Abstracts Vol. 1 [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Track B: Clinical Science
Mo.B.I 134
SURROGATE MARKER RESPONSES FROM AN OPEN-LABEL, EXTENDED USE
DELAVIRDINE MESYLATE (DLV) TREATMENT IN TRIPLE COMBINATION
(ZDV+DLV+DDI OR ZDV+DLV+DDC) FOR HIV-I+ PATIENTS
Ww Freimuth*,Y Wan, Sr Docsa, Ca Greenwald, Lk Wathen, Dh Batts, Bg Peel and
Delavirdine learn. Pharnracia & Upjohn, Inc., Kalamazoo, MI, USA.
About 200 patients have entered this clinical trial from other phase II/III DLV protocols who
have completed the orig inal protocol, or who have had an AIDS defining illness or 50%
decline in CD4 since entry into their respective protocol.This ongoing protocol permits the
study of the effect of switching patients to DLV triple therapy from prior nucleoside and/or
non-nucleoside (delavirdine) reverse transcriptase inhibitor (RTI) monotherapy or combination therapy. 82 subjects treated with either didanosine (ddl) or ddl+DLV obtained a 10-40
cell increase (avg. baseline C D4=42) and a 0.3-0.8 log decrease in HIV- I RNA for >24
weeks with either DLV triple therapy. 13 subects who were on zidovudine (ZDV)+DLV for
10-20 months had, riaverage sustained increase of 20-30 cells above baseline in CD4 and
decline in HIV- I RNA of s>0.5 logs up to 48 weeks after addition of either ddl or ddC. 65
naive or ZDV expeinenced patients on DLV monotherapy for up to 6 months had a 40-90
cell sustained increase in CD4 counts and a decrease in viral burden of 0.9- I.4 logs for _32
weeks after switching to DLV triple therapyThese preliminary surrogate marker data suggest that initial delavirdine monotherapy in naive patients does not inhibit the effectiveness
of subsequent combinations including ZDV+ddl or ddC. Most subjects with prior nucleoside RTI therapy (ZDV and/or ddl) achieved additional positive surrogate marker responses
with DLV combination therapy even after a patient has fiiled prior RTI therapy.These preliminary surrogate narker results suggest that delavirdine triple combination therapy can
offer additional CD4 cell counti ncreases and HIV- I RNA viral burden decreases for subjects on prior RTI monotherapy or double combination therapy
Willian Freimuth, M.D., 7000 Portage Road, Kalamazoo, MI 49001
Telephone: [phone] Fax: [phone]
Mo.B.I 135
EARLY ZIDOVUDINE TREATMENT EXTENDS AIDS-FREE TIME
Detels, Rome, Munoz A"*, Peng Y%*, Graham N*, Phair J, Mellors J~ *UCLA. Los
Angeles, California, USA: *Johns Hopkins U., Baltimore, Maryland, USA; Northwestern U.,
Chicago, Illinois, USA; ~U. of Pittsburgh, Pittsburgh, Pennsylvania, USA
Objectives: To compare time to AIDS between men receiving zidovudine before or not
before the diagnosis of AIDS, and time to death for men receiving zidovudine before or
only after AIDS.
Methods: For the time to AIDS, 82 I men receiving zidovudine prior to AIDS were pair
matched to men not treated on level of CD4 + cells (~75 cells), hemoglobin level (~75
g/dL), number of clinical symptoms, and study visit at the time of initiation of zidovudine. For
the time to death, I186 men who received zidovudine prior to AIDS were pair matched on
the sameto variables to men who received zidovudine only after the AIDS diagnosis.
Results: Men with 350 C 3D4+ /cc+ cells who received zidovudine prior to AIDS remained
AIDS-fee significa.ntly longer than their pair match who did not (P <.0001).The median
extension of time to AIDS was 0.61 years for men with < 200 CD4+ cells/cc3 and 1.13
years for the men with 200- 349 CD4+ cells/cc3. Cox regression analysis showed a significantly increased time to AIDS for the men with < 350 CD4 cells/cc3 both before and
after adjustment for the use of prophylactic drugs against PCP infection. No difference was
seen in the time to death betweenme n receiving zidovudine before or only after AIDS
diagnosis.
Conclusions: phis study confirms that zidovudine treatment of asymptomatic HIV-I infected
men provides significant benefit o to men with < 350 CD4+ cells/cc3 by extending AIDS-fee
time but not time to deasth.
Roger Detels, UCLA, Dept. of Epidemriology (CHS) 10833 Le Conte Ave., Los Angeles, CA
90095-1772, USA Tel: [phone] Fsx: [phone] e-mail: [email protected]
Mo.B.I 136
SURVEY OF ANTIRETROVIRAL SELECTION BY PHYSICIANS AND HIV-INFECTED
PERSONS
Dong, Betty I, Luber AD.
University ol Califeonr i at San Fraincisco General Hospital, San Francisco, California, USA
Objective: o describe the selection of antiretoviral agents by physicians and HIV-infected
persons located in 3 different geographic regions, the information sources that influence
decision miaking, ind whetr the 1993 NIAID guidelines represent the current standard
of practice.
Methods: A survey depictinrg S different clinical scenarios was mailed once between January
and Marth of 1995 to 678 physicians practicing in New York, California, and Florida.
Physicitns were randonsly stelected from DIV treastment directories, published clinical trials,
the Coinunity Consortium of the Bay Ares, oad the Gay and Lesbian Medical Association.
Two hcrndred eighty one s Drveys wore sent to eIV positive oembers provided by a
Califorii DIV idvoca ir, rtup; Now York aird Florida groups declined participation.
Results: A total of I196 physiciain survey were returnted for a total response rate of 28.6%:o
DIV positive per sorry r etmrnod 5 I surveys for in I8% response i-ate. California physicians
reported ar greaser numbelr of veirs experience wfrrle NewYork/Florida physicians had
more rionthly paient interactrons. For the synrptomatic person with a CD4 count of 500
and no prior antrelioviral therapy the majority of responses were censistent with the
NIAID guidelines. For the symptomatic person with CD4 count of 200 and no prior
antiretroviral thera.py, combiaron therapy including acyclovir, was preferred and many
chose investigitronal agents such as 3TC or ai proteinase inhibiter. For the symptomatic person wfho [rid r nip d CD4 dcino on ZDV, similar responses to the previous scenario was
obtainird. For the symptonritic person witfh disease progression on ZDV and a CD4 of I 0.
awide variety of investigattionatl agents wore chosen. DIV positive persons selected ZDV
loss oftern aid preferred acyclovir comparedl tcr physiciarns. Of intereott, many respondents
wore net twiro of the benefits of ZDV to pr-event masternal-fetal HIV trasnsnrissren.
Statistics antalysis is currently underway.

Conclusion: Because the survey return rate was approximately 20%, our conclusions are
lirited and done noecessarily represent the views of the profession or the HIV positive
communrty. Combination therapeutic regimens were selected earlier and more ftequently

Mo.B.I 134 - Mo.B.I 139
than those recommended by the NIAID guidelines.The responses reflect clinical practice
and indicate that the NIAID guidelines are obsolete and require revision.
Betty J. Dong, University of California, 52 I Parnassus Ave, C-152 San Francisco, California
94 I143-0622, USA Tel: [phone] Fax: [phone], email: bjdongditsa.ucsf.edu
Mo.B. I 137
CLINICAL AND VIROLOGICAL RESPONSES TO RITONAVIR,AN INHIBITOR OF HIV
PROTEASE
Korneyeva M, Molla A, Kempf D, Vasavanonda 5, Chernyavskia T Boucher C*, Schipper P*,
Lyons N, Gao Q, Norbeck D, Leonard J.
Abbott Laboratories, Abbott Park, USA;:*Utrecht University The Netherlands
Objectives: Ritonavir, a potent and selective peptidomimetic inhibitor of HIV protease,
exhibits high oral bioavailability and demonstrates profound antiviral and immunologic activity in HIV infected humans.
Methods: In Phase II studies, maximum declines (more than I order of magnitude) in plasma viral RNA were observed generally within 2 to 4 weeks of initiating drug therapy.
Results: With doses of 500 and 600 mg bid of ritonavir, breakthrough of HIV replication
was delayed in many patients for up to 32 weeks. At lower doses, however, a more rapid
return to baseline RNA was observed. Our studies demonstrate that this loss of effect was
linked to the stepwise, ordered accumulation of mutations in the protease gene.
Substitution were observed most often at position 82, wild type V to A, F,T or S.Variation
at residues 20, 33, 36, 46, 54, 71, 84 and 90 were also observed predominantly or exclusively after treatment with ritonavic
Conclusions: High plasma concentrations of drug appeared to delay the onset of resistance
by suppressing the replication of the initial mutants on the mutation pathways. Phenotypic
analysis of viral variants indicated that significant diminished susceptibility to ritonavir
requires multiple mutations in the protease gene.Viral strains of intermediate susceptibility
to ritonavir retained sensitivity to a panel of structurally diverse protease inhibitors.The
duration of viral suppression might therefore be extended by combination therapy with
ritonavir with other protease inhibitors with distinct resistance pathways.
Abbott Laboratories Marina N. Korneyeva, 100 Abbott Park Rd., D-47D AP9A Abbott Park
IL 60064 Tel: [phone] Fax: [phone]
Mo.B.I 138
EFFICACY AND SAFETY OF MDL 28,574A IN HIV-POSITIVE PATIENTS WITH
BASELINE CD4 VALUES OF 100 - 300
Zolnouni, Parvaneh*, Berger DS**, Perez G5 *, Hamedani P Frampton M* '", Gibson C,
Sidarous E, Stoltz M. *California Clinical Trials, Beverly Hills CA, USA; * Chicago Center for
Special Immunology, Chicago IL, USA; ***-NJ Community Research Initiative, Newark NJ,
USA; z**Hoechst Marion Roeussel, Kansas City MO, USA
Introduction: MDL28,574A (MDL) is a butanoyl derivative of casntanospermine (CAST),a
naturally occurring plant alkaloid, with 30-fold greater anti-HIV activity in-vitro than CAST.
MDL is under development for delay of the progression of disease in HIV-positive patients.
MDL is an a-glucosidase I inhibitor which acts in the latter phases of viral replication by
altering glycoprotein processing.This results in ireduced viral infectivity and syncytial formation. MDL's activity on a host (vs viral) enzyme is thought to provide long-term activity
against the virus. MDL acts synergistically in-vitro with ZDV, ddl, ddC, nevirapine, and
saquinavic
Objective: Discuss preliminary efficacy and safety results of Phase II multicenter studies
done in the US and Europe.
Methods/Results: This randomized, double-blind trial leooks at MDL in doses of 50, 150, 300,
or 400mg as compared to open-label ZDV in a 12 week meonotherapy treatment aret m.
MDL-randomized patients then entered a combination treatment arm, adding ZDV while
continuing on blinded MDL for an additional 12 weeks. Patients randomized to ZDV
monotherapy continued this treatment for a total of 24 weeks. Inclusion criteria consisted
of adult HIV-positive patients without active AIDS defining events at Entry. Exclusion criteria
consisted of patients who had _ 6 months exposure to any single antiretroviral agent.
Efficacy endpoints consisted of changes in HIV-RNA, CD4 and p24. Safety assessrtents
included serial clinical laboratoery testing and documentation of clinical adverse events. Over
200 patients have entered this trial. No significant treatment-related serious adverse events
have been attributed to MDL. Dropout rates of approximately 19% are due primarily to
voluntary withdrawal, noncompliance, and GI adverse effects. An internal safety review has
allowed enrollment to continue for greater than 9 months.
Conclusions: MDL at the tested doses was found to be safe when used alone or in combination with ZDV. Preliminary results f-om an interim assessment of efficacy and safety will
be given using the surroge ateffacy data and adverse event summarines, including sun--
maries of clinical laboratory trends.
Parvarnef Zolnouni, M1D; California Clinical Tras; 8500 Wilshire Blvd. 7th Fleet, Beverly Dilly
CA, USA, 902 I I Tel. #/: (3 10)/854-4949: FAX: (3 I0)/854-541I9
Mo.B. I 139
AN EVALUATION OF THE EFFECT OF INVIRASETM (SAQUINAVIR) HIV PROTEINASE INHIBITOR ON PLASMA HIV-l RNA:A SUBSTUDY OF THE INVIRASETM
OPEN-LABEL COMPASSIONATE TREATMENT PROGRAM (SV 14974)
Tomres, Ramdn* Barr M~Rt,Weber PF-(, Siemon -Dryczyc Mt. Silgo PP-,Yucartrs J~, LainW~
Busa Mv1~
*AIDS Center: St.Vrncent's Dospitail and Medical Cente: New York, NY IDoffmarnn-La
Roche, Ntlbey, NJ:, ~Parexel Intemrntional, Corp., Waltham, MA
Objective: To study the effects of saquinavir en plasma DIV- I RNA viral load using quantitative polymerase chain reaction (PCR) assays and to correlate the effect of these chinges
with clinical eutconse and survival in DIV- I infected pitrents with CD4 toll counts 300
cells/mm3 who hive previously boon treated with standard of tro and hive Gaibed or are
intolerant to such treatment.
Methods: A subset of 404 patients who enrolled in the lnviraseTM open libel consparssion
ate treatment program were enrolled in this substudy by 15 physicians f-om the top
enrolling sites. Participation in the substudy was limited to patients who had a baseline HIVRNA sample prior to starting therapy with saquinavir (600 org orally three times daily).The
study population was stratified into two groups: those with CD4 cell counts < 50 cells/mm3

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