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

Tu.B.2130 - Tu.B.2134

Tuesday July 9, 1996

Results: The median log decrease in viral RNA from baseline using the bDNA assay with a
500 copies/ml sensitivity limit, was I.4, 1.9. and I1.7 for the 500 mrg, 750 mg, and 1000 mg tic
dose cohorts, respectively. However, 20 % of the patients in the 500 mg tid group and 50 -60 % of the patients in the 750 mg and 1000 mg tid groups had viral load decreases that
fell below these assay limits. After a special request to look at values down to 100
copies/ml, the median decrease in viral RNA was 1.5, 2.4, and 2.3 for the three treatment
groups, respectively Even with the lower limit, a number of patients had values falling below
the level of detection. Mean increases in CD4 cell counts from baseline ranged from 37 to
100 cells/mm3 in the 28-day study period. All three dosing regimens were wNell tolerated.
The most frequently reported adverse events were loose stool and mild to moderate diarrhea.There were no clinically significant changes observed in laboratory parameters during
the trial.
Conclusions: Results suggest that excellent antiretroviral activity can be safely achieved with
VIRACEPT in a variety of dose regimens with viral load decreases exceeding assay limits of
sensitivity Controlled Phase II/11 trials are scheduled to proceed.
Marcus A. Conant, Conant Medical Group, I 635 Divisadero Street, Suite 601, San Francisco,
CA 94115 U.S.A. Telephone: [phone] FAX: [phone]
Tu.B.2130
COMBINATION ANTIRETROVIRAL THERAPY WITH STAVUDINE (D4T) AND
LAMIVUDINE (3TC):A RETROSPECTIVE ANALYSIS
Steinhart, Corklin R, Jacobsen. D,. George S. Mercy Hospital Special Immunology Services,
Miami, FL, USA.
Objective: To determine the safety and possible efficacy of combination antiretroviral therapy (ART) with d4T and 3TC in HIV-positive subjects with CD4 counts < 300/mm3.
Methods: 48 subjects, ages 30-62 (mean= 41.3 years) who qualified for the 3TC expanded
access program were given the combination of d4T (20-40 mg po bid) and 3TC (I 50-300
mg po bid) in a hospital-based private physician practice. 5 of the subjects were women, 35
were Hispanic, and all were ART-experienced. Complete hematological, biochemical,
immune profiles, and plasma HIV RNA (RT-PCR) were measured prior to beginning therapy
and monthly thereafter History and physical exams including weight anrid Karnofsky Scores
were also obtained.The study was conducted retrospectively
Results: All subjects completed at least 3 months of treatment (mean- 8.1). Mean CD4
count increased significantly (p<0.05) from 103/mm3 at baseline to I 31/mm3 at 3 months
of treatment. Mean plasma HIV RNA at baseline was 2. I x 105 copies/mI and did not
change. Sub-group analysis revealed an increase (p<0.05) in CD4 count in subjects with
baseline CD4-50-300/mm3 of 53 cells and CD8 cells increased from 741 to 1006 at 3
months (p<0.05). HIV RNA decreased from I. Ix 105 copies/ml at baseline to 4.7x 104
copies/ml at 6 months of treatment (p>0.05) in this sub-group.There were no significant
changes in hematologic or biochemcial parameters with the exception of transaminase elevations _ 3 times normal. Only 4/48 subjects discontinued therapy with d4T due to neuropathy 2/48 subjects discontinued treatment with 3TC due to rash.
Conclusions: We conclude that combination ART with d4T and 3TC is well-tolerated, user
friendly, and increases CD4 counts in ART-experienced subjects with CD4 counts 50-250
and may decrease viral load. Historical comparative trials between AZT-3TC and d4T-3TC
are warranted and studies using the combination of d4T and 3TC with protease inhibitors
are strongly encouraged.
CR Steinhart, 3659 S. Miami Ave., Suite 4006, Miami, FL 33133 USA Telephone: [phone] I Fax: [phone] email: [email protected]
Tu.B.213 I
BENEFITS AND SAFETY OF LAMIVUDINE (3TC) THERAPY IN HIV POSITIVE
PATIENTS WITH CHRONIC HEPATITIS B OR C
Sinclaii Fiona J,Womack M, Illeman M, Cafaro V, Conant M. Conant Medical Group, San
Francisco, CA United States
Objective: To determine the possible benefits and/or toxicities of 3TC use in HIV(+)
patients known to have either chronic hepatitis B or C by monitoring serological markers.
Methods: A retrospective chart review was done on 350 HIV(+) patients receiving 3TC in
the Glaxo Wellcome Open Label Protocol NUCA3004 at a large, private medical practice
in San Francisco. All patients were adult males on standard antiretroviral therapy and when
indicated, prophylaxis. Aspartate Aminotransferase (AST) and Alanine Aminotransfer-ase
(ALT), were obtained at entry into the study and at three months for patients with
Hepatitis B and at three and six months for patients with Hepatitis C.
Results: Five patients enrolled had evidence of chronic Hepatitis B. After three months, AST
values in four patients decreased by an average of 19.3% and ALT values decreased by an
average of 20.8%. One patient's values increased by I 6.4% and by I 6.9%, respectivelyThree
patients had evidence of chronic Hepatitis C. In all three their AST values decreased by an
average of 44.0% at three months and 44.3% at six months.The ALT values decreased by
33.6% at three months and 29.0% at six months.
Conclusions: In this review of 3TC in HIV(+) patients with Hepatitis B or C, there were no
significant increases in liver function tests. In the group we studied there is evidence that
3TC may help patients with ongoing Hepatitis infection. A large, prospective study is necessary to determine the possible benefit of 3TC therapy for Hepatitis B and C.
Fiona J. Sinclair I635 Divisadero St. #600, San Francisco, CA 94 I I5 Telephone: (415) 35 I3127 Fax [phone]
Tu.B.2132
COMPARISON OF AZT/3TC VS. D4T/3TC FOR THE TREATMENT OF HIV IN
PERSONS WITH CD4 COUNTS <300 AND PRIOR AZT EXPERIENCE.
Novak, Richard M., Colombo J., Linares-Diaz, M., Morema L. University of Illinois, Chicago
Illinois, USA
Objective: Lamivudine (3TC), a cytosine analog, with potent antiretroviral activity has
demonstrated benefit in AZT/3TC combination studies. Stavudine (D4T), like AZT is a
thymidine analog. At the present time, there is no information describing the interaction
between 3TC and D4T We compared the effects of AZT/3TC vs. D4T/3TC in persons
who were eligible for the 3TC expanded access program.

Methods: Entry criteria inluded CD4<300 and prior failure or intolerance to other antiretrovirals, including A7T and all were D4T naive. Patients were randomized to AZT/3 TC
(Group I) or D4F'3TC (Group 2). If they had a prior history of AZT intolerance, they
were nonrandmly as gned to D4T/3TC (Group 3) and analyzed separately Monthly follow-up included T cell sbets and quantitative viral burden assessments.
Results: There are currenty 17 persons with enough data to evaluate. Starting mean CD4
counts were: Group 1, 78.0 (range 10-220, N=5); Group 2, 33.8 (0-70, N=8); Group 3. 82.5
(10-170. N=4). After a men follow-up period of 24.7 weeks (range: 8-44 weeks), the three
groups were compared over time for four variables: absolute CD4 count, plasma viral burden, and changes from baseline CD4 count and plasma viral burden. Greater and more sustained increases in CD4 and declines in plasma viral burden variables were seen in the two
D4T arms compared to the AZT arm. Mean declines in plasma viral burden had returned
to baseline by week I 5 in Group I, week 36 in Group 2 and had not returned to basehline
by week 44 in Group 3. Mean increases in CD4 counts had returned to baseline by week
17 in Group I, week 36 in group two, and had not returned to baseline by week 44 in
Group 3.
Conclusions: Although the sample size is small, these results suggest that further study of
the D4T/3TC combination is warranted, particularly in persons with prior AZT experience.
Richard M. Novak, MD, University of Illinois, 808 S. Wood St. M/C735, Rm 886 Chicago, IL
60612 3 I12-996-6763; Fax: 312-4 13- I 657; Email: [email protected]
Tu.B.2133
ASSOCIATION BETWEEN ANTIRETROVIRAL TREATMENT WITH ZIDOVUDINE
AND RISK OF AIDS IN 1078 HIV-SEROCONVERTERS.
Dorrucci M*, Pezzotti P*, Phillips AN**, Rezza G*, Alliegro MB*.The HIV-Italian
Seroconversion Study group; *Istituto Superiore di Sanita, Rome, Italy; **Royal Free
Hospital and School of Medicine, London, UK.
Objectives: To evaluate the association between time since initiation of pre-AIDS antiretro
viral therapy with zidovudine (ZDV) and AIDS-free survival in a cohort of HIV-seroconverters.To assess possible differential effects of ZDV on HIV-disease progression by transmission
categories.
Methods: Observational study of 1078 HIV infected individuals (injecting drug users (IDU),
homosexuals (HM) or heterosexuals (HS)) with accurately estimated dates of seroconversion (SC), and enrolled in an ongoing prospective multicenter cohort (median follow-up: 5
years). Kaplan-Meier estimates of the probability of receiving ZDV some time before AIDS.
Crude and adjusted relative hazards (RHs) of AIDS and death from AIDS, using Cox proportional hazards models, where time since initiation of ZDV was entered as a time-dependent variable.
Results: The cumulative incidence (CI) of receiving pre-AIDS therapy within 7 years from
SC was 49.2% (95%CL: 45.3-53.0). IDU were less likely to undergo ZDV treatment before
AIDS [CI of starting ZDV: 40.6% (95%CL: 35.6%-45.7%)] compared with HM and HC [CI:
6 I1.0 (95%CI: 55.0%-67.0%)].The crude relative hazard (RH) of developing AIDS of patients
treated with ZDV was 2.44 (95% Cl: 1.58-3.77) and 4.10 (95% CI: 2.99-5.64) within the
first year since starting ZDV and after I year from ZDV initiation, respectivelyThe RHs
declined to 0.57 (95%CI: 0.36-0.9 I) and to 0.92 (95%CI: 0.64- i.33) after adjusting for
occurrence of acute disease, pre-AIDS HIV-related diseases, CD4 lymphocytes count. and
use of prophylaxis for PCPThe adjusted RHs of AIDS for patients who started ZDV less
than I and more than I year ago, were: 0.74 (95%CL: 0.40-1.38) and 0.99 (95%CL: 0.59 -1.66) among IDU, 0.31 (95%CL: 0.12-0.82) and 0.89 (95% CL: 0.43- 1.87) among HM 0.69
(95%CL: 0.24- I1.93) and 0.72 (95%CL: 0.29-1.79) among HC. respectively Similar results
were obtained after repeating the analyses using death from AIDS as an end-point.
Conclusions: Results from this non-randomised study in common with other studies, are
consistent with there being only a short-term clinical benefit of antiretroviral treatment with
ZDV received before AIDS.There was a stronger association between zidovudine use and
lower risk of AIDS in homosexual men, suggesting a possible different compliance of antretroviral therapy in this transmission group compared with injecting drug users.
Maria Dorrucci, Istituto Superiore di Sanita,Viale Regina Elena 299, 0016 I Roma, Italy Tel.
(39) (6) 49902337; Fax: (39) (6) 445674 1: e-mail: ccorte @ ISS.IT
Tu.B.2134
POPULATION PHARMACOKINETIC (PK) ANALYSIS OF STAVUDINE (d4T) IN HIVINFECTED PATIENTS WITH CD4 COUNTS BETWEEN 50 AND 500 CELLS/mm3.
Grasela,Thaddeus H*, Haworth SJ**, Fiedler-Kelley J*, Christofalo B**. *Pharmaceutical
Outcomes Research, Buffalo, NY: **Bristol-Myers Squibb, Princeton, NJ.
Objectives: To perform a population-based analysis of d4T PK in HIV-infected patients, and
to evaluate the nature and extent of drug interactions and the effect of patient covriates
on the PK of d4T
Methods: A population-based analysis of the PK of d4T was performed using 4 108 plasma
concentrations measured in 315 HIV-infected patients enrolled in a Phase 3 trial.The analsis was performed using a one compartment model with first order absorption, implemented within the computer program NONMEM.
Results: Based on this analysis, the total body clearance (CLT) for d4T in a 70 kg standard
patient was estimated to be 325 mL/min and the volume of distribution (Vd) was 70 L.The
estimated half-life (C) in the population was 2.5 hours. Although there was relatively little
information collected during the absorption phase for stavudine, tfhe absor-ption nate constant was estimated to be fast, i.e., 4.27 hrsI with large interindividual variability No effect
of food was detected. Selected patient characteristics emerged as statistically signiicant, but
clinically unimportant, influences on the CLT of d4T CLT was reduced by -20% in Blacks
and Hispanics as compared to Caucasians. CLT was estimated to be -50% larger in IV drug
abusers. -22% larger in patients with low CD4 counts ( 100) upon enrollment, I 4% smaller in patients who have CD4 counts between 100 and 300 at baseline, and -!8% larger in
patients who had a change in SGPT during the study. For Vd, females tend to have a 23%
smallerVd than males, adjusted for body size.Vd is -2 1% smaller in Blacks and 6% larger in
Hispanics than Caucasians. Of the concomitant drugs examined, only acyclovir emerged as
having a statistically significant effect on d4T PK; CLT was estimated to be -20% smaller and
Vd estimated to be - 17% larger resulting in a calculated half-life of 3.6 hours. After adjusting for patient-related covariates, d4T had only moderate interindivmdual variability in CLt
and Vd, i.e., 39% and 34%, respectively