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

Mo.B.412 - Mo.B.420

Monday, July 8, 1996

occurred in 85 (I
Stratified inalyses
Conclusion: fThis
prevents AIDS co
as combination ar

5.7%) versus I1 81 (33. I%, p<0.001, hazard ratio 0.44, 95% CI 0.34-0.56).
show increiased ritonavir effect with concomitant anti-HIV drug treatment.
study shows that ritonavir therapy in advanced HIV immunodeficiency
mrr pliations and prolongs life. Ritonavir treatment may be more beneficial
n t i V therapy.

This study was presented in part a it the 3rd Conference on Retroviruses and
Opportunistic Infections.
D.W. Cameron, G- 2, Ottawa General Hospital, 50 I Smyth Road Ottawa, Ontario Canada
KIH 81L6 Tel. [phone] Fax [phone] email: [email protected]
Mo.B.412
EXTENDED FOLLOW-UP OF PATIENTS IN A STUDY OF INDINAVIR AT 800 MG
Q8H (2.4 G/D), 1000 MG Q8H (3.0 G/D) AND 800 MG Q6H (3.2 G/D)
Steigbigel Roy, Berry PTeppler H, Mellors J. Drusano G, Leavitt R, Hildebrand C, Jonas L,
Nessly M, Deutsch P fChodakewitz J. SUNY Stony Brook, NY Pacific Oaks Med Grp, CA,
Thomas Jefferson Univ, PA, U Pitt, PA, Albancy Med Ctr, NY, Merck Res. Labs, PA, USA
Objectives:To obtain on -term (48 weeks) information on the antiviral effect of indinavir
(IDV) at> 2.4yg/d.
Methods: IDV stu adies have dermonstrated that initiation of therapy with 2.4 g/d results in
greater and more sustained changes in CD4 counts and viral RNA than lower doses over 24
weeks.This study evaluated the safety and efficacy of 3 total daily doses of IDV (2.4 g/d, 3.0
g/d, 3.2 g/d). To provide information on the long term activity of IDV, preliminary data from
patients (pts) participating in an open extension of this study through 48 weeks are reported.
Results: Seventy pts were enrolled. Median entry CD4 count was 250 cells/mm3; median
entry vRNA was 70,795 copies/mI. A total of 63 pts entered an open extension of this
study following 24 weeks of therapy. At ntry into the extension, the median decline in
vRNA from baseline was i2.3 to 2.6 iog 0 copies/mL and the median increase in CD4
count was 80 to 145 cells/rrsm. Approximately 40% of pts had vRNA levels below the limit
of detection (200 copies/mL).There were no sign ificant differences among the groups.
Efficacy: After 48 week s of therapy with IDV 800 mg q8h, declines in vRNA relative to pretreatment baseline ( 2.63 copies/sil and increases in CD4 counts (85 cells/rm3)
remained similar to that observed at Week 24.The proportion of pts with vRNA levels
below the limit of detection was 54%.With similar follow up, results demonstrated that
doses of 3.0 and 3.2 g/d had a simi ar antiviral effect. Safety: Only limited safety data are
available IDV was gerneraliy well tolerated; no pts discontinued due to drugrelated adverse
events. As in the initial study phase, isolated indirect hyperbilirubinemia was observed.
Nephroithiasis was reported i n 4/63 (6.3%) of pts; pts receiving > 2.4 g/d with nephrolithiasis had a dose reduction. Consistent with other studies, there does not appear to be a
change in the safety profile of IDV when administered for > 48 weeks.
Conclusions: IDV at >2.4 g/d exerted a sustained antiviral effect for at least 48 weeks based
on changes in vRNA and CD1 count. With extended follow-up, IDV doses above 2.4 g/d
did not appear to exert a greater antiviral effect. CXN was generally well tolerated.
R. Steigbigel, State Univ of NewYork at Stony Brook, Stony Brook, NY 11794 8153
Telephone: [phone], Fax: [phone]
Mo.B.413
A RANDOMIZED PHASE II STUDY OFVIRACEPTTM,A NOVEL HIV PROTEASE
INHIBITOR, USED IN COMBINATION WITH STAVUDINE (D4T)VS. STAVUDINE
(D4T) ALONE
Gathe, Jr:, Joseph, Burkhardt, B. Hawley, P*, Conant, M.*, Peterkin, J.*C**, Chapman; S."**,
'Montrose Clinic, IoustonTX, ''Whitman Walker Clinic, Inc.Washington, DC. *Conant
Medical Group, San Francisco, CA and " **Agouron Pharmaceuticals Inc., La Jolla, CA
Objective: To evaluate the safety and efficacy of the combination ofVIRACEPT and d4T
versus d4T alone.
Methods: A total of 33 HIV positive have been enrolled in a ongoing pilot clinical study of
the safety and efficacy of the combination ofVIRACEPT and d4T versus d4T alone. Patients
are d4T -naive with CD4 cell counts 200 cells/mm3 and quantitative HIV RNA titers >
15,000 copies/ml. After a two week antiretroviral therapy wash-out period, patients have
beern randomized to one of four ttryeatment arms: d4T plus either 500 mg, 750 mag, or 1000
mg tid ofVIRACEP1 or d4f alone.
Results: To date, tihe mea n log decrease in viral load has been in excess of 2.0 logs for
patients treated with combinationr therapy compared to the 0.9 log decrease observed for
patients on d i1 Ilo nie. Of the patients completing at east 28 days of therapy 75% treated
on the corsabination have experienced viral load nadirs below the levels of assay sensitivity
(i.e., S0 copies/ml 0 Mea n increases in absoa lute CD4 cell counts from baseline values have
ranged fom 80 to 195 cells/ram i3amon patients completing 28 days on combination
treatment.Therapy has been well tolerated in all four treatment arms. Adverse events
reported were loose stoo sdiarrhea and fatigue, with fatigue being the only event experienced in the d4T sontrol i r he mild to moderate diashea experienced by patients in
the conbrinatio n arms has beer well-controlled by anti diarrheal medication.To date, there
have been no clcrualy significant changes in laboratory parameters attributable to either
VIRACEPT or d4T.
Conclusions: These results suggest that VIRACEPT is both safe and highly effective in combination with d41 A controlled Phase1 II/11 trial of the combination is scheduled to proceed.
Joseph Gathe, Jr, Houston Clinical Researcht Network, 2 15 Westheimer Street, Houston,TX
77006 U.S.A.Telephone: (/ 3) 526 982 FAX: [phone]
Mo.B.414
CAUSES OF LONG TERM EFFICACY AND/OR DRUG FAILURE IN PROTEASE (PR)
INHIBITOR MONOTHERAPY.
Schapiro lonathan M,Winters MA,Vierra M*,Vanhove G*, Jacobsen HCC, GingerasTRt55,
Crawford SD', Mous JR Blaschke F*, Mceriran TC*. *Stanford University Stanford, CA;
eF.Hoffrnann La Roche Ltd. Basel, Switzerland; s*nAffymetrix Corp. Santa Clara, CA.
We conducted a clinical trial in 40 HIV + volunteers who received 3600 or 7200 mg/day
saquinavir monotherapy for 24 - 88 weeks depending on virological and immunological
response. Although almost all patients showed a significant rise in CD4 counts and drop in
viral load, the duration of this response vried widely throughout the group with loss of effi
cacy occurrirng a y Vwer,- s om I 2 to beyond -8
of long term eftic,c, - drug failure, we stridi
nodes for deweopmert - key PR resstance mut
for evidence of rep!;atio e rnhanc ing utat!or.
drug-taking behass, a,"ediation Event Moni
objectively determine patient compliance. PR resi(
temporal proximity it plasma, PBMC and lymph r
the appearance of iur tous in the lymph node
mutations alone did not ippear to explin the lo
overall compliance expressed as percentage o pr
98%, virological drug fiilure was associated vvit Ip
holidays" in patients lacking early resista e muts
have contributed to the subsequent development
studied, no evidence of significant mutations due
processing sites. In summary neither early lymph
the gag processing sites, appeared to expli Is 5
tions in circulating virus, whereas periods of low co
tor contributing to drug failure and possibly dr->

wee<s o therapy to deternmine the causes
ced ptienls p! asm, PBMC and lymph
ations a PR poi and gag processing sites
We al so ed electronic monitorin g of
toane,stel (MEMS) Caps devices to
starce nutations appeared within close
node RNA and DNA. In no patients did
precede th, t of the plsma virus. These
ss of dr s-u eti a ral patients. W hile
rescit' 1 oses taken ringed from 69
e d e( iecreased mphAnce or"drug
on,. Thse "drug holdays" may actually
o 5 t ttions in these patients. In 3 patients
ithcran were found in 8 PR pol and gag
ode vrl iroe sise mutatons, nor changes in
falu s ain io i( r' r,-ing csistnce mutamphane ippeared to be an important fac)[+ (r ][ qt f e_.,l0ance mLut,ttlOnS

Jonathan M. Schapiro, M.D., Stanford JUniversity ho of Medin I
Room S-156, Stanford, CA 94305-5107 Tel:,1 I 5 I i ' v) fx:,t
email: JMS.Leland.Stanford.edu

Prsteur Drie,
2 95

Mo.B.415
SAFETY AND EFFICACY OF RITONAVIR ADMINISTERED AT TWO POTENTIALLY
MAXIMUM TOLERATED DOSES
Hicks, Charles B, Lehman L,2 Eron,3 Ho ton J emsek Ke, Ne i eonard J.2 IDuke
University Medical Center. Durham NC At bott L; Abbsott P, i rk IL; Uniersity of NC,
Chapel Hill NC; 4Carolinas Medical Center, Chattits NI; Nille Clinic, Charlotte NC,
6PPD, Wilmington NC
Objective: To evaluate the antaiviral ac titytsaft iisof rtor-wr in an oper Iel study of
potentially maximum tolerated doses ir IV infected pairts wtt s FD4 cells/mm3
Methods: Multicenter, open-label study of 30 1HIV nir in apitients with CD-1 cell counts
>50 CD4/mm3, viral burden >25,000 copes/rn, (bDNA) Mot td received extensive
prior antiretroviral therapy Following 2 tweek washout perod, pat ents rece ved ritonavr
400mg tid or 700mg bid as inpatients f-or 2 we'as f 'llowedi)y yin outep ent extension
phase. Toxicity CD4 counts, viral burden were ssessed Jup to 3. weeks in '1 0 patients
Results: 30 patients (27 male, 3 fSis er entered the study: Ipater i srece Ied the
400mg tid dose (group 1):13recesed 700mcr bid (cup 2). Medi aCD counts and
mean viral burden (by POR) at study eiri (ba reline),r 5c I v s in 5n these parameters
from baseline as measured at 4, 26, and 3-1 es- into tl, ttudy:re I oted below:
Change fromn Base -N Du ' r of pt ptent
Baseline Week.1 Wei 1r Week 34

HIV RNA (log 10 copies)
Group I
Group 2
CD4 Count
Group I
Group 2

5.49 (1
5.42 (1

).8 (61 0.24 (7).95 (, 0.74 (3)

90 (17) 8 (8) + e (6) + I10 (7)
10 (13) 70 (7 + s) + 267(4)

Adverse events were noted in all patients, mo- 5ornnony
continued therapy for drug-related nausea or d.c rrhe.5, 5to
trations increased in both groups; there were so5idi( elevs
Conclusions: At daily doses of 1200 and 140Dm. n tonae,
potent antiretroviral activity with correspondirr inreas sn (
counts appear to persist longer than those on viral bur1 an
700mg bid in the formulation tested appear. o isspprx ae t
regimen, although alternative nitial reimens ( e. dose eoi r

istrointestinal 6 paetients disst-rol ind trnglycende concer
o,! r,in rscminases.
nontherpy idemonstrates
4 counts. Effects on CD4
nitling ri tonavr it either
i maxmally ttolerated dosinon) uld be investigated

CB Hicks, Box 3360, Duke University Medical Center, I.harm. -C 277 10 USA
Tel: [phone] Fax: 99 I- 681 847 F mn i cksiaistcpub duke.edu
Mo.B.420
HORMONAL AND CHRONOBIOLOGICAL IMPAIRMENT OF GH-IGFI-IGFBP3 AXIS
IN HIV INFECTED PATIENTS (CDC C3)UWITH WASTING SYNDROME. EFFECTS OF
TREATMENT WITH RECOMBINANT HUMAN GH.
Soterte S. B, Fioravanti M, Rondanels M,VnatG 1 "', Sev )a rnee. ' octell M Ferrar E.
Minoi R**. Depart. Internal Mcediine, 'Fab Ci11 Ms''-ist.a 'Infectious c)isease Inst.,
University of Pavia. Pavia, Italy.
Objective: It is still unclear the s nicance of endo rI- ition,; often described in AIDS
patients.The controversy concerns the possible relv ince of these chanes in theie cal
progression of the disease or the evaluaIo of endocr n Ituction asa consequenceof
HIV infection. On this light we studied the basal and the - is i vtr,1 'v of the GH-IGFIIGFBP3 axis in HIV infected patients
Methods: We evaluated the basal concent ra t i oa te e iscada r-wthi t KG- iLGFI and
IGFBP3 in II HIV-seropositive in-patients (9M., d 8), -Iassfied 1( )C (-1(CD4+
below 200x106/L) with Wasting Syndrome (BMI 1 6F K''/m ) 2nd n2 healthy controls
(aged: 30~5; BMI= 22~ I Kg/m ). GH, IGFI and IGFBP3 vere Sdeterned by specific RIAs,
IGFI was previously extracted with acid ethanol. GH ( IGFI IGFBP3 basal concentrations and
circadian rhythms were also studied after treatment w th recomb inant humarn GH (rhGH:
16U/m2/weekly for 4 weeks)
Results: Higher basal GH (p<0.01) and lower IGFI (p:0. )()ianl IGFBP3 (p 0.001) serum
levels were found in HIV-serorpositive patients than n he, lthy ontro These, nges were.present throughout 24-h of the study. A lack of the crcadn rhvthrnity of GH- IGFI and
IGFBP3 was also demonstrated in AIDS patients. IGFI/IGFBP and IGFI/GHt molar ratios
were significantly flattened in HIVseropositive patients compared to healthy control subjects. rh GH treatment significantly increases (p<0.001) the 2 h IGFI pattern and normalizes the circadian profile of GH secretion, already after 2 weks of therapy.

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