL COMPLICATIONS AIDS DEMENTIA COMPLEX TREATMENT TRIALS Treatment Results, page 131 ---------- --------------------------- -------- Sponsor ID: CNAAB 3001 DEMEN082 1592U89 + Antiretroviral therapy: AIDS Phase Il Randomized Double Blind Placebo Controlled / Open Label Trial Sponsor ID: 03-D95 DEMEN009 Thioctic Acid vs Thioctic Acid + Deprenyl: AIDS Phase Il Double Blind Placebo Controlled Open Label Trial Agent Arm 1: Thioctic Acid Deprenyl Arm 2: Thioctic Acid Placebo Route PO PO PO PO Dose/Frequency 600 mg bid 2.5 mg 3x a week 600 mg bid 3x a week Number of Subjects: 40 Start Date: July 1995 Time on Drug(s): 10 weeks Trial Duration: 10 weeks Site Columbia U Medical Center, New York, NY Johns Hopkins Hospital, Baltimore, MD U Rochester Medical Center, Rochester, NY Agent Route [ Arm 1: AZT use AZT PO 3 1592U89 or placebo PO 6 Arm 2: Non-AZT use Antiretroviral PO p 1592U89 or placebo PO 6 Time on Drug(s): 12 weeks Trial Duration: 52 weeks Site Mlount Sinai Medical Center, New York, NY San Francisco General Hospital, San Francisco, CA )ose/Frequency 300 mg tid 300 mg tid x 12 weeks )rescribe dose/frequency 300 mg tid x 12 weeks Number of Subjects: 90 Start Date: June 1996 Trial Information (212) 960-2207 (410) 955-1852 (716) 275-1279 Doctor Martyr Sacktor Schifitto Sponsor ID: M3331 0041 DEMEN006 U90 (Delavirdine): AIDS Placebo-Controlled Double-Blind Pilot Study Trial Information (212) 241-0784 (415) 476-9296 Doctor Simpson Kahn Agent Arm 1: U-90 Arm 2: Placebo Route PO PO ---- -------- r----2 ---.....-.. DEMEN008 Dextromethorphan: AIDS Phase I Open-Label Dose-Ranging Tolerance, Safety & Efficacy Trial Dose/Frequency 400 mg tid tid Number of Subjects: 30 Start Date: September 1994 Time on Drug(s): 12 weeks Trial Duration: 16 weeks Site Harvard Medical School, Boston, MA Trial Information (617) 726-3819 Doctor Navia Agent Dextromethorphan Time on Drug(s): 4 weeks Trial Duration: 7-10 weeks Site Mount Sinai School of Medicine, New Yoi Route Dose/Frequency IM dose-ranging Number of Subjects: Open Start Date: Novemebr 1994 Trial Information (212) 241-0466 Doctor Teitelman 200

Page  201 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 1{ 997 PERIPHERAL NEUROPATHY TREATMENT TRIALS Treatment Results, page 134 CPCRA: 022 NEURO005 Acupuncture vs (Acupuncture + Amitriptyline): HIV Infection Phase 11/111 Randomized Double-Blind Placebo-Controlled Trial Sponsor ID: 96-361 NE Glaxo NEURO83 Lamotrigine: HIV Infection Phase I Randomized Double Blind Placebo Controlled Trial Agent Lamotrigine Route Dose/Frequency PO 300 mg qd Time on Drug(s): Trial Duration: Number of Subjects: Start Date: November 1996 Agent Route I Arm 1: Amitriptyline PO i Acupuncture I Arm 2: Acupuncture I Arm 3: Amitriptyline PO Acupuncture Arm 4: Acupuncture Time on Drug(s): 14 weeks Trial Duration: 14 weeks Site Community Consortium, San Francisco, CA Denver CPCRA, Denver, CO East Bay AIDS Center, Berkeley, CA Eric B. Chandler Health Center, New Brunswick, NJ Harlem AIDS Treatment Group, New York, NY Hillman Health Center, New York, NY Morris Heights Health Center, Bronx, NY Mount Sinai School of Medicine, New York, NY Newark Community Health Centers, Newark, NJ Philadelphia FIGHT, Philadelphia, PA Research & Education Group, Portland, OR Dose/Frequency 25 mg qd loading dose with an ncrease of 25 mg every 2 to 3 day until 75 mg qd is reached biw x 6 weeks, then qw x 8 weeks biw x 6 weeks, then qw x 8 weeks 25 mg qd loading dose with an ncrease of 25 mg every 2 to 3 days jntil 75 mg qd is reached Alternate Points biw x 6 weeks then qw x 8 weeks Alternate Points biw x 6 weeks then qw x 8 weeks Number of Subjects: 260 Start Date: June 1993 Site Mount Sinai Medical Center, New York, NY Trial Information (212) 241-0784 Doctor Simpson ACTG:291 NEUR0007 Recombinant human nerve growth factor: HIV Infection Phase II Randomized Double Blind Placebo Controlled Dose Ranging Trial Agent rhNGF rhNGF Route SC SC Dose/Frequency 0.1 mcg/kg twice a week 0.3 mcg/kg twice a week Number of Subjects: 180 Start Date: June 1996 Trial Information (415) 476-9554 Closed to Enrollment (510) 204-1870 (908) 235-6700 (212) 939-2910 (212) 633-0800 (718) 716-4400 (212) 241-3932 (201) 565-0355 (215) 557-8265 (800) 875-8428 Doctor Abrams Brosgart Brown EI-Sadr George Traxler Sacks Vaughn Turner Sampson Time on Drug(s): 18 weeks Trial Duration: 22 weeks Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 201

Page  202 Actively Recruiting Trails for Opportunistic Infections ----------------------------F - - - P I C-~C- ~ OTHER COMPLICATIONS OF HIV DISEASE Treatment results, page 135 DEPRESSION TRIALS DEXE0002 Dexedrine: HIV Infection / Depression Phase III Double Blind Placebo Controlled Safety & Efficacy Trial Agent Route Dose/Frequency Dexedrine PO starting at 2.5 mg bid placebo PO bid Time on Drug(s): 6 months Number of Subjects: 80 Trial Duration: 6 months Start Date: August 1995 Site Trial Information Doctor New York State Psychiatric Institute, New York, NY (212) 960-2331 Wagner Drug description, page 78 DEPRESOI Testosterone vs Fluoxetine (Prozac): HIV Infection/AIDS Phase III Double Blind Placebo Controlled Comparative Efficacy Trial DYSPLASIA TRIALS Treatment Results, see Human Papilloma virus, page 129 Drug descriptions, page 71 ACTG: 200 5FU00001 5-FU: HIV Infection in Women Phase II/III Randomized Open-Label Safety & Efficacy Trial Agent Arm 1: 5-FU Arm 2: Observation Time on Drug(s): 6 months Trial Duration: 2 years Route Dose/Frequency topical 2,000 mg biw NA NA Number of Subjects: 158 Start Date: December 1992 Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) DIARRHEA & MALABSORPTION TRIALS Treatment Results, page 135 Agent Testosterone fluoxentine Route Dose/Frequency PO 200-400 mg biw PO 20-60 mg qd Time on Drug(s): 8-26 weeks Trial Duration: 6 months Site NY State Psychiatric Institute, New York, NY Number of Subjects: Start Date: September 1996 Trial Information (212) 960-5762 595-1220 Diethylhamospermine (DEHSPM): AIDS Phase II Randomized Double Blind Dose Escalating Trial Route Dose/Frequency SC 12.5, 25, or 50 mg every other day Agent DEHSPM Doctor Rabkin Time on Drug(s): 16 days Trial Duration: 10 weeks Site St Luke's Roosevelt Hospital, New York, NY Number of Subjects: Start Date: Trial Information (212) 523-3670 Doctor Kotler 202

Page  203 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 19 997 AISHI reten ircor;Vo, o 3 anay ~ DIARRH03 Oral Rehydration Solution vs Oligosaccharide-based ORS: Diarrhea Phase I Randomized Double-Blind Efficacy Trial CYTOP03 Lisofylline: HIV Infection Phase II Randomized Open-Label Trial Route Dose/Frequency IV 150 mg (<75kg) 240 mg (>75kg) Agent Lisofylline Agent Arm 1: Std ORS Arm 2: Oligosaccharide-based ORS Time on Drug(s): 4 weeks Trial Duration: Open Site St. Luke's Roosevelt Hospital; New York, Route Dose/Frequency IV IV Number of Subjects: Open Start Date: November 1994 Time on Drug(s): Trial Duration: Number of Subjects: Start Date: Site San Francisco General Hospital, San Francisco, CA Trial Information (415) 476-9296 Doctor Kaplan Trial Information (212) 523-3670 Doctor Kotler THROMBOCYTOPENIA TRIALS Treatment Results, page 136 CYTOP003 Anti-Rh Antibodies (Anti-D) + AZT + ddl: HIV Infection Phase II Efficacy Trial WASTING SYNDROME TREATMENT TRIALS Treatment Results, page 137 Sponsor ID: S95-1220 WASTE084 DEHSPM (Diethylhomospermine): Diarrhea Phase II Open Label Dose-Escalating Safety & Efficacy Trial Agent DEHSPM Route Dose/Frequency SC 12.5, 25 or 50 mg qod x 7 doses Agent Part I: AZT ddl Part II: Anti-D AZT ddl Route Dose/Frequency PO 120 mg/m2 q6h x at least 12 weeks PO 135 mg/m2 q12h x at least 12 weeks Time on Drug(s): 14 days Trial Duration: 90 days Site Georgetown U, Washington, DC Number of Subjects: 30 Start Date: Sept. 1996 Trial Information (202) 745-6111 Doctor Young IV PO PO 40 mcg/kg qw x at least 6 weeks current tolerated regimen current tolerated regimen Number of Subjects: 100 Start Date: November 1993 Time on Drug(s): up to 12 weeks Trial Duration: Open Site National Cancer Institute, Bethesda, MD Trial Information (301) 402-1391 Doctor Pizzo 203

Page  204 Actively Recruiting Trails for Opportunistic Infections Drug descriptions, page 73 WASTE036 L-Carnitine: HIV Infection Phase II Randomized Double-Blind Placebo-Controlled Safety & Efficacy Drug descriptions, pages 74, 78 ACTG: 313 313 Megestrol Acetate + Testosterone enanthate: HIV Infection Symptomatic / AIDS Phase II Randomized Double Blind / Open Label Safety & Efficacy Trial Agent Arm 1: L-carnitine Arm 2: Placebo Route PO PO Dose/Frequency qd qd Number of Subjects: Open Start Date: September 1993 Agent Megace Testosterone Megace placebo Route PO IM PO IM Time on Drug(s): 6 months Trial Duration: Open Site National Institutes of Health, Bethesda, MD Dose/Frequency 800 mg qd 200 mg (males) 100 mg (females) q2w 800 mg qd q2wks Number of Subjects: Start Date: October 1996 Trial Information (301) 402-4479 Doctor Cupler Time on Drug(s): 24 weeks Trial Duration: Drug descriptions, page 74 Sponsor ID: 69-93.007 WASTE040 Megestrol Acetate (Oral Suspension): HIV Infection in Women Phase IV Open-Label Safety & Efficacy Crossover Trial Agent Route Dose/Frequency Arm 1: Megace PO 800 mg qd Arm 2: Megace PO 400 mg qd x 12 weeks Dose evaluation with continuation x 12 weeks or crossover x 12 weeks Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) Drug descriptions, page 75 ACTG: 329 329 Nandrolone Deconate: HIV-associated weight loss in women Phase 1/ll Randomized Double Blind Placebo Controlled Trial Time on Drug(s): 24 weeks Trial Duration: Open Number of Subjects: 40 Start Date: September 1994 Agent Randomized phase Nandrolone placebo Open Label phase Nandrolone Time on Drug(s): 24 weeks Trial Duration: Route Dose/Frequency IM 100 mg q2wks x 12wks IM q2wks x 12 wks IM 100 mg q2wks x 12wks Number of Subjects: 38 Start Date: October 1996 Site Trial Information Georgetown U, Washington, DC (202) 745-6111 Memorial Sloan-Kettering Cancer Center, New York, NY (212) 639-7120 U California Davis Medical Center, Sacramento, CA (916) 734-3793 Yale University, New Haven, CT (203) 785-3557 Doctor Young White Flynn Friedland Site Information For trial sites call the AIDS Clinical Trial Information Service (ACTIS) 1-800-TRIALS-A (874-2572) 204

Page  205 AIDS/HIV Treatment Directory; Vol 8, No. 3; January 11 997 Drug descriptions, page 75 Sponsor ID: BTGIOXN 95-002 OXN95002 Oxandrolone: AIDS Phase IIIII1 Randomized Double Blind Placebo Controlled Trial Drug descriptions, page 78 WASTE013 Testosterone: HIV Infection/AIDS Phase Ill Double Blind Placebo Controlled Safety & Efficacy Trial Agent Arm 1: Placebo Arm 2: Oxandrolone Arm 3: Oxandrolone Arm 4: Oxandrolone Route PO PO PO PO DoselFrequency every morning qd 20 mg every morning qd 40 mg every morning qd 80 mg every morning qd Agent Testosterone Route Dose/Frequency IM 200 mg q 2weeks After 12 week double blind, patients eligible for 12 week open label Time on Drug(s): 12 weeks Trial Duration: 13-16 weeks Site Johns Hopkins Hospital, Baltimore, MD Number of Subjects: 50 Start Date: October 1995 Trial Information (410) 955-9862 Doctor Dobs Time on Drug(s): 12 weeks Trial Duration: 12 wk, then 12w Open Site Beer Medical Group New York University Medical Center, New York, NY St. Luke's Roosevelt Hospital, New York, NY U Texas Medical Center, Galveston, TX Number of Subjects: 300 Start Date: September 1996 Trial Information (213) 937-5151 (212) 953-1948 (212) 523-3670 (409) 772-4979 Doctor Beer Dietrich Kotler Pollard Sponsor ID: C-95-012 WASTE012 Testosterone Replacement Phase III Double-Blind Placebo-Controlled Safety & Efficacy Trial Sponsor ID: BTG OXN95-007 OXN95007 Oxandrolone: HIV-Associated Weight Loss In Women Phase III Double Blind Placebo Controlled Randomized Dose Ranging Trial Agent Testosterone Route Dose/Frequency topical 6 mg qd Time on Drug(s): 12 weeks Number of Subjects: 98 Trial Duration: Rollover to Open label Start Date: November 1995 Site Bowman Gray School of Medicine, Winstom-Salem, NC Johns Hopkins Hospital, Baltimore, MD Medical College of Wisconsin, Charleston, SC Oak Lawn Physicians, Dallas, TX Research & Education Group, Portland, OR St. Michael's Hospital, Newark, NJ Trial Information (910) 716-4152 (410) 955-1373 Closed at this site (214) 520-1810 Closed at this site (201) 877-2915 Doctor High Dobs Bemstein Brand Sampson Smith Agent Oxandrolone Route Dose/Frequency PO 20 mg, 40 mg or placebo divided into two doses a day Time on Drug(s): 12 weeks Trial Duration: 12 weeks open label Site St. Luke's Roosevelt Hospital, New York, NY Number of Subjects: Start Date: Trial Information (212) 523-3670 Doctor Kotler 205

Page  206 Actively Recruiting Trails for Opportunistic Infections Drug descriptions, page 78 Sponsor ID: W-001 WASTE039 Thalidomide: AIDS Phase II Randomized Double-Blind Placebo-Controlled Safety & Efficacy Site George Washington U Medical Center, Washington, DC Gottlieb Medical Group, Sherman Oaks, CA Kaiser Permanente of San Francisco, San Francisco, CA Marin County Specialty Clinic, Greenbrae, CA Rockefeller U, New York, NY San Francisco General Hospital, San Francisco, CA San Mateo County General Hospital, San Mateo, CA St. Michael's Hospital, Newark, NJ Thomas Jefferson U Hospital, Philadelphia, PA Trial Information (202) 994-2417 (818) 501-2600 (415) 202-3480 (415) 499-7377 (212) 327-7794 (415) 206-5882 (415) 573-2422 (201) 877-2915 (215) 955-8575 Doctor Parenti Gottlieb Fessel Lindquist Haslett Schambelan Israelski Smith Teppler Agent Arm 1: Thalidomide Arm 2: Thalidomide Arm 3: Placebo Route PO PO PO Dose/Frequency 100 mg qd x 8 weeks 200 mg qd x 8 weeks qd x 8 weeks Open-label drug will be offered at 200 mg qd for up to 4 weeks Time on Drug(s): 8-14 weeks Trial Duration: 12-14 weeks Number of Subjects: 93 Start Date: September 1994 206

Page  207 Compassionate Use / Treatment IND / Expanded Access AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 1997 COMPASSIONATE USE / TREATMENT IND / EXPANDED ACCESS Albendazole Amphotericin B liposomal-encapsulated (AmBisome) Amphotericin B collidial dispersion (Amphotec) Anti-Rh-Antibodies (WinRho) Azithromycin (Zithromax) Delavirdine (Rescriptor) ddC (HIVID) Fluconazole (Diflucan) Ganciclovir (oral) (Cytovene) Itraconazole, oral solution (Sporanox) Compassionate Use Protocol. Physician calls only. For HIV+ individuals with microsporidiosis. Drug provided on case-by-case basis. SmithKline Beecham Product Information. 1-800-877-7074 ext. 3909. Expanded Access Program. For individuals with cryptococcal meningitis who relapse or fail standard amphotericin B therapy. Compassionate Use Protocol. Physician calls only. Patients of any age who have invasive fungal infections and have failed or are intolerant to amphotericin B. Both programs sponsored by NeXstar Pharmaceuticals. Managed by BioPharm. 1-800-787-8268 Expanded Access program. Available to patients with suspected or documented fungal infections who fail to respond to or who can not tolerate conventional amphotericin B, and for whom no other approved antifungal is appropriate. Sequus Clinical Research (415) 617-3060. Expanded Access protocol. For individuals with primary or secondary ITP with no history of splenectomy. Rh+ blood factor only. Physician calls only. Univax Biologics through Winrho service office. (301) 770-3255. Compassionate Use Protocol. For individuals with a definitive or presumptive diagnosis of toxoplasmosis by CAT scan and some favorable response to prior treatment. Local IRB approval is required. Sponsored by Pfizer, Inc,. Managed by Premier Research Worldwide. 1-800-742-3029. Compassionate Use Protocol. For HIV+ individuals with proven cryptosporidiosis who have failed or are intolerantto conventional therapies. Sponsored by Pfizer, Inc,. Managed by Premier Research Worldwide. 1-800-742-3029. Compassionate Use Protocol. For individuals with disseminated MAC who have failed or are intolerant to existing therapies. Sponsored by Pfizer, Inc,. Managed by Premier Research Worldwide. 1-800-742-3029 Expanded Access protocol. For individuals 13 years of age or older, have CD4+ cell counts 300/mm3 or less, are failing other therapy and are receving at least one other antiretroviral agent. 1-800-779-0070. Open-Label Treatment Protocol. Pediatric symptomatic HIV infection for children who have failed or are intolerant to other approved therapies.. Physican calls only. Hoffman La-Roche. 1-800-332-2144. Compassionate Use Protocol. For children who cannot be treated with conventional anti-fungal therapy. Pfizer, Inc. (212) 441 -3739. For CMV maintenance in HIV+ individuals who cannot take ganciclovir intravenously. Physican calls only. Roche Laboratories, 1-800-569-4630 Compassionate Use Protocol. For individuals with documented oral candidiasis who have failed a minimum of 14 days fluconazole treatment (200 mg qd). Sponsored by Janssen. Managed by KMI. 1-800-378-4779. 207

Page  208 Compassionate Use / Treatment IND / Expanded Access AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 1997 Compassionate Use / Treatment IND / Expanded Access AIDS/HI V Treatment Directory, Vol. 8, No. 3; January 1997 Mitoguazone (MGBG, Zyrkamine) Nelfinavir - (AG-1343, Viracept) Nitazoxanide (NTZ) Sparfloxacin Thalidomide (Synovir) Compassionate Use Protocol. For HIV+ patients who have AIDS-related refractory or relapsed Non-Hodgkin's lymphoma ( NHL). Ilex Oncolcogy. 1-210-677-8000. Expanded Access Program. For HIV+ individuals age 13 and older with CD4+ cell counts less than 100 cells/mm3 whom are unable to take indinavir or ritonavir. Agouron Pharmaceuticals. 1-800-621-7111. Information Service Line open 8:00 am - 6:00 pm EST, Monday through Friday. Expanded Access Program. A powder formulation for HIV+ children aged 2 to 13 years Agouron Pharmaceuticals. 1-800-621-7111. Information Service Line open 8:00 am - 6:00 pm EST, Monday through Friday. Compassionate Use Protocol. For individuals with cryptosporidiosis. Unimed.Pharmaceuticals 1-800-864-6330 x 3032 Limited Compassionate Use Protocol for individuals with MDRTB Rhone-Poulenc Rorer, Inc. (610) 454-5467. Emergency IND Protocol (case by case). For apthous ulcers.Celegene. 1-800-896-6766. Compassionate Use Protocol. For individuals with HIV infection and wasting syndrome. Celegene. 1-800-896-6766 208 I

Page  209 State Drug Assistance Programs AIDS/HIV Treatment Directory, Vol 8, No. 3, January 1997 STATE DRUG ASSISTANCE PROGRAMS The following is a list of phone numbers for state departments of health and their pharmacy-assisted services to people with HIVIAIDS. Eligibility requirements an drugs/services covered vary from state to state. Questions regarding the reimbursement programs should be directed to your state department of health. Alabama (334) 613-5364 Louisiana (504) 568-7474 Oklahoma (405) 271-4636 Arkansas (501) 661-2292 Massachusetts (617) 566-8358 Oregon (503) 731-4029 Arizona (602) 230-5819 Maine (207) 287-5060 Pennsylvania 1-800-922-9384 California (916) 324-8429 Michigan (517) 335-9333 Puerto Rico Available through public health clinic Colorado (303) 866-2445 Minnesota (612) 297-3344 Rhode Island Rhode Island (401) 464-2183 Connecticut 1-800-238-2503 Missouri (314) 751-6439 South Carolina South Carolina (803) 734-6033 Delaware (302) 739-3032 Mississippi (601) 960-7723 South Dakota South Dakota (605) 773-3737 District of Columbia (202) 347-8888 Montana (406) 444-4744Tennessee Tennessee (615) 741-8530 Florida (904) 413-0674 North Carolina (919) 773-3091Texas Texas 1-800-255-1 090 Georgia (404) 657-3129 North Dakota 1-800-472-2180Utah Utah (801) 538-6096 Hawaii (808) 732-0315 Nebraska (402) 559-4673Virginia Virginia (804) 225-4844 Iowa (515) 242-5838 New Hampshire (603) 271-4576 Virgin Island Virgin Island (809) 776-8311 Idaho (208) 334-6657 New Jersey (609) 588-7038Vermont Vermont (802) 241-2880 Illinois 1-800-825-3518 New Mexico (505) 827-8426 Washington (360) 753-3493 Indiana 1-800-659-7580 New York 1-800-542-2437 Wisconsin (608) 267-6875 Kansas (913) 296-8891 Nevada (702) 687-4800 West Virginia (304) 242-9443 Kentucky (502) 564-6539 Ohio (614) 466-4669 Wyoming (307) 777-5800 d 209

Page  210 Drug Assistance Programs of Pharmaceutical Companies DRUG ASSISTANCE PROGRAMS OF PHARMACEUTICAL COMPANIES Acyclovir (Zovirax) Glaxo Wellcome Co 1-800-722-9294 Alpha Interferon-2A (Roferon-A) Hoffmann-La Roche, Inc. 1-800-443-6676 Alpha Interferon-2B (Intron-A) Schering-Plough Corp. 1-800-521-7157 Amitriptyline Roche Laboratories. 1-800-285-4484 Astemizole (Hismanal) Janssen Pharmaceutica 1-800544-2987 Atovaquone (Mepron) Glaxo Wellcome Co. 1-800-722-9294 Azithromycin (Zithromax) Pfizer, Inc. 1-800-646-4455 AZT, (Zidovudine Retrovir) Glaxo Wellcome Co 1-800-722-9294 Bleomycin (Blenoxane) Bristol-Myers Squibb 1-800-272-4878 Cefitaxime (Claforan) Hoechst-Roussel 1-800-422-4779 Ceftriaxone (Rocephin) Roche Laboratories 1-800-285-4484 Cefuroxime (Ceftin) Eli Lilly and Company 1-800-545-6962 Glaxo Wellcome 1-800-722-9294 Cimetidine (Tagamet) SmithKline Beecham 1-800-546-0420 Ciprofloxacin (Cipro) Miles Pharmaceuticals 1-800-998-9180 Clarithomycin (Biaxin) Abbott Laboratories 1-800-688-9118 Clindamycin (Cleocine) Upjohn Co. 1-800-242-7014 Clofazimine (Lamprene) Ciba Pharmaceuticals 1-800-257-3273 Clonazepam (Klonopin) Roche Laboratories 1-800-285-4484 Clotrimazole (Mycelex, Lotrimin) Miles Inc. 1-800-998-9180 Schering Laboratories 1-800-656-9485 Cyclophosphamide (Cytoxan) Bristol-Myers Squibb 1-800-272-4878 Cyclosporine (Sandimmune) Sandoz Pharmaceuticals 1-800-631-8184 Daunorubicin, lipsomal (DaunoXome) NeXstar Pharmaceuticals 1-800-226-2056 ddC (Zalcitbane HIVID) Hoffmann-La Roche, Inc. 1-800-285-4484. Dexamethasone (Decadron) Merck & Co. 1-800-994-2111 Didanosine (ddl, Videx) Bristol-Myers Squibb 1-800-272-4878. Dronabinol (Marinol) Roxane Laboratories 1-800-274-8651 Doxcycline (Vibramycin) Pfizer Inc. 1-800-646-4455. Doxorubicin, liposomal (Doxil) Sequus Pharmaceuticals 1-800-375-1658 Erythropoietin (EPO) (Procrit, Epogen) Ortho Biotech. 1-800-553-3851 Amgen 1-800272-9376 Ethambutol (Myambutol) Wyeth-Ayerst. 1-800-568-9938. Etoposide (VP16, Vepesid), Bristol-Myers Squibb 1-800-272-4878 Erythromcyin Wyeth-Ayerst. 1-800-568-9938. Famciclovir (Famvir) SmithKline Beecham. 1-800-546-0420. Famotidine (Pepcid) Merck & Co. 1-800-994-2111. Fentanyl (Duragesic) Janssen Pharmaceutica. 1-800-544-2987. Fluconazole (Diflucan) Pfizer, Inc. 1-800-869-9979. Flucytosine (Ancobon) Roche Laboratories 1-800-285-4484 Flucinonide (Lidex) Roche Laboratories 1-800-285-4484 Fluoxetine hydrochloride (Prozac) Eli Lilly and Company 1-800-545-6962 Foscarnet (Foscavir) Astra Pharmaceutical Products, Inc. 1-800-488-3247 Ganciclovir (Cytovene) Roche Laboratories 1-800-285-4484 Ganciclovir, Intraocular (Vitrasert) Chiron Vision 1-800-843-1137 G-CSF (Neupogen) Amgen 1-800-272-9376 210

Page  211 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 GM-CSF (Leukine) Immunex Corporation Physician calls only 1-800-466-8639 Granisetron (Kytril) SmithKline Beechman 1-800-866-6273 Hydrocortisone (Hydrocortone) Merck & Co. 1-800-994-2111 (Cortef) Upjohn Co. 1-800-242-7014 Hydroxyzine hydrochloride Pfizer, Inc. 1-800-646-4455 Hydroxyzine pamoate (Vistaril) Pfizer, Inc. 1-800-646-4455 Immune globulin, IV (WinRho SD) Univax 1-800-789-2099 Indinavir (Crixivan) Merck & Co. 1-800-927-8888 Itraconazole (Sporanox) Janssen Pharmaceutica 1-800-544-2987 Ketoconazole (Nizoral) Janssen Pharmaceutica 1-800-544-2987 Lamivudine (3TC, Epivir) Glaxo Wellcome Co 1-800-722-9294 Loperamide (Imodium) Janssen Pharmaceutica 1-800-544-2987 Loratadine (Claratin) Schering Laboratories 1-800-656-9485 Megestrol Acetate (Megace) Bristol-Myers Squibb 1-800-272-4878 Methotrexate (Rheumatrex) Wyeth Ayerst 1-800-568-9938 Methylprednisolone (Medrol) Upjohn Co 1-800-242-7014 Mexiletine (Mexitil) Boehringer Ingelheim 1-800-556-8317 Morphine sulfate (Roxanol) Roxane Laboratories 1-800-274-8651 Nizatidine (Axid) Eli Lilly and Co. 1-800-545-6962 Nystatin (Mycostatin) Bristol-Myers Squibb. 1-800-272-4878 Octreotide acetate (Sandostatin) Sandoz Pharmaceuticals Corp. 1-800-631-8184 Oxandrolone (Oxandrin) Bio-Technology General Corp. 1-800-741-2698 Paclitaxel (Taxol) Bristol-Myers Squibb. 1-800-272-4878 Paramomycin (Humatin) Parke-Davis 1-800-755-0120 Pentamidine, aerosolized (NebuPent) Fujisawa Pharmaceuticals. 1-800-366-6323 Pentoxifylline (Trental) Hoechst Roussel Pharmaceuticals. 1-800-422-4779 Phenytoin (Dilantin) Parke-Davis 1-800-755-0120 Prednisone Schering Laboratories 1-800-656-9485 Prochlorperazine (Compazine) SmithKline Beecham 1-800-546-0420 Pyrazinamide (P.USP) Wyeth-Ayerst 1-800-568-9938 Pyrimethamine (Daraprim, Fansidar) Glaxo Wellcome Co 1-800-722-9294 Roche Laboratories. 1-800-285-4484 Ranitidine (Zantac) Glaxo Wellcome 1-800-722-9294 Rifabutin (Mycobutin) Pharmacia 1-800-366-5570 Rifampin (Rimactane) Ciba Pharmaceuticals 1-800-257-3273 Ritonavir (Norvir) Abbott Labatories 1-800-659-9050 Saquinavir (Invirase) Roche Laboratories 1-800-282-7780 Sertraline hydrochloride (Zoloft) Pfizer, Inc 1-800-646-4455 Stavudine, (d4T) Bristol-Myers Squibb 1-800-272-4878. Streptomycin (S.USP) Pfizer, Inc 1-800-254-4445 Sucralfate (Carafate) Marion Merrell Dow 1-800-552-3656 Terfenadine (Seldane) Marion Merrell Dow 1-800-552-3656 Testosterone (transdermal patch) Alza Pharmaceuticals 1-800-634-8977 Trimethroprim/ sulfamethoxazole TMP/SMX (Septra,Bactrim) Glaxo Wellcome Co 1-800-722-9294 Hoffmannn- La Roche 1-800-285-4484 Trimetrexate (NeuTrexin) US Bioscience. 1-800-285-4484 Valacyclovir (Valtrex) Glaxo Wellcome. 1-800-722-9294 Vinblastine (Velban) Eli Lilly and Company 1-800-545-6962 Vincristine (Oncovin) Eli Lilly and Company 1-800-545-6962 211

Page  212 Index of Manufacturers I INDEX TO MANUFACTURERS Acyclovir (Zovirax) Glaxo-Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Albendazole SmithKline BeechamPhiladelphia, PA Medical Dept.: (215) 751-4000 All- trans Retinoic Acid Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 Alpha Interferon Glaxo Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 Interferon Sciences, New Brunswick, NJ Stan Schutzbank: (908) 249-3250 Schering-Plough Corp Madison, NJ Medical Information: 1-800-526-4099 ALX40-4C Allelix Biopharmaceuticals, Mississauga, Ontario, Canada Linda Willis: (905) 677-0831 Amikacin Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 Amikacin, Liposomal (Mikasome) NeXstar, San Dimas, CA Theo Brandt-Sarif: (909) 394-4113 Amitriptyline (Elavil) Zeneca Pharmaceuticals Wilmington, DE Professional Services: (302) 886-2231 Amphotericin B Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 NeXstar., San Dimas, CA Theo Brandt-Sarif: (909) 394-4113 Amphotericin B colloidal dispersion (Amphotec) SEQUUS Pharmaceutical Menlo Park, CA Gwen Coffey: (415) 323-9011 Amphotericin B lipid Complex (ABLC) Bristol-Myers Squibb Co., New York, NY Jennifer True: 609) 252-6540 The Liposome Company, Princeton, NJ Gary Horwith: (609) 520-6555 Amphotericin B, liposomal (AmBisome) Fujisawa Pharmaceuticals, Medical Information: 1-800-727-7003 Anti-B4 blocked ricin Immunoconjugate Immunogen, Cambridge, MA Dixie Esseltine, M.D. (617) 661-9312 x 282 AR-177 (Zintevir) Aronex Pharmaceuticals, Inc. The Woodlands,TX (713) 367-1666 Atovaquone (Mepron) Glaxo-Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Autologous CD8 Infusion BPR Gencel, Inc.Santa Clara, CA Thomas Okarma: (408) 492-9200 Azithromycin (Zithromax) Pfizer Inc., New York, NY Medical Information: 1-800-438-1985 AZT (Zidovudine, Retrovir) Glaxo Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-335-0089 BACI (Bovine Anti-Cryptoporidium Immunoglobulin) Immucell Corporation, Portland, ME Joseph Crabb: (207) 878-2770 Bleomycin Bristol-Myers Squibb Oncology Divison., Evansville, IN Medical Services: (812) 429-5000 BW 882C87 Glaxo-Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 CD4-IgG Genentech, South San Francisco, CA Professional Services: 1-800-821-8590 CD4-PE40 The Pharmacia & Upjohn Company, Kalamazoo, MI Professional Information: (616) 323-6319 Ceftriaxone Hoffman LaRoche laboratories, Nutley, NJ Diane Donlon: (201) 562-2203 Cidofovir (HPMPC) Gilead Sciences, Inc., San Francisco, CA Howard Jaffe: (415) 476-6356 CI-1012 Warner Lambert - Parke Davis Morris Plains, NJ 07950 1-800-537-9978 Ciprofloxacin Bayer Corp, West Haven, CT Professional Services: (203) 937-2000 Clarithromycin (Biaxin) Abbott Laboratories, Abbott Park, IL Carl Craft: (708) 937-8147 Clindamycin Pharmacia & Upjohn Co. Kalamazoo, MI Jim Van Sweden: (616) 323-4696 212 I

Page  213 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 Clofazimine CIBA-GEIGY Corp., Summit, NJ Lucy Castro: (908) 277-3572 Clotrimazole (Mycelex) Bayer Corp, West Haven, CT Professional Services: (203) 937-2000 CMVIg Medlmmune, Gaithersburg, MD Franklin Top: (301) 417-0770 Cyclobut-G (Cygalovir) Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 Cyclophosphamide Adria Laboratories, Columbus, OH Sunil Gupta: (614) 764-8178 Bristol Myers Pharmaceuticals, Evansville, IN Medical Information: (812) 429-5000 Elkins-Sinn, Inc. Cherry Hill, NJ Research & Development: (609) 424-3700 Cycloserine (Seromycin) Eli Lilly and Co., Indianapolis, IN Product Information: (317) 276-3714 Cyclosporine (Sandimmune) Sandoz Pharmaceuticals, East Hanover, NJ Medical Service: (201) 503-7500 Dapsone Jacobus Pharmaceutical Co., Inc., Princeton, NJ. Thomas Roddenbery: (609) 921-7447 Daunorubicin, liposomal (DaunoXome) NeXstar Inc., San Dimas, CA Theo Brandt-Sarif: (909) 394-4113 ddC (Dideoxycytidine, HIVID) Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 ddl (Didanosine, Videx) Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 d4T (Stavudine) Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 Delavirdine (U-90; BHAP compound) Pharmacia & Upjohn Co., Kalamazoo, MI Information Hotline: 1-800-432-4702 Dexamethasone Merck, Sharp & Dohme, West Point, PA Professional Services: (215) 661-7300 DMP 266 Dupont Merck Wilmington, DE (302) 892-8530 Doxorubicin (Adriamycin) Adria Laboratories, Columbus, OH Sunil Gupta: (614) 764-8178 Doxorubicin, liposomal (Doxil) SEQUUS Pharmaceuticals, Inc. Menlo Park, CA Professional Services: 1-800-323-9049 Dronabinol (Marinol) UNIMED, Inc., Somerville, NJ Terry Plasse: (908) 526-6894 EPO (Epogen, Procrit) Amgen Inc, Thousand Oaks, CA Kimberly Dorsey: (805) 499-5725 x4367 Ortho Biotech, Raritan, NJ Craig Rothernberg: (908) 218-6090 Ethambutol Lederle Laboratories, Wayne, NJ Jeff Hoyak: (201) 831-4619 Ethionamide (Trecator) Wyeth-Ayerst Laboratories, Philadelphia, PA Audrey Ashby: (215) 688-4400 Etoposide (VP-16) Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 F105 Monoclonal Antibody Centocor Inc., Malvern, PA Richard McCloskey: (215) 889-4793 Famciclovir (BRL 39123A) SmithKline Beecham Co., Philadelphia, PA Medical Services: 1-800-366-8900 Fansidar Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 Fluconazole (Diflucan) Pfizer Inc., New York, NY Medical Information: 1-800-438-1985 Flucytosine (5-FU, Ancobon) Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 Matrix Pharmaceuticals, Menlo Park, CA Jayne Dedo: (415) 326-6100 Fluoxymesterone (Halotestin) The Pharmacia & Upjohn Company, Kalamazoo, MI Jim Van Swedens: (616) 323-4696 Foscarnet (Foscavir) Astra Pharmaceuticals, Westborough, MA Sandra Stamos: (508) 366-1100 x2309 Gamma Globulin (IVIG) Cutter Biological Berkeley, CA Marylin Davis: (415) 420-5492 Gamma Interferon Genentech, South San Francisco, CA Professional Services: 1-800-821-8590 Ganciclovir (Cytovene) Hoffman LaRoche, Nutley, NJ Diane Donlon: (201) 562-2203 213 I

Page  214 Index of Manufacturers Ganciclovir, intravitreal Chiron Intraoptics, Irvine, CA Penny Johnson: (714) 768-4690 x371 G-CSF (Filgrastim) Amgen Inc., Thousand Oaks, CA Michael Klein: (805) 447-3937 GEM-91 Hybridon, Inc., Worcester, MA Medical Information: (508) 752-7000x7191 GM-CSF (Leukine) Immunex Corp., Seattle, WA Professional Services: 1-800-334-6273 Sandoz Pharmaceuticals Corp., East Hanover, NJ Medical Service: (201) 503-7500 Schering-Plough Corp. Madison, NJ Medical Information: 1-800-526-4099 gp120 Vaccines rgp120 CHO Chiron, Emeryville, CA Dino Dina: (415) 655-8730 IIB rgp120/HIV-1MN rgpl20/HIV-1 Genentech, South San Francisco, CA David Graves: 1-800-821-8590 ENV 2,3 rgpl20 Biocine Co., Emeryville, CA David Chernoff: (510) 601-2775 gp160 Vaccines gp160 IMMUNO-U.S., Inc., New York, NY Sherri Michelstein: (212) 557-7111 VaxSyn rgp160 MicroGeneSys, Inc., West Haven, CT Professional Services: (203) 686-0800 HIV-Immunogen Immunization Products, San Diego, CA Burt Slade: (215) 454-5479 HIVIG North American Biologicals, Inc.,Miami, FL Medical Information: (305) 625-5303 Human Growth Hormone (Serostim) Serono Laboratories, Inc. Norwell, MA Gina Cella (617) 982-9000 Hypericin VIMRX Pharmaceuticals, Stamford, CT Richard I. Podell: (203) 321-2115 Indinavir (Crixivan, MK-639. L-735,524) Merck & Co. Inc., Rahway, NJ Linda Distlerath: (908) 423-4165 Insulin-like Growth Factor Genentech South San Francisco, CA Professional Services: 1-800-821-8590 Interleukin-1 (rhulL-1R) Immunex Corp., Seattle, WA Jan Agosti: (206) 587-0430 Interleukin-2 (PEG-IL-2) Cetus Corp., Emeryville, CA Professional Services: 1-800-238-8779 Interleukin-2 (Fusion Toxin) Seragen, Inc., Hopkinton, MA Medical Information: (508) 435-2331 Interleukin-3 (IL-3) Sandoz Pharmaceuticals Corp.,East Hanover, NJ Medical Information: (201) 503-7500 Interleukin-4 (IL-4) Schering-Plough Corp., Madison, NJ Mary Ellen Rybak: 1-800-526-4099 Interleukin-12 (IL-12) Genetics Institute Cambridge, MA Dennis Harp: (617) 876-1170 ISIS 2922 ISIS Pharmaceuticals, Carlesbad, CA Medical Information: (619) 929-3898 Isoniazid Hiscia, Switzerland Inmaculada Marti: (415) 255-7941 Hoechst Marion Roussel Kansas City, MO (816) 966-5000 Isotretinoin (Accutane) Roche Dermatologics, Nutley, NJ Diane Donlon: (201) 562-2203 Itraconazole Janssen Research Foundation, Piscataway, NJ Professional Services: 1-800-526-7736 Ketoconazole Janssen Research Foundation, Piscataway, NJ Professional Services: 1-800-526-7736 L-Carnitine (Carnitor) Sigma-Tau Pharmaceuticals, Inc.,Gaithersburg, MD Product Information: (301) 948-1041 L-Ofloxacin (Levofloxacin) R.W. Johnson PharmaceuticalResearch Institute, Raritan, NJ Professional Services: (908) 704-4745 Lentinan Lenti-Chemico Pharmaceuticals Lab, Teaneck, NJ Maxwell Gordon: (201) 836-1196 Letrazuril Janssen Research Foundation, Piscataway, NJ Professional Services: 1-800-526-7736 Leucovorin Lederle Laboratories, Wayne, NJ Jeff Hoyak: (201) 831-4619 Levamisole Janssen Research Foundation, Piscataway, NJ Professional Services: 1-800-526-7736 LGD 1057 Ligand Pharmaceuticals Inc., San Diego, CA Lisa Bauman: (619) 550-7738 214 I

Page  215 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 Loviride (Alpha-APA Derivatives) Janssen Research Foundation, Piscataway, NJ. Professional Services: 1-800-526-7736 MDL 28,574A (BuCAST) Hoechst Marion Roussel, Inc Kansas City, MO (816) 966-5000 Mechlorethamine Merck & Co. Inc., Rahway, NJ Medical Information: (908) 594-4000 Megestrol acetate (Megace) Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 Metronidazole (Flagyl) G.D. Searle & Co., Chicago, IL Customer Services: 1-800-323-1603 Mexiletine Boehringer Ingelheim Corporation, Inc. Ridgefield, CT David W. Nurnberger: (203) 798-4700 Mitoguazone (Zyrkamine, MGBG) Ilex Oncology, Inc. San Antonio, TX Susan Smith: (210) 677-8000 Mitoxantrone (Novatrone) Lederle Laboratories, Wayne, NJ Craig Engesser: (201) 831-3253 MSL-109 Protein Design Labs, Inc., Mount View, CA Peter Dworkin: (415) 903-3721 Mycelex Troches Bayer Corp, West Haven, CT Professional Services: (203) 937-2000 NAC (N-acetylcysteine) Zambon Corporation, East Rutherford, NJ Lloyd Gabel: (201) 896-2200 x145 Nelfinavir (AG-1343, Viracept) Agouron Pharmaceuticals, Inc. San Diego, CA Donna Nichols: (619) 622-3000 Nevirapine (BI-RG-587) Boehringer Ingelheim Corporation, Inc. Ridgefield, CT David W. Nurnberger: (203) 798-4700 Nimodipine Bayer Corp., West Haven, CT Professional Services: (203) 937-2000 Nystatin Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 Octreotide acetate(Sandostatin) Sandoz Pharmaceuticals Corp., East Hanover, NJ Medical Service: (201) 503-7500 Ofloxacin (Floxin) Ortho Pharmaceuticals, Raritan, NJ Sahun Mickus: (908) 218-6725 1592U89 Glaxo-Wellcome Co. Research Triangle Park, NC Drug Information: 1-800-334-0089 OPC-8212 (Arkin-Z) Otsuka America Pharmaceuticals, Inc. Rockville, MD Robert Petit: (301) 990-0036 x2146 OTC (Procysteine) Free Radical Sciences, Cambridge, MA Dr. Cynthia Leaf: (617) 374-1213 Oxandrolone (Oxandrin) BTG Pharmaceuticals Corp. Iselin, NJ Medical Information(908) 632-8800 Paclitaxel (Taxol) Bristol-Meyers Oncology Division, Evansville, IN Medical Services: (812) 429-5000 Paromomycin (Humatin) Parke-Davis, Morris Plains, NJ Dave Rhodes: 1-800-223-0432 Passive Hyperimmune Therapy HemaCare Corp., Sherman Oaks, CA Tanya Youvan: (818) 986-3883 Penciclovir (BRL 39123A) SmithKline Beecham, Philadelphia, PA Medical Services: 1-800-366-8900 x5231 Pentamidine Fisons Corp., Rochester, NY Michael Saunders: (716) 475-9000 Fujisawa Pharmaceuticals, Deerfield, IL Medical Information: (708) 317-0600 Pentoxifylline (Trental) Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ Ed Cummings: (908) 231-2008 Piritrexim Glaxo-Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Platelet Factor 4 (PF4) Repligen Corp., Cambridge, MA Maryanne Visconti: (617) 225-6000 x7058 PMEA (BisPOM PMEA) Gilead Sciences, San Francisco, CA Howard Jaffe: (415) 573-4702 Primaquine Winthrop Pharmaceuticals, New York, NY Medical Information: 1-800-446-6267 Procarbazine Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 p24 Vaccine MicroGeneSys, Inc., West Haven, CT Mary Lyons: (203) 686-0800 Pyrazinamide Lederle Laboratories, Wayne, NJ Jeff Hoyak: (201) 831-4619 215

Page  216 Index of Manufacturers I Pyrimethamine Glaxo Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Ranitidine (Zantac) Glaxo-Wellcome Co,, Research Triangle Park, NC Drug Information: 1-800-334-0089 Rifabutin Adria Laboratories, Columbus, OH Beverly Wynne: (614) 764-8307 Rifampin CIBA-GEIGY Corp., Summit, NJ Lucy Castro: (908) 277-3572 Hoechst Marion Roussel Kansas City, MO (816) 966-5000 Rifapentine Marion Merrell Dow Inc. Kansas City, MO Stephen Gardner: (816) 966-7635 Ritonavir (Norvir, ABT 538) Abbott Laboratories Abbott Park, IL John Leonard: (708) 938-4545 RMP-7 Alkermes, Inc. Cambridge, MA Bill Graney: (617) 494-0171 Saccharomyces boulardii Biocodex, Inc., Seattle, WA Kris Moyer: (206) 322-5602 Saquinavir (Ro 31-8959) Hoffmann-La Roche Inc., Nutley, NJ Diane Donlon: (201) 562-2203 SC-49483 G. D. Searle & Co., Skokie, IL Susan Smith: (708) 982-8975 SC-52151 G.D. Searle & Co., Skokie, IL Susan Smith: (708) 982-8975 Sodium tetradecyl sulfate Injection Elkins-Sinn, Inc., Cherry Hill, NJ Medical Information: (609) 424-3700 Sorivudine (BV ara-U) Bristol-Myers Squibb Co., New York, NY Jennifer True: (609) 252-6540 Spiramycin Rhone-Poulenc Pharmaceuticals, Princeton, NJ Medical Affairs: (609) 520-0880 SP-303T Shaman Pharmaceuticals South San Francisco, CA Debbie Persante: (415) 952-7070 Streptomycin Pfizer - Roerig, New York, NY Medical Information: (212) 573-2187 Sulfasalazine Kabi Pharmacia, Piscataway, NJ Product Information: 1-800-526-3619 Suramin FBA Pharmaceuticals, West Haven, CT Kevin Higgins: (203) 937-2373 Tecogalan (DS-4152/SP-PG) Daiichi Pharmaceuticals, Fort Lee, NJ, Medical Information: (201) 944-4333 Terbinafine (Lamsil) Sandoz Pharmaceuticals, West Haven, CT. Medical Services: (201) 503-7500 Thalidomide Celgene Corporation, Warren, NJ Steven Thomas: (908) 805-3914 Pediatric Pharmaceuticals Edison, NJ (908) 225-0989 3TC (Lamivudine, Epivir) Glaxo-Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Thymic Humoral Factor Adria Laboratories, Columbus, OH Robert Nolan: (614) 764-8192 Thymopentin Immunobiology Research Institute, Annandale, NJ Michael DeRisi: (908) 730-1752 TMP/SMX (Bactrim(Septra) Hoffman LaRoche, Nutley, NJ Diane Donlon: (201) 562-2203 Glaxo Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 TNP-470 Takeda Chemicals Osaka, Japan 06-204-21110 Trifluridine (TFT) Glaxo Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Trimethoprim Barr Laboratories, Inc. Northvale, NJ Harold Cohen: (914) 362-1100 x2823 Biocraft Laboratories, Elmwood Park, NJ Regulatory Affairs: (201) 703-0400 Danbury Pharmacal Inc., Danbury, CT Thomas Culkin: (914) 278-3724 Trimetrexate (NeuTrexin) U.S. Bioscience, West Conshohocken, PA Edith Mitchell, MD: (215) 832-4525 Tumor Necrosis Factor Immunex Corp. Seattle, WA Professional Services: 1-800-334-6273 Valacyclovir (BW 256U87) Glaxo-Wellcome Co., Research Triangle Park, NC Drug Information: 1-800-334-0089 Vidarabine Warner-Lambert Co. Morris Plains, NJ Medical Information: (201) 540-4243 216

Page  217 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 7 NEWSLETTERS AND OTHER INFORMATION RESOURCES There are a number of sources of information about treatments for AIDS/HIV. Many publications and services are available for free or at little cost for a person with AIDS/HIV. You may want to peruse one or more of them. Your personal physician and your local AIDS organization may also benefit from the information you gather. AMFAR-PRODUCED RESOURCES The AIDS/HIV Treatment Directory is published by the American Foundation for AIDS Research (AmFAR). It provides a directory of open AIDS-related clinical trials, and comprehensive information on treatments for HIV, and HIV-related disorders. For information or to subscribe call 1-800-38-AmFAR or e-mail txdir@amfar.org. AmFAR also publishes the AIDS/HIV Clinical Trial Handbook, which answers the most frequently asked questions about participating in clinical trials in easy-to-understand, non-technical language. Available in English and Spanish. For subscriptions call (800) 38AmFAR. NATIONAL PREVENTION, TREATMENT AND INFORMATION RESOURCES For information about AIDS/HIV clinical trials conducted by the National Institutes of Health, and FDA-approved efficacy trials, call 1-800-TRIALS-A (1-800-874-2572). 1-800-AIDS-012 (1-800-243-7012) TTY/TTD for deaf and hearing-impaired callers. Spanish spoken. For information about FDA-approved treatments for HIV and related disorders call the federal government's AIDS Treatment Information Services. 1-800-HIV-0440. To find out about new drug studies being done at the National Institutes of Health (NIH) Clinical Center, call 1-800-AIDS-NIH (1-800-243-7644). Monday through Friday from 12:00pm - 3:00pm EST. The National Library of Medicine provides three on-line AIDS databases, AIDSLINE, AIDSDRUGS and AIDSTRIALS. To obtain a free information packet, call 1-800-638-8480. For a wide variety of AIDS/HIV information, resources and publications call the Centers for Disease Control's National AIDS Clearinghouse. 1-800-458-5231. Spanish spoken. CDC fax information service: (404) 332-4565. To find out about AIDS resources in your area, call the 24 hour National AIDS Hotline at 1-800-342-AIDS (2437). For Spanish-speaking callers, the number is 1-800-344-SIDA (7432) from 8 AM to 2 AM, Eastern Time. For the deaf and hearing-impaired, call 1-800-AIDS-TTY (243-7889), 10 A.M. to 10 P.M., Eastern Time. All three services are provided by the U.S. Centers for Disease Control Consumer Nutrition Hotline: (800) 366-1655. American Dietetic Association hotline. Callers can speak with a registered dietitian about HIV/AIDS and nutrition, or ask for a referral to a registered dietitian. HANDI (Hemophilia and AIDS/HIV Network for the Dissemination of Information: (800) 424-2634 (English, extension 3051; Spanish, extension 3054). Provides publications and referrals to local service providers. National Patient Air Transport Hotline: 1-800-296-1217. Provides information on compassionate travel programs of the airline industry and volunteer organizations for adults and children traveling for medical treatment. Native American AIDS Information Hotline: (800) 283-2437. Monday-Friday, 8:30 A.M. - 12:00 noon Pacific Time. Operated by the National Native American AIDS Prevention Center. Serves as a resource to Native communities and to support community efforts by providing education and information services, thereby enhancing the physical, spiritual, and economic health of Native people. The following resources are not produced by AmFAR, but contain a wide range of information. AIDS Clinical Care. A publication founded in cooperation with AmFAR. Massachusetts Medical Society, 1440 Main Street, Waltham, MA 02154-1649. Specifically targeted at physicians with AIDS patients. US delivery first class, $89.00/year for twelve issues, International $117.00/year. Also available: a guide to HIV patient care: HIV Infection: A Primary Care Approach, 2nd Edition. US $9.95. (20+ copies US $7.95) For credit card orders, 1-800-843-6356. ADAPT (Association for Drug Abuse, Prevention and Treatment). 552 Southern Boulevard, Bronx, NY 10455. AIDS oriented outreach, support groups and education resource for users of injectable drugs. (718) 665-5421. AEGIS (AIDS Education General Information System). P.O. Box 184, San Juan Capistrano, CA 92693. A free 24 hour AIDS information bulletin board system 217

Page  218 For More Information and on-line database. International conferences and full text articles from a number of newsletters and papers are available. BBS number is (714) 248-2836 (Full Dulex, 8-N-1, 1200 to 9600 band). AIDS Action Bulletin. Directory of clinical research in AIDS for Baltimore and Washington. Published by AIDS Action Baltimore, Inc., 2105 North Charles Street, Baltimore, MD 21218. (410) 837-2437. AIDS Link. Published by East Central AIDS Education & Training Center (covering Ohio, Michigan, Tennessee, and Kentucky) for health care professionals. Write to Rebecca Atterrin, ed., AIDS Link University of Cincinnati; Medical Center Information and Communications (MCIC) 231 Bethesda Ave. Cincinnati, OH 45267. AIDS Medicines In Development. Published by the Pharmaceutical Research and Manufacturers Association (PhRMA), Communications Division, 1100 15th Street NW, Washington, DC 20005. An annual chart of antivirals, immunomodulators, and anti-infectives as well as information on diagnostics and vaccines. Free. (202) 835-3400. AIDS Policy and Law. A biweekly report on AIDS law and policy developments from the courts, NIH, federal and state AIDS agencies, advocacy organizations, and elsewhere. Buraff Publications, 1350 Connecticut Avenue, NW, Washington, DC, 20036. (800) 333-1291. AIDS Treatment Data Network Inc. 259 West 30th Street, 9th Floor, New York, NY 10001. The Network provides HIV treatment and research information, educational resources and training to professionals service providers and the individuals and communities which they serve. It also assists HIV+ individuals with lower English and Spanish literacy levels, in addition to those with little or no scientific background or expertise. (212) 260-8869; Nationwide 1-800-734-7104. AIDS Treatment News. ATN, P.O. Box 411256, San Francisco, CA 94141. Published twice-monthly by John S. James reporting on developments in treatments for HIV disease and related opportunistic infections. Also covers issues relating to research and treatment access. For subscription information, call 1-800-TREAT-1-2 (1-800-873-2812). Subscriptions available on a sliding scale. AIDS Update. Dallas Gay Alliance, P.O. Box 190712, Dallas, TX, 75219. Newsletter includes general information on AIDS issues and treatments. Also accessible are the AIDS Resource Center, Dallas Legal Hospice and the Nelson-Tebedo Clinic. (214) 528-4233. AIDS Weekly. P.O. Box 830409, Birmingham, AL 35283-0409. A monthly newsletter with short abstracts of AIDS-related news items, journal articles, conference reports, etc. $995 a year. AIDS Weekly also publishes AIDS Therapies, a 200 page binder with monthly updates, $995 a year. 1-800-633-4931. APICHA News. Quarterly newsletter published by the Asian & Pacific Islander Coalition on HIV/AIDS (APICHA). Provides information on prevention education, client services and advocacy for Asians and Pacific Islanders. APICHA, 41 John Street, 3rd floor, New York, NY, 10038. (212) 349-3293. ATIN (AIDS Targeted Information). A monthly publication which provides abstracts of and critical commentary on the latest scientific and medical literature. A TIN highlights those scientific reports deemed to be most significant by its board of editors. Williams & Wilkins, 428 East Preston Street, Baltimore, MD 21202. $295/yr individual, $350/yr institutions. For credit card orders, 1-800-638-6423. Being Alive. Published by the PWA Action Coalition, 3626 Sunset Boulevard, Los Angeles, CA 90026. Medical updates, plus information on AIDS advocacy, a calendar of local events, listings of AIDS support groups, peer support, counselling, etc. (213) 667-3262. BETA (Bulletin of Experimental Treatments for AIDS). A publication of the San Francisco AIDS Foundation, P.O. Box 2189, Berkeley, CA 94702 (510) 549-4300. Medical Information published quarterly; a $55 personal subscription, $125 Institutional. For telephone subscriptions call 1-800-959-1059. Body Positive. 19 Fulton Street, Suite 308B, New York, NY 10038. Produces a number of magazines and resources. Body Positive: a monthly magazine for HIV+ individuals and their loved ones; El Cuerpo Positivo, a quarterly spanish-language magazine; Positive Options, a resource guide to living well with HIV. They also operate HIV Helpline for counseling information and referrals. Donations for publications are appreciated; subscriptions are available. 1-800-566-6599. E-mail: bodypos800@aol.com. Body Positive Resource Center. 175 NE 36th Street, Miami, FL 33137. A non-profit community center dedicated to healing and empowering the HIV community through education outreach and support groups. Publishes a quarterly newsletter including AIDS/HIV treatment news and other general AIDS/HIV related information. (305) 576-1111. Canadian AIDS News. A newsletter focusing on AIDS education in Canada, published bimonthly by the Canadian Public Health Association, AIDS Education and Awareness Program, 400-1565 Carling Avenue, Ottawa, ON, Canada KIZ 8R1. Subscriptions are free. (613) 725-3769. 218

Page  219 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199; 7 Canadian HIV Trials Network. Network Update. 200-1033 Davie Street, Vancouver, BC V6E 1M7 Registry of Canadian HIV Clinical Trials. Includes brief description of trials and locations of trial centers. Call (604) 631-5327 or fax (604) 631-5210 between 7:30am - 4:30pm Pacific Standard Time. National Hotline: (800) 263-1638. Clinical Trials: Talking It Over. Published by the National Institute of Allergy and Infectious Diseases. An educational pamphlet designed for those considering participation in an AIDS/HIV clinical trial. NIAID, Office of Communications, National Institutes of Health, Building 31, Room 7A32, Bethesda, MD 20892. The Common Factor. A newsletter of the Committee of Ten Thousand, an organization by, for and of people infected with HIV through blood and blood products. Includes treatment articles, early intervention and resource list. Free for HIV+ persons, donations accepted. The Committee of Ten Thousand, c/o The Packard House, 583 Plain St., Stoughton, MA 02072. (617) 344-9634. Critical Path AIDS Project. 2062 Lombard Street, Philadelphia, PA 19146. Published monthly, with articles and reprints on experimental treatments and alternative therapies, and a listing of Philadelphia-area resources. $50.00 a year, free to HIV+ subscribers. (215) 545-2212. 24 hour hotline. Directory of HIV Clinical Research in the Bay Area. Published by the San Francisco Community Consortium, 3180 18th Street, Suite 201, San Francisco, CA 94110. Free. (415) 476-9554. Directory of Philadelphia Area HIV/AIDS Clinical Trials. Published by Philadelphia FIGHT, 201 North Broad Street, 6th Floor, Philadelphia, PA 19107. (215) 557-8265. European AIDS Treatment News. Publication containing European medical information, clinical trials and pre-clinical research. Deutsche AIDS-Hilfe, Dieffenbachstr. 33, Postfach 610149, D-10921 Berlin, Germany. 030-690-0870. FAACTS (Facts on Alternate AIDS Compounds and Treatments). 111 Gates Street, San Francisco, CA 94110. Provides summaries and reprints from the scientific and popular press concerning emerging treatments for HIV disease. Nominal fee. (415) 648-1357. FOCUS. Published by the University of California AIDS Health Project. Monthly newsletter outlining specific AIDS research and counseling issues. FOCUS, UCSF AIDS Health Project, Box 0884, San Francisco, CA 94143-0084. (415) 476-6430. HIV/AIDS Resources. Published by Guides for Living. Lists of AIDS-related services in the United States, including local health departments, community-based organizations, social support services, home health-care agencies, and others. $116.00 includes S&H. To order by phone 1-800-225-1860; by fax 1-800-413 -1781. (This resource replaces the discontinued publication Local AIDS Services: The National Directory produced by the U.S. Conference of Mayors.) HIV Frontline. Monthly newsletter aimed at mental health and healthcare professionals who counsel people living with HIV. NCM Publications, HIV Frontline Newsletter, 200 Varick Street, New York, NY 10014. (212) 691-9100. Infosheet. Published by Infoshare International. A bulletin designed to provide Russian individuals and organizations with the tools and information required to address HIV/AIDS issues and human rights violations in the Russian healthcare system. Infoshare International USA, 743A Addision Street, Berkeley, CA 94710. (510) 204-9099; E-mail: info2intl@aol.com. AIDS Infoshare Russia, P.O. Box 51, Moscow, Russia 105037. E-mail: infoshare@glas.apc.org. JUST KIDS. Newsletter covering medical and social issues faced by HIV+ children, teens and their parents. Yearly subscriptions are ten dollars for individuals, twenty dollars for professionals and institutions, and $30 for international orders. Send subscription requests to JUST KIDS, c/o 3 Corners, Inc. P.O. Box 42, Village Station, New York, NY 10014. Life-Link. A quarterly newsletter from the PWA Coalition of Long Island, 1170 Route 109, Lindenhurst, NY 11757. Includes AIDS information and local resources. PWAC also provides support groups, education, and a hotline for current AIDS/HIV information and service referrals. Donations accepted. Hotline (516) 225-5700. Local AIDS Services: The National Directory. Published by the United States Conference of Mayors AIDS Program. This publication has been discontinued please see listing HIV/AIDS Resources for like publication (not affiliated with U.S. Conference of Mayors. NAPWA-Link. The National Association of People with AIDS provides this bulletin-board system-reached through computer modem-including full text of several treatment newsletters, updated AIDS press clips, and on-line information exchange. $65 for direct line access. (703) 998-3144. National AIDS Manual NAM Publications, Unit 52, Eurolink Center, 49 Essra Road, London, England SW2 1B2. A comprehensive and extensively cross-referenced guide to information about AIDS treatments, prevention, and services in Great Britain. A monthly clinical trial directory is also available. 011-44-71-737-1693. 219

Page  220 For More Information National Association of People With AIDS. Medical Alert and The Active Voice. Two newsletters focusing on treatment information and public policy. NAPWA, 1413 K Street, NW, Washington, DC, 20005. (202) 898-0414. NMAC Update. National Minority AIDS Council. 300 I Street, NE, Suite 400, Washington, DC, 20002-4389. A bimonthly newsletter reporting on public policy issues and information on subjects in organizational management, for people in communities of color who work with issues of HIV infection. (202) 5441076. The News. Published by the Atlanta Gay Center, 63 12th Street, Atlanta, Georgia, 30309. A monthly newsletter reporting on treatment issues and community outreach programs. (404) 876-5372. NIAID AIDS Agenda and Dateline: NIAID. Two publications produced by the National Institute of Allergy and Infectious Diseases (NIAID) outlining treatment and basic research for AIDS and other infectious diseases. NIAID, National Institutes of Health, Building 31, 7A50, Bethesda, MD, 20892. North American Syringe Exchange Network. National needle exchange resource. Point Defiance AIDS Project, 535 Dock Street, Suite 112, Tacoma, WA, 98402. (206) 272-4857. Notes from the Underground. Published six times a year by the PWA Health Group, 150 West 26th Street, Suite 201, New York, NY 10001. Current information on therapies and treatment strategies, concentrating on "underground" AIDS treatment access. (212) 255-0520. Suggested subscription is $35 individual and $75 institutional. Also, available on a sliding scale. PAACNOTES. 101 West Grand Avenue, Suite 200, Chicago, IL 60610. A monthly newsjournal of the Physicians Association for AIDS Care. Features articles on clinical management, scientific research, and a diverse range of legal, ethical, psychosocial, economic issues directly affecting the care of persons with HIV disease. For subscription and membership information call (312) 222-1326. P.I. Perspective. A quarterly newsletter of Project Inform; donation appreciated. Other information is mailed in a Treatment Information Packet. National hotline: 1-800-822-7422. PLUS Voice: The Magazine About Life and HIV. A bimonthly magazine about living with HIV. PLUS Magazine, Inc., 945 West George Street, Chicago, IL 60657-9974. (312) 929-9761. Positive Directions News. A quarterly publication published by Positive Directions, 140 Clarendon Street, Suite 805, Boston, MA, 02115. Donations accepted. (617) 262-3456. Also available is a peer support phone line: 1-800-794-PEER. Positive Living. Published monthly by AIDS Project Los Angeles. Contains clinical trial, treatment and other AIDS/HIV-service information. APLA, 1313 N. Vine Street, Los Angeles, CA, 90028. (213) 993-1362. Hotline: (800) 922-2438. Positive Outlook. 2655 Swann Avenue, # 107, Tampa, FL 33609. A quarterly newsletter published by a nonprofit clinical trials organization. Focuses on local people and issues in West Central Florida. Donations accepted. (813) 877-5696. Positive Social Support Newsletter. P.O. Box 163654, Sacramento, CA 95816. Newsletter sponsored by and for people with HIV. Contact the Lambda Center, (916) 442-0185. Positively Aware. The monthly newsletter of Test Positive Aware (TPA) Network, 1340 West Irving Park, Box 259, Chicago, IL 60613. Chicago-area HIV related services directory, includes AIDS-related news items, events and clinical trials in the Chicago area. $25 donation suggested, free for people with AIDS. (312) 404-8726. POZ Magazine. A bimonthly national magazine devoted to everyone affected by AIDS. POZ, P.O. Box 1279, Old Chelsea Station, New York, NY, 10113-1279. (800) 883-2163. PWA Rag. Prisoners with AIDS Rights Advocacy Group, P.O. Box 2161, Jonesboro GA 30327. Newsletter containing articles, treatment updates, and resources for prisoners. Donations (including postage stamps) appreciated. (404) 946-9346. PWA Support. A newsletter providing legal assistance to Prisoners with AIDS. Published by the Prisoner's Legal Services of New York, 105 Chambers Street, New York, NY, 10007. Seasons. A quarterly newsletter of the National Native American AIDS Prevention Center featuring articles and artwork by Native Americans impacted by HIV/AIDS. Subscriptions are free in the U.S. American AIDS Prevention Center, 3515 Grand Avenue, Suite 100, Oakland, CA 94610. (510) 444-2051. Southern California Treatment Directory. Published by Southwest Community-Based AIDS Treatment Group (ComBAT), 1800 N. Highland, Suite 610, Los Angeles, CA 90028. A listing of clinical trials being conducted in Southern California. Free of charge. (213) 469-5888. 220 I

Page  221 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199 17 STEP Perspective. Seattle Treatment Exchange Project, 127 Broadway East, Suite 200, Seattle, WA 98102. Updates on treatments for HIV and related OIs condensed from journals, conferences and databases by their scientific review committee. STEP also publishes fact sheets/position papers, and staffs a telephone hotline Monday through and Friday 1-5pm. Good for both U.S. and Canada. (206) 329-4857 or (800) 869-7837. TAGline. A monthly paper of research and policy from the Treatment Action Group (TAG), 147 Second Avenue, #601, New York, NY, 10003. (212) 260-0300 Treatment and Data Digest. 135 West 29th St., 10th Floor, New York, NY 10001. Review of issues addressed by the Treatment and Data Committee of ACT-UP/New York. $40/yr individuals and $80/yr for institutions. Treatment Issues. Newsletter of experimental AIDS therapies, and treatments for opportunistic infections, published 12-14 times a year by Gay Men's Health Crisis (GMHC), Department of Medical Information, 129 West 20th St, New York, NY 10011. One year subscriptions: Individuals, 30$; Institutions, $50; International $60. Sliding scale subscriptions are possible. (212) 337-1950. Hotline: (212) 807-6655. Treatment Update / Traitement Sida. Published by Community AIDS Treatment Information Exchange, 517 College Street, Suite 327, Toronto, Ontario, Canada M6G 4A2. A newsletter reviewing current experimental treatments and trials, and updates on local issues. Available in French or English; individual subscription $15 a year for individual subscriptions. Free copies of AmFAR's AIDS/HIV Treatment Directory are also distributed to HIV+ Canadians from this office. (416) 944-1916 or 1-800-263-1638. Up Front Drug Information. Street Pharmacologists Update. 5701 Biscayne Blvd., Suite 9PH, Miami, FL 33137. Published four times yearly, providing information on drugs and drug referrals. (305) 757-2566. Vancouver PWA. 1107 Seymour Street, Vancouver, BC V6B 5S8. Monthly newsletter of the Vancouver Persons with AIDS Society, including short medical updates, local news, and a listing of upcoming events. (604) 893-2250. Wisconsin AIDS Update. Published by the Wisconsin AIDS/HIV Program, Department of Health, P.O. Box 309, Madison WI 53701. A quarterly compendium including epidemiological and clinical care articles, selections from the most important current abstracts in ATIN, and a comprehensive state wide list of events and resources. (608) 267-5287. TREATMENT INFORMATION RESOURCES FOR WOMEN LAPNOTES: A quarterly newsletter of the Lesbian AIDS Project, GMHC, 129 West 20th St., New York, NY 10011. Free. (212) 337-3532. Lovenotes: A quarterly newsletter published by Sisterlove, featuring treatment information and events calendar. Free. 1432 Donnelly Ave, Atlanta, GA. 30310. (404) 753-7733. WISE WORDS. A monthly publication providing treatment advocacy, access and information for women living with HIV/AIDS. Donations appreciated. WISE, 125 5th NE, Atlanta, GAZ 30308. (404) 817-3441. Women Alive. A quarterly newsletter focusing on treatment information, written by and for women with HIV/AIDS. $12.00/yr. Free to HIV+ women. Being There, 3526 Sunset Blvd, Los Angeles, CA 90026. Women's Link. A psychosocial service agency for women with HIV/AIDS. Publisher of Woman to Woman newsletter. Martin-Lyon Women's Health Services, 4410 Sepulveda, Culver City, CA 90230. (310) 313-5139. Women and HIV/AIDS: An International Resource Book. Written and edited by Marge Berer with Sunanda Ray. Published by Pandora Press, 1993. Information, action and resources on women and HIV/AIDS, reproductive health and sexual relationships. World. P.O. Box 11535, Oakland, CA 94611. Monthly newsletter on women and HIV/AIDS. Containing articles by HIV+ women and others about living with HIV, letters, advice, events calendar, and information on support groups in Northern California. Available in English or Spanish (Mujer Imagen de Vida). Subscriptions on a sliding scale. (415) 658-6930. WOMEN'S HOTLINES Lesbian AIDS Project (LAPS), GMHC, New York, NY. (212)337-3532 Women and HIV/AIDS, Women Alive, Los Angeles, CA. 1-800-544-4876 Women & HIV/AIDS, Sister Connect, New Jersey. 1-800-747-1108 221

Page  222 For More Information PARA MAYOR INFORMACION SPANISH NEWSLETTERS AND PUBLICATIONS Accidn en Sida. Un bolet6n internacional sobre la prevenci6n y control de SIDA. Incluye signos y sintomas de varias enfermedades y articulos sobre SIDA en la comunidad latina. P6ngase en contacto con Francisco Rosas, CRISSOL. c/o Colectivo SOL. Apartado Postal 13-320. Mexico, D.F. Tel6fono: (525) 605-8299. Amigos Contra El SIDA. Una revista dedicada a las personas que viven con VIH/SIDA. Publicaci6n bimestral de la Organizaci6n Mundial de la Salud. Envie su cheque o giro de $28 (6 n6meros), $50 (12 nimeros) a Amigos Contra El SIDA. A.C. Apdo. Postal 13-589 Mexico, D.F. 03500, Mexico. BETA, Boletin de Tratamientos Experimentales para el SIDA. Para informaci6n sobre subscripciones, Ilame gratis al 1-800-959-1059. FAX (510) 549-4342. Correspondencia editorial: PO Box 426182, San Francisco, CA 94142. FAX (415) 552-1583. Tel. (415) 863-2437 (Linea de Informaci6n sobre SIDA de la San Francisco AIDS Foundation). Boletin LATINO. Es una publicaci6n trimestral de Latinos Unidos Contra El Sida del Estado de Washington en Ingl6s y en Espafiol. Para subscribirse, favor contactar a LUCES c/o POCAAN 1200 South Jackson, suite 25, Seattle, Washington 98144. Tel6fono (206) 322-7061. El Cuerpo Positivo. Una revista publicada quatro veces al afio por Body Positive para personas VIH infectada y afectada. La revista es completamente en Espanol. Par mas informaci6n pongase en contacto con Body Positive, 2095 Broadway, Suite 306, New York, NY 10023. Telkfono: (212) 721-1346. Pregunte por Carmen Navarro. Guia para Benificios de Incapacidad del Seguro Social. Un folleto explicando c6mo el Seguro Social puede ayudar a personas infectadas con VIH. Visite su oficina local del Seguro Social y pida el folleto "Medicare" (publicaci6n #05-10943). Inventario de Recursos de Investigacidn en SIDA. Publicado y realizado por la Organizaci6n Panamericana de la Salud/Organizaci6n Munidad de la Salud. Este inventario es un instrumento basico para facilitar el conocimiento sobre SIDA/VIH en los deferentes paises de las Regi6n. La finalidad que se persigue es detectar vacios en la investigaci6n y fomentar el desarrollo de proyectos que apoyen a los programas de prevenci6n, control, diagn6stico y tratamiento del SIDA en nuestros paises. Organizaci6n Panamericana de la Salud. (202) 861-3200. (In)visibles Woman. Un video sobre latinas con SIDA que desafian el miedo que el publico tiene sobre el SIDA. $59.95 para individuales o contribuciones. Se estren6 en 1991. Docomuntal de 26 min. En espaniol e ingl6s. Video Data Bank, 37 South Wabash Ave. Chicago, IL 60603. Telefono: (312) 899-5172. Libro Sobre Derechos de PCS. AIDS legal Rights Handbook. P6ngase en contacto con NGRA, 540 Castro St., San Francisco, CA 94114. Mujer Imagen de Vida c/o WORLD P.O. Box 11535, Oakland CA 94611. Tel6fono: (415) 658-6930. Una revista publicada cada tres meses por y para las mujeres con VIH. Es una publicaci6n hermana de WORLD. Es gratis, pero se aceptan donaciones. Pacto Latino. Un boletin en ingl6s y espaniol pos PACTO, un programa para latinos afectados con el VIH/SIDA. El peri6dico se publica cuatro veces al afio. P6ngase en contacto con PACTO, P.O. Box 84027, San Diego, CA 92138. Tel6fono: (619) 294-6622 or (619) 692-2077. Que es un Virus? Un libro para nifios que explica VIH y SIDA. Por David Sasller y Kelly McQuee. Traducido del ingl6s. Publicado por Waterfront Books, 98 Brooks Avenue, Burlington, VT 05401. Ord6nalo de Lambda Rising Bookstore, Washington, D.C. 1-800-621-6969. Quipui. Un boletin nacional de educaci6n y infomaci6n sobre VIH/SIIDA. En espaflol, publicado trimestralmente. Pongase en contacto con Rhode Island AIDS project/AIDS, 95 Chestnut St., 3rd floor, Providence, RI 02903-4161. Tel6fono: (401) 831-5522. SIDAmerica. Informaci6n sobre el SIDA en las Americas. P6ngase en contacto con The Panos Institute, Inc. 1717 Massachusettes Ave., NW, Suite 301, Washington, DC 20036. Tel6fono: (202) 483-0044. SIDAahora. El prop6sito de SIDAahora es el de presentar a la comunidad hispana viviendo con VIH y/o SIDA, informaci6n sobre tratamientos, complicaciones y otros temas relacionados con el SIDA. SIDAahora acepta contibuciones de articulos, dibujos, fotografias y otros trabajos escritos y graficos para ser publicados en la revista. Los mismos deben ser enviados a: SIDAahora PWAC/NY, 50 West 17th Street, 8th Floor, New York, NY 10011. (212) 647-1419. 222 222

Page  223 AIDS/HIV Treatment Directory, Vol. 8, No. 3, January 199; SIDAvances. Publicacidn del Instituto del SIDA de San Juan. P6ngase en contacto con Advance Community Health Services, Inc., Ave. Ponce de Le6n, Edif. Banco de Ponce, oficina 711, Santurse, Puerto Rico, 00907. Hospital Municipal. Telefono: (809) 725 0320. Sociedady SIDA. Queretaro 219-H, Col. Roma, Mexico, D.F., 06700. Mexicana. Telefono: (5) 564-5579. Otros fuentes de informaci6n sobre las pruebas clinicas en su area podrian incluir: * Clinicas locales y grupos de servicios para el SIDA/VIH. * Centros medicos locales (particularmente los departmentos de enfermedades infectuosas, oncologia y hematologia). * Departmentos de salud locales y estatales. 223

Page  224 Glossary GLOSSARY ABSOLUTE CD4+ CELL COUNT (T4 Count): The number of T helper cells (lymphocytes) in a cubic millimeter of blood. Normal range for adults is 800-1200. The CD4+ cell count is significantly lower in people whose immune system has been affected by HIV. ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS): The late manifestations of infection with the human immunodeficiency virus (HIV). The Centers for Disease Control and Prevention lists numerous opportunistic infections and neoplasms which, in the presence of HIV infection, constitute an AIDS diagnosis. In addition, a CD4 count below 200/mm3(when the risk of Ois markedly increases) in the presence of HIV infection constitutes an AIDS diagnosis. ACROMEGALY: A chronic disease caused by excessive secretion of growth hormone from the pituitary gland. It is characterized by enlargement of many parts of the skeleton, especially the nose, ears, jaws, fingers, and toes. ACTG: See AIDS Clinical Trials Group ACTIVE IMMUNITY: Immunity produced by the body in response to stimulation by a disease-causing organism or other antigen, as in a vaccine. ADENOPATHY: Enlargement of glands, especially the lymph nodes. ADJUVANT: Any substance that enhances the immune-stimulating properties of an antigen or the pharmacologiceffect of a drug. ADMINISTRATION (route of administration): How a drug or therapy is introduced into the body (e.g. intravenously, or orally). ADVERSE REACTION: Any undesirable effect of a medication. ADVERSE EXPERIENCE (A.E.): Any undesirable event that occurs while under treatment, whether due to medication, disease, or other reasons. AEROSOLIZED A form of administration in which a drug, such as pentamidine, is turned into a fine spray or mist by a nebulizer, and inhaled. AFEBRILE Without a fever. AGAMMAGLOBULINEMIA A total or near total absence of immunoglobulins,or antibodies in the blood. AIDS CLINICAL TRIALS GROUP (ACTG): A network of medical centers, supported by the National Institute of Allergy and Infectious Disease, that conducts multi-center trials of treatments for AIDS/HIV and opportunisticinfections. AIDS DEMENTIA COMPLEX (ADC): A degenerative neurological condition, generally attributed to HIV disease, with a wide variety of clinical presentations including loss of coordination, mood swings and loss of inhibitions, and widespread cognitive deficit. ALKALINE PHOSPHATASE: An enzyme measurement that indicatesthe health of the liver. ALOPECIA: Hair loss ALUM: An odorless, colorless, crystalline substance used as a topical application. ALVEOLAR: Pertaining to the alveoli sac, the site of gas exchange in the lungs. AMEBIASIS: Infection with amebas, especially Entameba histolytica. AMINO ACID: Any one of 20 or more organic acids that are the building blocks of proteins, necessary for metabolism and growth. AMNIOCENTESIS: A procedure in which a hollow needle is inserted into the uterus of a pregnant female to obtain amniotic fluid. AMYLASE: A digestive enzyme secreted by the pancreas into the small intestine and by the parotid gland (into the saliva). High levels in the blood may indicate pancreatic damage. ANABOLIC STEROIDS: Muscle or weight-building steroids. ANALOG (ANALOGUE): A chemical compound with a structure similar to that of another but differing from it in respect to a certain component; it may have a similar or different action metabolically. ANAMNESTIC RESPONSE The heightened immunologic reaction elicited by a second or subsequent exposure to a particularpathogenicmicroorganismor antigen. ANAPHYLACTIC SHOCK: A life-threatening allergic reaction characterized by a swelling of body tissues (including the throat) and a sudden decline in blood pressure. ANEMIA: When blood is deficient in red blood cells or hemoglobin. ANERGIC: The state of being so immunologically suppressed that one is unable to produce cutaneous delayed type hypersensitivity reaction (DTH) to antigenic skin tests. Such persons will usually not test positive for TB on a PPD test even if they have been infected. ANGIOMATOSIS: A condition characterised by the formation of a tumor that is composed chiefly of blood or lymphatic vessels. ANOREXIA Lack or complete loss of appetite for food. ANTI-IDIOTYPE An antibody that recognizes and binds to another antibody (idiotype). ANTI-NEOPLASTIC Inhibiting or preventing the proliferation of tumor (cancer) cells. ANTIBIOTIC: A chemical substance that kills bacteria or inhibits its growth; antibiotics are used to treat infectious diseases. ANTIBODIES: Molecules in the blood or bodily secretions that tag, destroy or neutralize bacteria, viruses, or other harmful toxins. They are members of a class of proteins known as immunoglobulins, which are produced and secreted by B-lymphocytes in response to stimulation by antigens. ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC): An immune response in which antibodies bind to target cells, identifying them for attack by the immune system. ANTIEMETIC: An agent that prevents vomiting. ANTIFOLATE: An agent that inhibits intracellular production of folinic acid. ANTIGEN: A substance that, when introduced into the body, is capable of inducing the production of a specific antibody. ANTIGENEMIA: The presence of antigen in the blood. 224

Page  225 AIDS/HIV Treatment Directory; Vol. 8, No. 3; January 199i 7 ANTIOXIDANT A substance that inhibits oxidation or reactions promoted by oxygen or peroxides. Antioxidant nutrients are thought to protect human cells from damage. ANTIRETROVIRAL A substance, drug, or process that destroys a retrovirus or inhibits its replication. Often used to describe a drug active against HIV. ANTITOXINS: Antibodies that recognize and inactivate toxins produced by certain bacteria, plants or animals. ANTIVIRAL A substance or process that destroys a virus or suppresses its replication. ARC (AIDS Related Complex): An outmoded term to describe patients with some HIV-related symptoms but no AIDS-defining diagnoses. These may include recurrent fevers, unexplained weight loss, swollen lymph nodes, and/or fungus infection of the mouth and throat. Also commonly described as symptomatic HIV infection. ARRHYTHMIA Abnormal heart rhythm. ARTHRALGIA: A pain in a joint. ASPERGILLOSIS A fungal infection resulting from Aspergillus it is also known as aspergillomycosis. ASYMPTOMATIC: Without symptoms. ATTENUATED VIRUS: A weakened virus with reduced ability to infect or produce disease. Some vaccines are based on attenuated viruses. AUTOANTIBODY: An antibody directed against the body's own tissue. AUTOIMMUNIZATION The induction in an individual of an immune response to its own cells (tissue). AUTOLOGOUS: Pertaining to the same organism or one of its parts; originatingwithin an organism itself. AZOLES: A class of antifungal drugs (fluconazole, itraconazole, ketoconazole, etc.) That are used to treat fungal infections, including candidiasiis, cryptococcosis, histoplasmosis,etc. AZOTEMIA: an excess of urea or other nitrogen-containing compounds in the blood. B CELL LYMPHOMA: A malignancy of the B lymphocytes. B-LYMPHOCYTES (B-cells): One of two major classes of lymphocytes. During infections, these cells are transformed into plasma cells that produce large quantities of antibody directed at a specific pathogen. This transformation occurs through interactions with various types of T cells and other components of the immune system. B CELLS: See B-Lymphocytes. BACTERICIDAL: Capable of killing bacteria. BACTERIOSTATIC: Capable of inhibiting reproduction of bacteria. BACTERIUM: A microscopic organism composed of a single cell. Many bacteria can cause disease in humans. BASELINE CHARACTERISTICS A variable that is measured, observed or assessed in a patient at the beginning of a trial, prior to the initiation of treatment. BASOPHIL A type of white blood cell, also called a granular leukocyte, filled with granules of toxic chemicals, that can digest microorganisms. Basophils are responsible for the symptoms of allergy. BCG VACCINE (bacille Calmette-Guerin vaccine): A tuberculosis vaccine made from an attenuated live strain of M. bovis. It is contra-indicated in HIV-infected people. bDNA (BRANCHED DNA ASSAY): A test using for measuring the number of HIV fragments in the blood of people with HIV. The test quantifies HIV-RNA using a methodology that differs from polymerase chain reaction (PCR). BILIRUBIN: A bile pigment measurement that indicates the health of the liver. BIOAVAILABILITY The rate and extent to which a substance is absorbed and circulated in the body. BIOLOGICAL RESPONSE MODIFIERS (BRMs): Substances, either natural or synthesized, that boost, direct, or restore normal immune defenses. BRMs include interferons, interleukins, thymic hormones and monoclonal antibodies. BIOPSY: Removal and laboratory examination of tissue from the living body. BIOSYNTHESIS The building up of a chemical compound in the physiologic processes of a living organism. BIOTECHNOLOGY The use of living organisms or their products to make or modify a substance. These include recombinant DNA techniques (genetic engineering) and hybridoma technology to create monoclonal antibodies used as therapies. BLOOD-BRAIN BARRIER The barrier between brain blood vessels and brain tissues whose effect is to restrict what may pass from the blood into the brain. BODY FLUIDS: Term used for a number of fluids manufactured within the body. Usually used when referring to semen, blood, urine and saliva. BONE MARROW: Soft tissue located in the cavities of the bones where blood cells are formed, including erythrocytes, leukocytes and platelets. BREAKTHROUGH See "TREATMENT FAILURE" BRONCHI: The hollow branches in the lungs that connect the trachea to the alveoli. BRONCHOSCOPY: Visualization of the trachea and lungs with flexible fiber optics. CACHEXIA General weight loss and wasting. CANDIDA A yeast-like fungus, commonly found in the normal flora of the mouth, skin, intestinal tract and vagina. In immune compromised people it can cause infections including thrus and esophogeal disease. CANDIDIASIS An infection with a fungus of the Candida family, generally C. albicans CARCINOGEN Any cancer-producing substance. CARDIOMYOPATHY: A degenerative condition of the heart muscle, cardiomyopathy may be caused by HIV, other viruses, or by some drugs. CASE-CONTROL STUDY: A study that involves the identification of persons with the disease or condition of interest (cases) and an otherwise comparable group of persons without the disease or condition of interest (controls). Cases and controls are then compared with respect to some current or past attribute or exposure that may be causally related to the disease or condition. CATHETER: A tube used to inject or drain fluids from the body. A semi-permanently installed venous catheter may be placed to deliver intravenous medictions or nutrients on a chronic basis. 225 I

Page  226 Glossary CD4: (T4) A protein embedded in the cell surface of helper T-lymphocytes; also found to a lesser degree on the surface of monocyte/macrophage, Langerhans cells, astrocytes, keratinocytes, and glial cells. HIV invades cells by first attaching to the CD4 molecule (CD4 receptor). CD8: (T8) A protein embedded in the cell surface of suppressorand killer T-lymphocytes. CELL-MEDIATED IMMUNITY (CMI): See cellular immunity. CELL LINES: Specific cell types artificially maintained in the laboratory ("in-vitro") for scientific purposes. CELLULAR IMMUNITY: The branch of the immune system that relies primarily upon specific defense cells rather than antibodies. See also: humoral immunity. CENTRAL NERVOUS SYSTEM: Composed of the brain, spinal cord, and its coverings (meninges). CEREBRAL: Pertaining to the cerebrum, which is the main portion of the brain. CERVICAL DYSPLASIA The development of abnormal tissue on the cervix, the outlet of the uterus; may progress to cancer. CERVIX The cylindrical, lower part of the uterus leading to the vagina. CHELATE: A chemical that reacts with metallic ions, used to treat metal poisoning. CHEMOPROPHYLAXIS Prevention of disease by chemical means. CHEMOTHERAPY: The treatment of disease by chemical agents; usually refers to cancer treatment. CHRONIC: Referring to a process, such as a disease process, that persists over a long period of time; in contrast to acute. CIDP: Chronic idiopathicdemyelinating polyneuropathy. CIRCULATING IMMUNE COMPLEXES (CIC): See Immune Complex. CLINICAL TRIAL: A study in people that evaluates medications or medical procedures. CLINICAL: Pertaining to or founded on actual observation and treatment of patients, as distinguished from theoretical or basic science. CLONE: A group of genetically identical cells or organisms descended from a common ancestor. CLOSTRIDIUM DIFFICILE (C. DIFFICILE): A normal gastrointestinal tract bacteria that is resistant to many antibiotics. Antibiotics can cause overgrowth of C. difficile, which may lead to serious abdominal infection and bleeding. CNS (Central Nervous System): Composed of the brain, spinal cord, and their coverings (meninges). CO-FACTORS: Substances, microorganisms, or characteristics of individuals that may influence the progression of a disease or the likelihood of becoming ill. COCCIDIOIDOMYCOSIS:A fungal disease that results from infection with Coccidioidesimmitis. CODON: A sequence of three nucleotides of messenger RNA that specifies addition of a particularamino acid to, or termination of, a polypeptide chain during protein synthesis. COHORT: In epidemiology, a group of individuals with some characteristicin common. COLITIS: Inflammation of the colon. COLON: A division of the intestine where solid waste is compacted into feces, extending from the cecum to the rectum; also called the large intestine. COLONIZATION Residence of bacteria in, or on, part of the body and causing neither disease nor a response by the individual's immune system. COLORECTAL Relating to the colon and rectum, or to the entire large bowel (large intestine). COLPOSCOPY A type of examination of a living tissue surface, under magnification, to identify location and extent of lesions. COMMUNITY-BASED CLINICAL TRIAL (CBCT): A clinical trial conducted primarily by primary-care physicians, rather than in academic research facilities. COMPASSIONATE USE: A method of providing experimental drugs to very sick patients who have no other treatment options. Often, case-by-case approval must be obtained from the FDA for "compassionate use" of a drug. COMPLEMENT CASCADE: A precise sequence of events, usually triggered by an antigen-antibody complex, in which each component of the complement system is activated in turn. COMPLEMENT: A group of proteins in normal blood serum and plasma that, in combination with antibodies, causes the destruction of antigens (particularly bacteria and foreign blood corpuscles). COMPUTED TOMOGRAPHY (CAT/CT SCAN): A computer aided imaging that assembles multiple X-rays of "slices" of the body to produce a three dimensional picture. CONCOMITANT DRUGS: Drugs that are taken together. Certain concomitant medications may have adverse interactions. CONFIDENCE INTERVAL A range in which there is a specified degree of assurance that the value of a given parameter can be found. CONTAGIOUS: Any infectious disease capable of being transmitted by casual contact from one person to another. CONTRAINDICATION ("to indicate against'): A specific circumstance when the use of certain treatments could be harmful. CONTROLLED 1. Constrained, monitored, or watched. 2. A system of observation and data collection that provides a basis for comparison, as with a comparison group. CORE PROTEIN: An integral component of HIV composed of three sub-units: p24, p15, and p1 8. CORTICOSTEROIDS Any of a number of steroid substances obtained from the cortex of the adrenal gland or manufactured synthetically. CREATININE: A protein found in muscles and blood and excreted by the kidneys in the urine. The level of creatinine in the blood and urine provides a measure of kidney function. CROSSOVER When a study participant changes from one assigned treatment to another assigned treatment. CRYPTOCOCCOSIS A fungal disease that results from infection with the fungus Cryptococcus neoformans, which is acquired via the respiratorytract. CRYPTOCOCCUS NEOFORMANS: A fungus, pathogenic in the immune-suppressed, which is acquired via the respiratorytract. Cryptococcosismost frequently causes meningitis, with symptoms of headache and stiff neck. CRYPTOSPORIDIOSIS An opportunistic infection of the intestines caused by a protozoan parasite (Cryptosporidiumparvum). CT: Computed Tomography (CAT Scan) 226

Page  227 AIDS/HIV Treatment Directory; Vol. 8, No. 3; January 199 7 CULTURE: The process of growing bacteria or other microorganisms in the laboratory, often for use in diagnostic studies. CUTANEOUS: Of, pertaining to or affecting the skin. CYLINDRURIA The presence of tube casts in the urine. CYTOKINES: Soluble, hormone-like substances, produced and secreted by lymphocytes and monocytes/macrophages, which act as inter-cellular messengers. CYTOMEGALOVIRUS (CMV): A herpes virus that is a common cause of opportunistic diseases in people with AIDS and other people with immune suppression. While CMV can infect most organs of the body, people with AIDS are most susceptibleto CMV retinitis and colitis. CYTOPENIA: Decrrease in the cellular elements of the blood. CYTOTOXIC: An agent or process that is toxic to cells that results in suppression of function or cell death. CYTOTOXIC T LYMPHOCYTE: (CTL) A lymphocyte that is able to kill foreign cells that have been marked for destruction by the cellular immune system; primarily CD8+ T cells. DELAYED-TYPE HYPERSENSITIVITY (D.T.H.): A cell-mediated immune response that produces a cellular infiltrate and edema (swelling), redness and in duration (hardness) between 48 and 72 hours after exposure to an antigen. DTH response is the basis for PPD testing of tuberculosis exposure. DEMENTIA Chronic intellectual impairment (loss of mental capacity) with organic origins that affects a person's ability to function in a social or occupational setting. DEMYELINATION: Destruction, removal, or loss of the myelin sheath of a nerve or nerves. See also MYELIN. DENDRITIC CELL: Bone-marrow derived immune cells found throughout the body. When exposed to antigen, these cells migrate to the lymphoid tissues and function as potent antigen-presenting cells. DESENSITIZATION The reduction or abolition of allergic sensitivity or reactions to the specific antigen (allergen). DIAGNOSIS: The determination of the presence of a specific disease or infection, usually accomplished by evaluating clinical symptoms and laboratory tests. DIARRHEA: Abnormally high frequency and liquidity of fecal discharges. DIPLOPIA: Double vision. DISSEMINATED: Spread throughoutthe body. DISSEMINATED Spread throughoutthe body. DNA: (Deoxyribonucleic Acid): A complex molecule that is the carrier of genetic information. HIV can insert itself into a cell's DNA and use cellular mechanisms for replication. DORMANCY: See latency. DOUBLE BLIND: A clinical-trial design in which neither the participating patients or doctors know which patients are receiving the experimental drug and which are receiving placebo or another therapy. Double-blind trials help to produce objective results, since the doctor's and patient's expectations about the experimental drug are less likely to affect the outcome. DYSMENORRHEA Difficult and painful menstruation. <B%-2>DYSPLASIA<D>: The abnormal development of tissue. In disease, the alteration of size, shape and organization of adult cells.<%0> DYSPNEA: Difficultor labored breathing. ECHOCARDIOGRAPHY The use of ultrasound in the investigation of the heart and great vessels for diagnosis of cardiovascularlesions. ED50: Short for "Effective dose 50;" the dosage of a drug or poison that kills, or stops replication in 50 percent of the organisms it is tested against in a culture. EDEMA: Swelling due to increased extracellularwater. EFFICACY: Effectiveness. EIA (Enzyme Immunoassays): see ELISA. ELISA (Enzyme linked immunosorbent assay): A laboratory test to determine the presence of specific antibodies in blood that indicates infection, such as with HIV. Also see: Western Blot. ENCEPHALITIS A general term denoting inflammation of the brain. ENCEPHALOPATHY: Lesions in the brain, or general degeneration of brain matter. ENDEMIC: Pertaining to diseases associated with particular locales or population groups. ENDOCRINE Relating to the internal secretion of hormones into systemic circulation. ENDOGENOUS: Relating to or produced by the body. ENDOMYOCARDIAL BIOPSY: Removal of tissue from the innermost layer of the heart muscle for laboratory examination. ENDOSCOPY Viewing the inside of a body cavity with a device using flexible fiber optics. ENDOTOXIN: A toxin present inside a bacterial cell. ENDPOINT A primary or secondary outcome variable used to judge the effectiveness of a treatment. ENTERAL: Within or by way of the intestine or gastrointestinaltract. ENTERIC: Pertaining to the intestines. ENTERITIS: Inflammation of the intestine. ENVELOPE In virology, a protein covering that packages the virus' genetic information. The HIV envelope is composed of two units: gp120 and gp41. gp120 is the portion of HIV that binds to a helper T cell's surface protein, CD4. ENZYME: A protein that makes chemical reactions proceed at a faster rate, without itself being consumed in the reaction. EOSINOPHIL A type of white blood cell, called a granulocyte, that can digest microorganisms, usually parasites. EPIDEMIOLOGY A discipline concerned with the determination of the specific causes or distribution of a disease or the interrelation between various factors determining a disease. EPITOPE: A unique shape or marker carried on an antigen's surface that triggers a corresponding antibody response. EPSTEIN-BARR VIRUS (EBV): A herpes-like virus that causes one of the two kinds of mononucleosis(the other is caused by CMV). It infects the nose and throat and is contagious. EBV usually lies dormant in the lymph glands and has been associated with Burkitt's lymphoma and hairy leukoplakia. ERYTHEMATOUS: Red or reddened. ERYTHROCYTES: Red blood cells. The primary function of erythrocytes is to carry oxygen to cells. ETIOLOGY: The study or theory of factors that cause disease. EXOGENOUS: Developed or originating outside the body. EXOTOXIN: A toxic substance made by bacteria that is released outside the bacterial cell. 227

Page  228 Glossary EXPANDED ACCESS: A general term for methods of distributing experimental drugs to patients who are unable to participate in ongoing clinical efficacy trials and have no other treatment options. Specific types of expanded-access mechanisms include parallel track, Treatment IND, and compassionate use. EXTRAPULMONARY Outside the lungs. FEASIBILITY STUDY: A preliminary study designed to determine the practicality of a larger study. See "PILOT STUDY." FEBRILE With a fever. FIRST-LINE THERAPY: The preferred therapy for a particularcondition. FLORA Plant life; the population of microorganisms inhabiting internal or external surfaces. FLOUROQUINOLONES A family of antibiotics, including ciprofloxacin, ofloxacin, and sparfloxacin. FOLATE: A salt or ester of folic acid, a crystalline vitamin of the B complex. FOLLICULAR DENDRITIC CELL (FDC): Cells found in the lymphoid tissue that present antigen to B cells, stimulating the B-cell memory (antibody) response of the immune system. FOLLICULITIS An infection or inflammation of the follicle, at the root of a hair. FOMITE: An object that can harbor pathogenic microorganisms, and thus serve as an agent of transmission of an infection. FUNDOSCOPIC EXAM: Visual inspection of the interior of the eye. Often used to diagnose CMV retinitis. FUNGICIDAL A substance that kills a fungus. FUNGUS: A general term used to denote a class of microbes including mushrooms, yeasts and molds. G-CSF (GRANULOCYTE-COLONY STIMULATING FACTOR): A cytokine that stimulates the growth of granulocytes, a type of white blood cell. It is marketed as a medicine to alleviate the neutropenia that is a side effect of certain drugs. GALLIUM SCAN: A diagnostic procedure where mildly radioactive gallium particles are injected, and inflammatory disease processes (often Pneumocystis carinii pneumonia) is diagnosed by scanning the body for radioactive signature. Also used to detect B cell lymphomas. GANGLION: A mass of nervous tissue, composed principally of nerve-cell bodies, usually lying outside the central nervous system. GASTRIC: Relating to the stomach. GASTROINTESTINAL Relating to the stomach and intestines. GASTROSTOMY TUBE: A tube inserted into the stomach via a surgically created artificial opening. GENE: A unit of DNA that carries information for the bio-synthesis of a specific product. GENOME: One set of chromosomes containing the complete genetic makeup of an organism. GIARDIASIS: A common protozoal infection of the small intestine spread via contaminated food and water and direct person-to-person contact. GM-CSF (GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR): A cytokine that stimulates the growth of granulocytes and macrophages. Like G-CSF, GM-CSF is marketed to alleviate neutropenia but has more side effects. GONORRHEA A sexually transmitted disease; inflammation of genital mucous membranes caused by the bacteria gonococcus GP-120: See envelope. GP-41: See envelope. gp160: The "precursor' protein to both gp41 and gp120 components of the envelope of HIV. It is cleaved by viral enzymes into the two surface proteins at a late stage of viral assembly. GRANULOCYTES: A cell type of the immune system filled with granules of toxic chemicals that enable them to digest microorganisms. Basophils, neutrophils, and eosinophils, are examples of granulocytes. GROSCHUNG CATHETER An indwelling line inserted into the large veins of the chest, used for administering medication and total parenteral nutrition over long durations. Also see "HICKMAN CATHETER." GROWTH FACTOR: A substance that promotes the growth of specific cells. GROWTH HORMONE: A pituitary hormone that regulates growth. Human growth hormone is being used experimentally in wasting syndromes associated with cancer, burns and HIV. GUILLIAN-BARRV SYNDROME: An acute febrile polyneuritis. HAIRY LEUKOPLAKIA A whitish, slightly raised lesion that appears on the side of the tongue. Thought to be related to Epstein-Barr virus infection, it was not observed before the HIV epidemic. HELPER T CELLS (T4, CD4): A subset of T cells that carry the CD4 receptor that are essential for activating antibody production, cytotoxic T cells, and other immune responses. HELPER-SUPPRESSOR RATIO: The ratio of helper (CD4+) T-cells to suppressor(CD8+) T-cells. HEMATOCRIT: A laboratory measurement that determines the percentage of packed red blood cells in a given volume of blood. HEMATOLOGIC Pertaining to, or involving the blood, or its constituent cells. HEMATOPOIETIC Pertaining to the the formation of blood cells. HEMATOTOXIC: Poisonousto the blood or bone marrow. HEMOGLOBIN The component of red blood cells that carries oxygen. HEMOLYSIS: The rupture of red blood cells. HEMOPHILIA An inherited disease that prevents the normal clotting of blood. HEPATIC: Pertaining to the liver. HEPATITIS: Inflammation of the liver. HEPATITIS C: A viral disease that causes inflammation of the liver and may cause severe, life-threatening liver damage; formally known as "non-A non-B hepatitis." HEPATITIS B: A viral liver disease that can be acute or chronic and even life-threatening, particularly in people with weakened immune systems. Can be transmitted by sexual contact, contaminated needles or contaminated blood or blood products. HERPES VARICELLA ZOSTER VIRUS (HVZ or VZV): The varicella virus causes chicken pox in children and may reappear in adulthood as herpes zoster. Herpes zoster, also called shingles, consists of very painful blisters on the skin that follow nerve pathways. 228 I

Page  229 AIDS/HIV.Treatment Directory; Vol. 8, No. 3; January 1997 r HERPES SIMPLEX VIRUS II (HSV II): A virus causing painful sores of the anus or genitals that may lie dormant in nerve tissue and can be reactivated to produce the symptoms. HSV II may be transmitted to a neonate during birth from an infected mother. HERPES SIMPLEX VIRUS I (HSV I): A virus that causes cold sores or fever blisters on the mouth or around the eyes and can be transmitted to the genital region. The latent virus can be reactivated by stress, trauma, other infections or suppression of the immune system. HHV-6 (HUMAN HERPESVIRUS-TYPE 6): A herpesvirus that preferentially infects CD4+ and CD8+ T lymphocytes. It is widespread, and is beinginvestigated as a possible co-factor for HIV disease progression. HHV-8 (HUMAN HERPESVIRUS-TYPE 8): A newly identified herpesvirus implicated in the development of Kaposi's sarcoma. HICKMAN CATHETER An indwelling line inserted into the large veins of the chest, used for administering medication and total parenteral nutrition over long durations. Also see "GROSCHUNG CATHETER." HISTOCOMPATIBILITY TESTING: A method of matching the self antigens (HLA) on the tissues of a transplant donor with those of a recipient. The closer the match, the better the chance that the transplant will not be rejected. HISTOPLASMOSIS: A fungal disease resulting from infection with Histoplasma capsulatum. HIV-2: See Human ImmunodeficiencyVirus Type 2. HIV-1: See Human ImmunodeficiencyVirus Type 1. HORMONE: An active regulatory chemical substance formed in one part of the body and carried by the blood to another part of the body, where it signals the coordination of cellular functions. HOST: A cell or organism that supports the growth of a parasite or virus. HTLV-1 (HUMAN T CELL LYMPHOTROPIC VIRUS-TYPE 1): A retrovirus with an affinity for T-lymphocytes, which appears to be the causative agent of certain T cell leukemias and T cell lymphomas. HUMAN PAPILLOMAVIRUS (H.P.V.) A member of the papova family of viruses. HPV causes warts or nipple-like protrusions. HPV has also been associated with cervical cancer in women and anal cancer HUMAN IMMUNODEFICIENCY VIRUS TYPE 2 (HIV-2): A virus closely related to HIV-1 that has been found to cause immune suppression. Most common in Africa. HUMAN LEUKOCYTE ANTIGENS (HLA): Markers that identify cells as "self and prevent the immune system from attacking them. HUMAN IMMUNODEFICIENCYVIRUS TYPE I (HIV-1): The retrovirus isolated and recognized as the etiologic agent of AIDS. HIV-1 is classified as a lentivirus in a subgroup of the retroviruses. HUMORAL IMMUNITY: The branch of the immune system that relies primarily upon antibodies. See also: cellular immunity. HYPERSENSITIVITY Abnormal sensitivity; medically, when the body responds in an exaggerated manner to a foreign agent; allergy. HYPERURICEMIA: Excess of uric acid or urates in the blood; it precedes the development of gout and may lead to renal disease. HYPOGAMMAGLOBULINEMIA Abnormally low levels of immunoglobulins. HYPOXIA: Reduction of oxygen supply to tissue. IDIOTYPES: The unique and characteristic parts of an antibody's variable region, which can themselves serve as antigens. IMMUNE RESPONSE The activity of the immune system against foreign substances. IMMUNE SYSTEM: The complex functions of the body that recognize foreign agents or substances, neutralize them, and recall the response later when confronted with the same challenge. IMMUNE DEFICIENCY: A breakdown or inability of certain parts of the immune system to function, making a person susceptible to certain diseases which they would not ordinarily develop. IMMUNE COMPLEX Clusters formed when antigens and antibodies bind together. IMMUNITY: A natural or acquired resistance to a specific disease. Immunity may be partial or complete, long lasting or temporary. IMMUNOCOMPETENT Possessing a normal immune system. IMMUNOGLOBULIN See antibodies. IMMUNOMODULATOR Any substance that influences the immune system. IMMUNOSTIMULANT Any agent or substance that triggers or enhances the body's defenses; also called immunopotentiators. IMMUNOSUPPRESSION A state of the body in which the immune system is damaged and does not perform its normal functions. Immunosuppression may be induced by drugs or result from certain disease processes (such as HIV infection). IMMUNOTHERAPY: Treatment aimed at improving impaired immune function. IMMUNOTOXIM A monoclonal antibody linked to a toxic drug or a radioactive substance. IN UTERO: Latin for "in the uterus," or womb. IN VIVO ("in life"): Studies conducted within a living organism, e.g., animal or human studies. IN VITRO ("in glass"): An artificial environment created outside a living organism, e.g., a test tube or culture plate, used in experimental research to study a disease or process. INCIDENCE The number of new cases of a disease that develop in a population during a specific period of time. INCUBATION PERIOD: The time interval between the initial exposure to infection and appearance of the first symptom or sign of disease. INDUCED SPUTUM: A test where saline mist is inhaled to induce a cough. Resultant sputum (mucous expectorated from the air passages) is cultured or stained to look for microorganisms. INDUCTION The initiation of a particulartherapy. INFECTION The state or condition in which the body (or part of it) is invaded by an infectious agent. When it multiplies and produces an injurious effect it is called an active infection. INFECTIOUS Capable of being transmitted by infection, with or without actual contact. INFORMED CONSENT: Protection required for people considering entering a clinical trial. Before entering the trial, participants must sign an informed-consent statement that acknowledges that they understand important information about the trial, including possible risks, benefits, and alternatives. 229

Page  230 Glossary INSTITUTIONAL REVIEW BOARD (IRB): A committee of physicians, statisticians, community advocates and others that ensures that a clinical trial is ethical and that the rights of the study participants are protected. All clinical trials in the United States must be approved by an IRB before they begin. INTENT-TO-TREAT ANALYSIS: A statistical method for data analysis in which outcome data are compared among the originally randomized groups, regardless of whether or not patients continued to take their assigned therapy. INTERFERON One of a family of proteins, some of which are secreted by virus-infected cells. There are three classes: alpha-, beta-, and gamma-intererons; the former two inhibit virus replication in uninfected cells. INTERFERON A general term used to describe a family of 20-25 proteins that cause a cell to become less susceptible to a wide variety of viruses. They are produced by cells infected by almost any virus. INTERLEUKIN A chemical hormone messenger (cytokine) secreted by and affecting many different cells in the immune system. INTERLEUKIN 2 (IL-2): A cytokine that is produced by T helper and suppressor lymphocytes following recognition of certain antigens. IL-2 activates growth of T lymphocytes and enhances natural killer cell function. IL-2 synthesis and release is characteristic of a cell-mediated, or TH-1 immune response. INTRAMURAL Research that is done at the National Institutes of Health, often within the NIH clinical research facility. INTRAMUSCULAR Into the muscle; frequently in reference to injections. INTRATHECAL: Injection of a substance through the theca of the spinal cord into the subarachnoid space. INTRAVENOUS: Within a vein. INTRAVITREAL: Within the eye. INVESTIGATIONAL NEW DRUG APPLICATION (I.N.D): An application submitted to the Food and Drug Administration for permission to test a new drug or an old drug for a new indication in humans.<B%0> ISOMER: A compound exhibiting or capable of exhibiting isomerism. ISOMERISM: The relationship that exists between two or more different chemical compounds that have the same molecular formula. ISOSPOROSIS A protozoal infection, usually restricted to the lower gastrointestinaltract. ITP (immune thrombocytopenic purpura): A condition in which the body produces antibodies against the platelets, components of the blood that are responsible for blood clotting, resulting in low platelet counts and easy bleeding. ITP is common in HIV-infected people. JAUNDICE Yellowish discoloration of the skin and eyes due to bilirubin. Usually associated with some form of liver damage or malfunction. JC VIRUS: A virus that is believed to be the cause of the neurological disease progressive multifocal leukoencephalopathy(PML). KAPLAN-MEIER CURVE: A way of graphing outcomes (e.g., number still alive or free of infection) against time; in clinical trials life table curves show the percent of people in each treatment group free of a specific event at times following randomization. KAPOSI'S SARCOMA (KS): A tumor of the wall of blood vessels, or the lymphatic system. Usually appears as pink to purple, painless spots on the skin but may also occur internally(such as in the lungs and intestines). KAPOSI'S SARCOMA HERPES VIRUS (KSHV): See HHV8 KARNOFSKY SCORE: A subjective score between 0-100, assigned by a physician to describe a patient's ability to function and perform common tasks. Normal functioning is scored as 100. KILLER T CELL: See cytotoxic T lymphocyte. KINASE: An enzyme that mediates the conversion of a proenzyme to an active enzyme. Natural nucleosides and drug analogues (such as AZT, acyclovir, ddC, etc.) must be phosphorylatedto become biologically active. KUPFFER CELLS: Specialized macrophages in the liver. LAK CELLS: Lymphocytes transformed in the laboratory into lymphokine activated killer cells, which attack tumor cells. LANGERHANS CELLS: Dendritic cells in the skin that pick up antigen and transport it to the lymph nodes. LAS (Lymphadenopathy Syndrome): A chronic enlargement of lymph nodes, often associated with HIV infection. LATENCY: The period when an organism is in the body and not producing any ill effects. LAV: (LymphadenopathyAssociated Virus): See HIV. LAVAGE: Washing. LEGIONELLA PNEUMOPHILAE An ubiquitous bacteria causing pneumonia, also known as "legionnaire's disease." Most exposure is from tap water, often aerosolized by a shower head or air conditioner. LENTIVIRUS: A sub-family of retroviruses that is cytopathic and causes chronic diseases. HIV is a type of lentivirus. LESION: A general term to describe an area of altered tissue; the infected patch or sore in a skin disease. LEUKOCYTES: All white blood cells. LEUKOPENIA A lower than normal level of leukocytes in the blood. LIPOSOMES: A spherical particle in an aqueous (water) medium, formed by a lipid bilayer enclosing an aqueous compartment. LUMBAR PUNCTURE: A procedure in which fluid from the subarachnoid space in the lumbar region is tapped for examination; also known as a spinal tap. LUMBAR PUNCTURE A procedure in which cerebrospinal fluid from the lower back is withdrawn with a long needle for examination; also known as a spinal tap, often abbreviated as LP. LYMPH: A transparent, slightly yellow fluid that carries lymphocytes. Lymph is derived from tissue fluids collected from all parts of the body and is returned to the blood via lymphatic vessels. LYMPH NODES: Small bean-sized organs of the immune system, distrbuted widely throughout the body. Lymph fluid is filtered through the lymph nodes in which all types of lymphocytes take up temporary residence. Antigens that enter the body find their way into lymph or blood and are filtered out by lymph nodes or the spleen respectively, for attack by the immune system. LYMPHADENOPATHY: Swollen, firm and possibly tender lymph nodes. The cause may range from a infection such as HIV, the flu, mononucleosis, or lymphoma (cancer of the lymph nodes). LYMPHATIC VESSELS: A bodywide network of channels, similar to the blood vessels, that transports lymph to the immune organs and into the bloodstream. 230

Page  231 AIDS/HIV Treatment Directory; Vol. 8, No. 3; January 199 7 LYMPHOCYTES: Cells produced chiefly by the lymphoid tissue that are the cellular mediators of immunity. See T cells and B cells. LYMPHOKINES: Non-antibody mediators of immune responses, released by activated lymphocytes. LYMPHOMA: A malignancy of cells of the lymphoid tissue. LYSIS: Rupture and destruction of a cell. MACROLIDES: A group of antibiotic drugs, such as erythromycin and azithromycin. MACROPHAGE A scavenger cell specializing in the ingestion and processing of large particulate matter, especially harmful bacteria. The macrophage may be a reservoir for HIV. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) A group of genes that control aspects of the immune response. The products of these genes, the histocompatibility antigens, are present on every cell of the body and serve as markers to distinguish self from non-self cells. MALABSORPTION SYNDROME: Decreased intestinal absorption resulting in loss of appetite, muscle pain, weight loss, and diarrhea. MALAISE: A generalized nonspecificfeeling of discomfort. MALNUTRITION: Poor nutrition resulting from inadequate diet, under eating or abnormal absorption of nutrients from the gastrointestinaltract. MAST CELL: A granulocyte found in tissue. The contents of the mast cells, along with those of basophils, are responsible for the symptoms of allergy. MEAN: The average, or the sum of the quantities divided by the number of quantities summed. MEAN CORPUSCULAR VOLUME (MCV): The average volume of erythrocytes, conventionally expressed in cubic micrometers per red blood cell. MEDIAN: The value such that for a group of numbers such that one-half are above the value, and one-half are below. MEMBRANE: A thin sheet or layer of tissue, surrounding an organ, or of lipids (fats) embedded in protein when surrounding a single cell, that serves as a semi-permeable covering. METABOLITE: Any substance produced by metabolism or by a metabolic process. METHEMOGLOBINEMIA The presence of methemoglobin, a compound formed from hemoglobin, which does not function as an oxygen carrier. MICRO-ORGANISM: See microbes. MICROBES: Microscopic living organisms, including bacteria, protozoa, and fungi. MICRONUTRIENT A trace element; an organic compound like a vitamin that is essential but only in small amounts for physical health, growth and metabolism. MICROSPORIDIOSIS: Disease resulting from infection with a protozoal pathogen from the Microsporida order. MITOGENS: Natural substances that stimulate cell division. MOLECULE A single unit of a specific substance. MONOCLONAL ANTIBODIES: Antibodies produced by a single cell or its identical progeny, specific to a given antigen. Monoclonal antibodies are useful as a tool for identifying specific protein molecules. MONOCYTE: A large white blood cell that acts as a scavenger, capable of destroying invading bacteria or other foreign material. Precursorto the macrophage. MORBIDITY: The condition of being diseased or sick; also the incidence of disease or rate of sickness. MORTALITY: Death; also death rate. MRI: Magnetic resonance imaging; a non-invasive diagnostic technique that can provide information on the form and function of internal tissue and organs of the body. MUCOCUTANEOUS Pertaining to the mucous membranes adjacent to the skin, e.g., vagina, lips, anal area. MUCOSA: Mucous membrane. MUCOSAL: Pertaining to the mucous membranes, as in mouth, vagina, rectum, etc... MUCOUS MEMBRANE: A moist layer of tissue that lines body cavities or passages that has an opening to the external world, e.g., the lining of the mouth, nostrils, or vagina. MYCOBACTERIUM AVIUM COMPLEX (MAC): A common opportunistic infection in advanced AIDS caused by two very similar mycobacterial organisms, Mycobacterium avium and M. intracellulare MYCOSIS: Any disease caused by a fungus. MYELIN: A substance that sheathes nerve cells, acting as an electrical insulator that facilitates the conduction of nerve impulses. MYELOSUPPRESSION: Impairment of the blood cell producing function of the bone marrow. MYELOTOXIC: Destructive to bone marrow. MYOPATHY: A degenerative condition of the muscles. Can be caused by both HIV, AZT, and other diseases and drugs. NATURAL KILLER CELLS: (NK cells) Large granular lymphocytes that attack and destroy tumor cells and infected body cells. They are known as "naturar' killers because they attack without first having to recognize specific antigens. NEBULIZED See aerosolized. NEBULIZER A device used to convert liquid medication into extremely fine cloud-like particles; useful in delivering medication to deeper parts of the respiratory tract (into the lungs). NECROLYSIS: Separation or exfoliation of tissue due to necrosis. NECROSIS: Cell decay and death. NEONATAL: Concerning the first weeks of life after birth. NEOPLASM: An abnormal and uncontrolled growth of tissue; a tumor. NEPHROTOXIC: Poisonous to the kidneys. NEURALGIA A sharp, shooting pain along a nerve pathway. NEUROPATHY: Any abnormal, degenerative or inflammatory state of the peripheral nervous system. NEUROPATHY, PERIPHERAL A disorder of the nerves that involves the feet or hands and sometimes the legs, arms and face. Symptoms may include numbness, a tingling or burning sensation, sharp pain, weakness and abnormal reflexes. It is a common dose-related side effect of antiretroviraldrugs ddC and d4T. NEUTRALIZATION Binding of an antibody to a microorganism resulting in elimination of the infectivity of the microorganism. NEUTROPENIA An abnormal reduction of circulating neutrophils. 231

Page  232 Glossary NEUTROPHIL (polymorphonuclear neutrophils, PMNs) A white blood cell that plays a central role in defense of a host against many infections (especially bacterial); they engulf and kill foreign microorganisms. NK CELLS: See natural killer cells. NOSOCOMIAL Infection or illness acquired in a hospital or other health care facility. NSAID: Non-steroidalanti-inflammatorydrug. NUCLEIC ACIDS: Large, naturally occurring molecules composed of chemical building blocks known as nucleotides or nucleosides. There are two kinds of nucleic acids, DNA and RNA. NUCLEOSIDE ANALOGUE: A synthetic compound similar to one of the components of DNA or RNA; a general type of anti-viral drug with structural similarities to the natural neucleosides(e.g. acyclovir and AZT). OCULAR: Pertaining to the eye. OOCYST: A stage in the life of a sporozoan marked by encapsulation. OPEN-LABEL A clinical trial in which the study physician and/or participant are not blinded to study treatment(s). In other words, both the doctor and patient know what study treatment the patient is taking. OPPORTUNISTIC INFECTIONS An infection in an immune compromised person caused by an organism that does not usually cause disease in healthy people. OROPHARYNGEAL Relating to that division of the pharynx between the soft palate and the epiglottis. OUTCOME: An event of interest, generally indicating disease progression. Patients in a trial are observed for the occurrence of the outcome at one or more time points after enrollment for the purpose of assessing the effects of the study treatments. P.C.R. (POLYMERASE CHAIN REACTION): A highly sensitive test that can detect DNA or RNA fragments of viruses or other organisms in blood or tissue; distinguishes specific sequences of DNA. p24: A core protein HIV. PALLIATIVE: A treatment that provides symptomatic relief, but not a cure. PANCREATITIS: Inflammation of the pancreas that can produce severe pain and debilitating illness. PANCYTOPENIA Deficiency of all cell elements of the blood. PANDEMIC: Referring to an epidemic disease of widespread prevalence. PAP SMEAR: See Papanicolaou smear. PAPANICOLAOU SMEAR: A staining procedure used to detect various abnormal conditions of the female genital tract (cervix). PARALLEL TRACK: A system of distributing experimental drugs to patients who are unable to participate in ongoing clinical efficacy trials and have no other treatment options. PARASITE: A plant or animal that lives and feeds on or within another living organism. Does not necessarily cause disease. PARENCHYMA Essential structuralelements of an organ. PARENTERAL Not through the mouth. Intravenous, intramuscular, and intradermal routes of administration of drugs are all parenteral. PARESTHESIA: Abnormal physical sensations. PATHOGEN: Any disease-producing microorganism or material. PATHOGENESIS Description of the development of a particular disease, especially the events, reactions and mechanisms involved at the cellular level. PCP: See Pneumocystiscarinii Pneumonia. PEDIATRIC: Relating to the medical specialty concerned with the development, care and treatment of children from birth through adolescence. PEPTIDE: Two or more chemically linked amino acids. PERIANAL: Around the anus. PERINATAL Events that occur at or around the time of birth. PERSISTENT GENERALIZED LYMPHADENOPATHY (PGL): Chronic, diffuse, non-cancerous lymph node enlargement. PGL: See persistent generalized lymphadenopathy. pH: The acidity or alkalinity of a solution, measured by the hydrogen ion concentration of a solution. Neutral, or normal, body pH is 7.4. PHAGOCYTE: A cell that is able to ingest and destroy foreign matter, including bacteria. PHAGOCYTOSIS The process of ingesting and destroying a virus or other foreign matter by phagocyte (monocyte/macrophage,PMN). PHARMACOKINETIC Concerning the study of how a drug is processed by the body, with emphasis on the time required for absorption, distribution in the body and method of excretion. PHASE II TRIAL: The second stage in testing a new drug in humans. Usually randomized, the main purpose is to provide preliminary information on treatment efficacy and to supplement information on safety obtained from Phase I trials. PHASE I TRIAL: The first stage in testing a new drug in humans. These studies usually generate preliminary information on the chemical action and safety of the drug. PHASE II/III TRIALS: Similar to Phase II studies, but called 11/111 when the drug being studied is a new drug for a lifethreatening disease. Expedited review is expected to follow completion of this stage. PHASE IV TRIALS: Studies designed to evaluate the long-term safety and efficacy of a drug, usually carried out after licensure of the drug for that indication. Also known as "Post-Marketing" studies. PHASE III TRIALS: The third and usually final stage prior to approval by the FDA in testing a new drug in humans. These trials are concerned primarily with assessment of dosage effects, and efficacy and safety in large numbers of people. Often includes a control treatment and random allocation to treatment. PILOT STUDY: A preliminary study designed to indicate whether a larger study is practical. See "FEASIBILITY STUDY." PLACEBO: An inactive substance against which investigationaltreatments are compared for efficacy. PLACEBO EFFECT: A change that occurs after a placebo is taken, due to the expectations of the patient. PLACENTA A combination of fetal and maternal cells that serves as the organ of exchange for nutrients and other chemicals between mother and fetus during pregnancy. PLASMA: The fluid of blood in which the red and white blood cells are suspended. PLASMA CELLS: Large antibody-producing cells that develop from B cells. 232 I

Page  233 AIDS/HIV Treatment Directory; Vol. 8, No. 3; January 1997 p, PLASMAPHERESIS: The removal of blood, separation of plasma, and reinjection of blood. PLATELETS: Circulating cellular fragments critical for blood clotting and sealing off wounds. PML: See Progressive Multifocal Leukoencephalopathy PNEUMOCYSTIS CARINII PNEUMONIA (PCP): A protozoal infection of the lungs; the most common life-threatening opportunisticinfection in AIDS patients. POLYMORPHONONUCLEAR LEUKOCYTES: See granulocyte. POLYNEURITIS: Inflammation of many nerves at once. POST-PARTUM: After giving birth. POWER: The probability of finding a treatment effect that actually exists. In clinical trials, the power of the study is the ability of the study to detect an hypothesized difference between treatment groups if it in fact exists. PRECLINICAL Refers to research that has been done before a compound is tested in humans, i.e., laboratory and animal studies. PRENATAL Relating to the period before birth. PRESUMPTIVE Presumed but not proven. In the diagnosis of a disease or infection, a presumptive diagnosis is one where signs and symptoms are characteristic, but tissue confirmation is not obtained. PREVALENCE The proportion of people in a specific population who have a certain disease or condition at a point in time. PRINCIPAL INVESTIGATOR: The lead scientist in a research project. PROCTITIS: Inflammation of the rectum. PRODROME A symptom that indicates the onset of a disease. PROGENITOR: Parent or ancestor. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): An opportunistic infection resulting from re-activation or new infection with the JC virus. PROPHYLAXIS: Treatment intended to preserve health and prevent the occurrence of a disease. PROTEINS: Organic compounds made up of amino acids. Proteins are one of the major constituents of plant and animal cells. PROTEINURIA The presence of excess serum proteins in the urine. PROTOCOL A detailed plan for performing an experiment, such as studying a treatment for a specific condition in people. PROTOZOA A group of one-celled animals, a few of which cause human disease. PROVIRUS: Viral genetic material, in the form of DNA, that has been integrated into the human host genome. PRURITUS: Itching. PULMONARY: Pertainingto the lungs. RACEMIC: A mixture containing both enantiomers of an optically active compound. RADIOLOGY: The science of diagnosis and/or treatment using radiant energy. Includes X-rays, Magnetic Resonance Imaging (MRI), destruction of tumors by radiation, etc. RANDOMIZATION The process of assigning patients to treatment by chance, i.e. using a random process. RECOMBINANT: Produced in a laboratory from a construct that was produced by genetic engineering laboratory. RECURRENCE The return or flare-up of a condition thought cured or in remission. REFRACTORY: Resistant to treatment, as of a disease. REGIMEN: Any particular treatment plan specifying which drugs are used, in what dose, according to what schedule, and for how long. REGRESSION ANALYSIS: A method of explaining or predicting the variability of a dependent variable using information about one or more independent variables. REMISSION: The lessening of the severity or duration of outbreaks, or the abatement of symptoms altogether over a period of time. RENAL: Pertaining to the kidneys. RESISTANCE The ability of some pathogens to grow and multiply even in the presence of certain drugs which normally kill them. RETICULOENDOTHELIAL CELLS: Pertaining to tissues having both reticularand endothelial characteristics. RETINITIS: Inflammation of the retina, linked in AIDS to CMV infection. Untreated, it can lead to blindness. RETROVIRUS: Any group of RNA-containing viruses that produce reverse transcriptase, which they use for making DNA, using RNA as a template. HIV is a retrovirus. REVERSE TRANSCRIPTASE A retroviral enzyme that is capable of copying RNA into DNA, an essential step in the life-cycle of HIV. AZT, ddl and ddC work by inhibiting reverse transcriptase. RIBONUCLEIC ACID (RNA): A complex nucleic acid responsible for translating genetic information from DNA and transferring it to the cells' protein-making machinery. SALMONELLA An ubiquitous family of gram-negative bacteria that can cause serious disseminated disease in HIV- positive persons. A common cause of food poisoning in undercooked poultry and eggs. SAMPLE SIZE: The number of participants required to conduct a clinical trial. SCOTOMA An area of lost or depressed vision. SEBORRHEIC DERMATITIS: A chronic inflammatory disease of the skin of unknown etiology, characterized by moderate erythema; dry, moist or greasy scaling; and yellow crusted patches on various areas; including the mid-parts of the face, ears, supraorbital regions, umbilicus, genitalia, and especiallythe scalp. SEPSIS: The potentially fatal presence of harmful microorganisms or associated toxins in the blood, characterized by high fever. SEPTICEMIA Disease due to sepsis, the presence of harmful microorganisms or associated toxins in the blood. SEROCONVERSION The development of antibodies detected by blood testing. SEROLOGIC TEST: Any of a number of tests that are performed on the clear, liquid portion of blood (serum). Often refers to a test that determines the presence of antibodiesto antigens such as viruses. SEROSTATUS: The presence or absence of antibodies to a specific pathogen (such as HIV) in the serum portion of blood. SERUM: The clear, non-cellular portion of the blood containing antibodies. SHINGLES: See herpes zoster. 233

Page  234 Glossary SIDE EFFECTS: The action or effect of a drug other than that desired. The term usually refers to undesired or negative effects, such as headache, skin irritation, or liver damage. Experimental drugs must be evaluated for both immediate and long-term side effects. SIGNIFICANCE, STATISTICAL Infers that an observation was unlikely to have occurred by chance alone. SINUSITIS: An infection of the sinus cavities in the head, often bacterial. SIV (SIMIAN IMMUNODEFICIENCY VIRUS): A family of naturally-occurring lentivirus in certain species of African monkeys that apparently cause no disease in their natural hosts. In macaque monkeys, these viruses can cause a persistent infection that shows many parallels to human AIDS. SPLEEN: A lymphoid organ in the abdominal cavity that helps clear the blood of undesirable elements. People can live without a spleen. SPLENOMEGALY: An enlarged spleen. STANDARD ERROR: A statistic indicating how greatly the mean score of a single sample is likely to differ from the mean score of the population. STANDARD DEVIATION: A statistic that shows the spread or dispersion of scores in a distribution of scores. STAPH: Short for staphylococcus, a common bacteria that can cause serious infections. STD: Sexually transmitted disease. STEM CELLS: Cells from which all blood cells derive. Bone marrow is rich in stem cells. STEVENS-JOHNSON SYNDROME: A severe and sometimes fatal form of erythema multiforme that is characterized by conjunctivitis, Vincent's angina (trench mouth), and ulceration of the genitals and anus. It is one of the most severe and life-threatening reactions to sulfa-containing drugs. It can often results in blindness. STOMATITIS: Inflammatory condition of the mouth having various causes (as mechanical trauma, irritants, allergy, vitamin deficiency, or infection). STRATIFICATION The process of classifying observation units in groups (strata), or the process of classifying patients into strata as part of the randomization process or for purposes of data analysis. SUBCLINICAL INFECTION: An infection, or phase of infection, without readily apparent symptoms or signs of disease. SUBCUTANEOUS Beneath or introduced beneath the skin (e.g., subcutaneous injections). SUBTYPE: A genetic and/or immunologicvariant. SULFONAMIDES: A group of sulfa-based antibioticdrugs. SUPPRESSOR T CELLS: (T8, CD8) Subset of T cells that halt antibody production and other immune responses. SURROGATE MARKER: A test, measurement, or score that is used in place of a clinical event in the design of a trial or in summarizing results from it (e.g., CD4 count for HIV disease progression). Used because the variable is believed to be related to the clinical event of interest and because of its perceived utility in yielding detectable treatment differences. SUSCEPTIBLE Vulnerable or predisposedto a disease. SYMPTOMS: Any perceptible, subjective change in the body or its functions that indicates disease or phases of disease, as reported by the patient. SYNCYTIUM ("giant cell"): A dysfunctional multicellular clump formed by cell-to-cell fusion. Some strains of HIV readily induce syncytia, which may play an important role in the pathogenesisof AIDS. SYNDROME: A group of symptoms and diseases that together are characteristic of a specific condition. SYNERGISM/SYNERGISTIC An interaction between two or more agents (drugs) that produces or enhances an effect that is greater than the sum of the effects of the individual agents. SYPHILIS: A sexually transmitted disease resulting from infection with the spirochete Treponema pallidum. It can be cured with penicillin in most patients. SYSTEMIC: Throughout the body. Sometimes applies to medications that are taken orally or parenterally that saturate the entire body. T CELLS (T lymphocytes): A thymus-derived white blood cell that participates in a variety of cell-mediated immune reactions. Three fundamentally different types of T cells are recognized: helper, killer, and suppressor (each has many subdivisions). T SUPPRESSOR CELLS: T lymphocytes responsible for turning the immune response off after infection is cleared, a subset of CD8+ lymphocytes. T-LYMPHOCYTE See T-Cells. T KILLER CELLS: A major component of cytotoxic lymphocyte response (CTL), responsible for lysing infected or cancerous cell; a subset of CD8+ lymphocytes. T4: See CD4. TABES DORSALIS: A syphilitic disorder involving the spinal cord and sensory nerve trunks marked by wasting, pain, lack of coordination, and disorders of sensation, nutrition and vision. TERATOGENICITY: The production of physical defects in an embryo or fetus in utero. TH1/TH2 CELLS: Subsets of T-helper lymphocytes, involved in cell-mediated immune response. THROMBOCYTOPENIA: A decreased number of blood platelets, cell fragments important for blood clotting. THRUSH: Oral candidiasis. THYMUS: A lymphoid organ in the upper chest cavity where T cells mature. TINNITUS: A ringing or buzzing noise in the ears. TITER ("titre"): A laboratory measurement of the amount (or concentration)of a given component in solution. TOPICAL Applied to the skin or other external area. TOTAL PARENTAL NUTRITION (T.P.N.): A type of nutritional feeding that delivers all nutrients in liquid form through a plastic tube into a vein. TOXICITY: The extent, quality, or degree of being poisonous or harmful to the body. TOXIN: See endotoxin/exotoxin. TOXOPLASMOSIS An opportunistic infection caused by the protozoan Toxoplasma gondii. It frequently causes focal encephalitis (inflammation of the brain). Toxoplasmosis may also involve the heart, lung, adrenal, pancreas, and testis. TRANSAMINASE: A liver enzyme. A laboratory test that measures transaminase levels is used to help assess the health of the liver. TRANSFER FACTOR: A fraction of white blood cells that apparently "transfers" capability to mount an immune response to a specific antigen. TRANSIENT: Short-lived; passing, not permanent. 234

Page  235 AIDS/HIV Treatment Directory; Vol. 8, No. 3; January 199 7 TREATMENT IND: A protocol that provides experimental treatments to a class of patients lacking satisfactory alternative treatment. TUBERCULOSIS The disease caused by Mycobacterium Tuberculosis Condition in which tuberculous infection has progressed so that the individual typically has signs and symptoms of illness, usually in the lungs. UBIQUITOUS: Present everywhere; common and prevalent. UVEITIS: an inflammation of the middle coat of the eye, including the iris, ciliary body and the choroid VACCINE: A substance that contains antigenic components from an infectious organism. By stimulating an immune response (but not disease), it protects against subsequent infection by that organism. VARIABILITY: The degree to which a set of quantities vary. The larger the variability, the further individual cases are from the mean. The smaller the variability, the closer the individual scores are to the mean. VARIABLE REGION: The part of an antibody's structure that differs from one antibody to another. VARIABLE Any trait, characteristic, test, measurement, or assessment that is recorded for participants in a clinical trial. VARIANCE See "VARIABILITY' VARICELLA: See Herpes Varicella Zoster virus. VARICELLA-ZOSTER VIRUS (V.Z.V.) A virus in the herpes family that causes chicken pox during childhood and may reactivate later in life to cause herpes zoster (shingles) in immunosuppressedindividuals.. VERTICAL TRANSMISSION Transmission of HIV from mother to fetus. VIRAL CULTURE: A laboratory method for growing viruses. VIRAL LOADIBURDEN The concentration of a virus in the blood. VIREMIA The presence of virus in the blood stream. VIRION: A virus particle existing freely outside a host cell. VIROLOGY: The study of viruses and viral disease. VIRUCIDAL (virucide) See antiviral. VIRULENCE The ability of a microorganism to produce serious disease. VIRUS: A group of infectious agents characterized by their inability to reproduce outside of a living host cell. Viruses may subvert the host cells' normal functions, causing the cell to behave in a manner determined by the virus. VISCERAL: Pertainingto the major internal organs. WASTING SYNDROME: Progressive, involuntary weight loss associated with advanced HIV infection. WESTERN BLOT: A laboratory test for the presence of specific antibodies that more accurate, but also more expensive and difficult, than the ELISA test. WILD-TYPE VIRUS: The prevalent type of a virus in the host population before genetic manipulation or mutation; virus that is isolated from a host, as opposed to one grown in a lab culture. 235

Page  236 NOTES NOTES 236 II

Page  237 AIDS/HIV Treatment Directory, Vol. 8, No. 3; January 199; 7 INDEX A ABT-538 See Ritonavir ABV' 67 ABVD * 67 Accutane * see Isotretinoin Actimmune ' see Gamma interferon Acupuncture -134 Trials with: ~ 201 Acyclovir * 67, 198, 210, 212 Trials with: * 199 Acyclovir-resistant herpes simplex * see herpes simplex ADC ~ see AIDS Dementia Complex Adefovir - see PMEA Adenine * see Vidarabine Adriamycin ' see Doxorubicin AG-1 343 see Nelfinavir AIDS Dementia Complex * 131 Trials for: 200 Albendazole * 67 207, 212 Alferon-N * see Alpha-Interferon Alpha Interferon * 67, 210, 212 Trials with: 164, 197, 198, 199 ALX40-4C * 47, 212 Ambisome ' see Amphotericin B Amikacin * 67, 212 Amitriptyline * 210, 212 Trials with: 201 Amphotericin B * 67, 207, 212 Trials with IV: 177, 179, 180 Trials with lipid complex: 177 Trials with liposomal: 179, 180, 181 Ancobon * see Flucytosine Anti-B4 blocked ricin Immunoconjugate * 68, 104, 212 Trials with: 188 Anti-CD19 * 104 Anti-CD22 * 104 Trials with: 189 Antiretroviral Compounds, Other' 47 See also * ALX40-4C ' Gem 91 ~ Hydroxyurea * MDL 28,574A Anti-Rh-Antibodies WinRho, 207 Trials with: 203 Antisense compound ' see GEM 91 Aphthous Ulcers * 135 Aqueous crystalline penicillin G potassium ' see Penicillin G AR-177 '46, 212 Trials with: 158 Ara-A * see Vidarabine Arabinoside ' see Vidarabine Ara-C * 68 Trials with: 187 Arkin-Z * see OPC-8212 Aspergillus * see Aspergillosis Aspergillosis ' 91 Astemizole '210 Atovaquone '68, 210, 212 Trials with: 175 191 193 ATRA ' see retinoic acid All-trans Autologous CD4-Zeta Gene Modified T Cells' see Gene Therapy Trials with: 168 Autologous CD8 Infusion ' 62, 212 Axsain 'see Capsaicin Azidothymidine 'see AZT Azithromycin ' 68, 207, 210, 212 AZT * 15, 210,211 B BACI * 211 Bacterial Infections ' 80 Trials for: 173 Bactrim * see TMP/SMX Benzathine Penicillin G ~ see Penicillin G BHAP Compounds ' see Delaviridine BI RG 587 ' see Nevirapine Biaxin * see Clarithromycin BisPom PMEA 'see PMEA Blenoxane -see Bleomycin Bleomycin ' 68, 210, 212 Trials with: 189 Bovine immunoglobulin concentrate C. Parvum Trials with: 192 BuCAST ' see MDL 28,574A BV ara-U ' see Sorivudine Trials with: 199 BW 882C87 ' 212 C C.glabrata ' see Candidiasis C. krusei see Candidiasis C. parapsilosis ' see Candidiasis C. tropicalis ' see Candidiasis Campylobacter~ see Bacterial Infections Candida albicans * see Candidiasis Candidiasis '91 Trials for: 177-178 Capreomycin ' 68 Capsaicin '68 Carbamazepine 68 Carbon dioxide laser ' 129 Carnitor see L-Carnitine Castanospermine analog ' see MDL-28,574A CCNU ' see Lomustine CD4-PE40 '212 Cefitaxime '210 Ceftriaxone e 68 210,212 Cefuroxime ' 210 Central nervous system (CNS) ' see Neurological Complications Chlorhexidine gluconate ' see Peridex CHOP ' 69 Cl -1012 ' 212 Trials with: 159 Cidofovir' 69, 212 Trials with: 195 Cimetidine ' 210 Cipro ' see Ciprofloxacin Ciprofloxacin ' 69, 210, 212 Cisplatin ' 69 Clarithomycin ' 69, 210, 212 Trials with: 174 Clindamycin ' 69, 210, 212 Clofazimine '69, 210, 213 Clonazepam ' 210 Clotrimazole ' 69, 210, 213 CMV ' see Cytomegalovirus CMV Colitis ' see Cytomegalovirus CMV Encephalitis 'see Cytomegalovirus CMV Esophagitis 'see Cytomegalovirus CMV Gastritis 'see Cytomegalovirus CMV Radiculopathy 'see Cytomegalovirus CMV Retinitis 'see Cytomegalovirus CMVIg ' 213 CNS Lymphoma, Primary'see Lymphoma Coccidioides immitis' see Coccidioidomycosis Coccidioidomycosis '95 Trials for: 179 COMP '70 Corticosteroids, adjunctive' 69 Co-trimoxazole 'see TMP/SMX Cryptococcus neoformans' see Cryptococcal Meningitis Cryptosporidium parvum' see Cryptosporidiosis Crytococcal Meningitis '95 Trials for: 179-180 Cryptosporidiosis 106 Trials for: 191 Cuniculi ' see Microsporidiosis Cyclobut-G (lobucavir) ' 69, 213 Trials with: 196 Cyclophosphamide '70, 210, 213 Cycloserine ' 70, 213 Cyclosporine 210, 213 Cytarabine 'see Ara-C. Cytokines 'see Interleukin-2; Interlukin-4; Interleukin-10; Interleukin-12 Cytomegalovirus' 119 Trials for: 193-197 Cytopenia 'see Thrombocytopenia Cytosine arabinoside 'see Ara-C Cytovene 'see Ganciclovir D d4T ' 22, 213 Trials with: 147,148, 149 d4T & AZT ' 27 d4T & ddl ' 27 Dacarbazine ' 70 Dapsone ' 70, 213 Daunorubicin' 70, 211, 213 DaunoXome ' see Daunorubicin ddC ' 18, 207, 210, 213 ddC & AZT * 25 ddl ' 19, 213 Trials with: 143-149, 156 ddl & AZT ' 26 Deca-derabolin ' see Nandrolone DEHSPM ' see Diethylhomospermine Delatestryl 'see Testosterone 237

Page  238 Index I Delavirdine' 31, 207, 213 Trials with: 149, 200 Delavirdine & AZT ~ 34 Dementia ~ 131 Depo-testosterone ~ see Testosterone Depression Trials for: 202 Dexamethasone * 211, 214 Dexedrine Trials with: 202 Dextromethorphan Trials with: 200 DHPG ' see Ganciclovir Diarrhea ~ 135 Trials for: 202 Didanosine ~ see ddl Dideoxycytidine 'see ddC Diethylhomospermine * 136 Trial with: 203 Diflucan ' see Fluconazole Dilantin ' see Phenytoin Dipivoxil see PMEA DMP 266 ~ 32, 213 Trial with: 150, 151 Doxcycline ' 210 Doxil * see Doxorubicin, liposomal Doxorubicin liposomal' 70, 210, 213. Trials with: 181 Doxycycline ' 87, 116 Dronabinol ' 70, 210, 213 E E. bieneusi* see Microsporidiosis Efudex * see 5-Fluorouracil Encephalitozoon hellem' see Microsporidiosis Enterocytozoon bieneusi' see Microsporidiosis ENV 2,3 (recombinant gp120) ' see Vaccines Epivir ' see 3TC EPO ' see Erythropoietin Epoetin alpha ' see Erythropoietin Epogen ' see Erythropoietin Erythromcyin ' 210 Erythropoietin ' 70, 210 Esophageal Candidiasis ' see Candidiasis Ethambutol ' 70, 210, 213 Ethionamide ' 71, 213 Etoposide ' 70, 210, 213 Trials with: 181 F 5-ASA * 71 5-azacytdine Trials with: 187 5-FC 'see Flucytosine 5-Fluorouracil ' 71 Trials with: 202 5-FU ' see 5-Fluorouracil F105 63, 213 Famciclovir' 71, 210, 213 Trials with: 198 Famvir ' see Famciclovir Fansidar * 213 f-ddA Trials with: 142 Filgrastim ' see G-CSF Flagyl ' see Metronidazole Floxin ' see Ofloxacin Flucinonide * 135, 210 Fluconazole ' 71, 207, 210, 213 Trials with: 177-180 Flucytosine ' 71, 210, 213 Fluoxymesterone ' 71, 213 Folinic acid ' 116 Foscarnet ' 71, 210, 213 Trials with: 193, 194 Foscavir ' see Foscarnet Fungal Infections ' 91 see Aspergillosis; Candidiasis; Coccidioidmycosis; Cryptococcal Meningitis; Histoplasmosis G Gallium Nitrate (NSC 15200) Trials with: 189 Gamimune N ' see Immune globulin, intravenous Gamma Globulin ' 213 Gamma Interferon ' 213 Trials with: 175 Gammagard ' see Immune globulin Ganciclovir' 72, 207, 210, 213 Trials with: 194, 196, 197 G-CSF ' 72, 210, 214 GEM 91 ' 47, 214 Gene Transfer Therapy ' 54 Trials with: 168 Gentamicin, liposomal' see TLC G-65 GM-CSF ' 72, 211,214 Trials with: 171, 177 GM-CSF/IL-3 fusion protein ' see PIXY321 gp 160 Vaccines ' see Vaccines gp120 Monoclonal Antibody ' see F105 gp120 Vaccines ' see Vaccines Granisetron '211 GS 840 ' see PMEA. Guanfacine ' 72 H H. Influenzaetype b polysaccharide (PRP) vaccine ' see Vaccines Haemophilus influenzae' see Bacterial Infections (Pyogenic) Halotestin ' see Fluoxymesterone HAV ' see Hepatistis A HBV ' see Hepatitis B HBY 097 Trials with: 152 hCG ' see Human Chorionic Gonadotropin HCV ' see Hepatitis C Hepatitis A, B, C, D, G ' 125 Tr