Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

12th World AIDS Conference

Abstracts 12217-12221 55

other NNRTIs, did occur during this study, but neither event was drug-related. After oral administration, CA has a long absorption/distribution phase and a half-life
of 20 hours. Cmax values in humans are higher than anticipated from animal data.
Both AUC and Cmax increased with increasing dose. Levels achieved were well
above the EC90 of CA against a number of HIV-1 strains.
Conclusions: CA is generally well tolerated in single doses up to 800 mg
and its toxicity profile is different from other approved NNRTIs. Based on the
in vitro EC90 values against HIV-1, therapeutic levels of CA can be achieved in
humans. Combination of CA with other antiretroviral drugs demonstrated to be
synergistic in vitro and therefore may open new possibilities for treatment of HIV
infections.
12217 Nevirapine/lamivudine drug-drug interaction study in HIV
infected patients
Gerhard Leitz, M. Lamson, D. Lionetti, J. Sabo, M. Myers. Boehringer Ingelheim
Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT 06877, USA
Objective: Nevirapine (NVP) is a non nucleoside RT inhibitor of HIV that is
metabolized by Cytochrome P450 3A in the liver. lamivudine (3TC) is a nucleoside RT inhibitor which is largely excreted unchanged in the urine. The two
drugs are frequently used in combination with other annti-retrovirals. This study
was designed to determine the effects of multiple-dose NVP administration on
the steady-state serum concentrations of 3TC and the effect of 3TC on NVP
pharmacokinetics when administered together on a background of anti-retroviral
therapy.
Methods: A population pharmacokinetic approach was employed to assess
the effects of nevirapine on the pharmacokinetics of lamivudine in 100 patients
who were randomized into a large clinical endpoint study. Patients received either
NVP (200 mg q.d. for two weeks then 200 mg b.i.d.) + 3TC (150 mg b.i.d.) or
placebo + 3TC on an anti-retroviral background therapy. At the beginning of the
study patients were instructed to take their morning NVP/3TC doses together at
the same time every day and to take their evening doses 12 hours later. Four
weeks after treatment start, blood samples to determine NVP/3TC concentrations
were taken at defined time points. In addition, patients were required to document
the time they took the morning dose of NVP/3TC that day.
Results: The preliminary results suggest that nevirapine co-administration resulted in a non-significant increase in lamivudine serum concentrations from 792
~612 ng/mL (725 ng/mL, median) to 917 ~ 719 ng/mL (759 ng/mL, median).
The effects (apparent clearance, volume of distribution, T1/2) of nevirapine on
lamivudine as well as those of lamivudine on nevirapine will be presented utilizing
the mixed-effects population pharmacokinetic program NONMEM.
12218 The pharmacokinetic interactions of nevirapine and
ketoconazole
Michael Lamson, Patrick Robinson, M. Gigliotti, M.W. Myers. Boehringer
Ingelheim Pharmaceuticals, Rigdefield, CT, USA
Nevirapine (NVP) and (ketoconazole) Keto are metabolized by the hepatic p450
isozyme system. NVP induces p450 metabolism (CYP2B6 > CYP3A4), whereas
Keto inhibits CYP3A4. Both have the potential for important interactions with each
other. We performed an open-label, single arm trial of Keto alone and with NVP
in HIV-infected patients to examine NVP and Keto's pharmacokinetic (PK) effects
on each other.
Methods: 26 patients with CD4+ count >100 cells/mm3 were begun on Keto
400 mg q.d. NVP was added on day 5 (200 mg/d x 14 days, then 200 mg
bid x 14 days). Plasma samples were obtained on day 4 for Keto concentrations and on day 32 for NVP and Keto concentrations. The effect of nevirapine
coadministration on the steady-state pharmacokinetics of Keto was evaluated by
comparing (Wilcoxon Signed Rank test, a = 0.05) the mean difference in the
steady-state Keto AUC and Cmaxss determined before and after addition of NVP.
NVP pharmacokinetic parameters were compared to historical controls.
Results: NVP coadministration resulted in a significant 62.8% (median) reduction (p: 0.05) in Keto AUC from 44.9 to 15.4 t/g/mL and a 39.5% reduction (p
< 0.05) in Keto Cmax from 6.72 to 4.20 tpg/mL compared to baseline (n = 22).
The results of the NVP pharmacokinetic analysis suggest that Keto had a slight
inhibitory effect on NVP metabolism as evidenced by an approximately 15-20%
increase in NVP Cmaxss (6.7 ~ 2.2 /tg/mL) and Cminss (5.3 ~ 2.1 lrg/mL)
compared to historical controls, although the inhibitory interaction may have been
muted by the induction effect by NVP on Keto.
Conclusion: An alternative antifungal agent to Keto should be considered
when NVP is part of the anitretroviral regimen.
129* /12219 Interim analysis of plasma viral burden reductions
and CD4 increases in HIV-1 infected patients with
Rescriptor (DLV) + Retrovir (ZDV) + Epivir (3TC)
Stephen Green1, M.F. Para2, P.W. Daly3, W.W. Freimuth4, L.D. Getchel4,
C.A. Greenwald4, L.K. Wathen4. 1Hampton RD Medical SPEVC PC, 2112

Executive Drive, Hampton, VA; 20hio State University Hospitals, Columbus, OH;
3 Nelson-Tebedo-Community Clinic, Dallas, TX; 4 Pharmacia & Upjohn Inc.,
Kalamazoo, Ml, USA
Objectives: To compare the plasma HIV-1 RNA PCR and CD4 levels in 373
HIV-1+ patients with treated with DLV+ZDV+3TC, ZDV+3TC, or DLV+ZDV.
Design: Blinded, randomized study.

Methods: HIV-1+ patients with mean CD4 = 354-360 cells/mm3 and mean
viral burdens of 22,000-31,000 copies/mL were randomized to a DLV+ZDV+3TC,
ZDV+3TC, or DLV+ZDV treatment regimen and treated for a mean of one year.
Results: In an interim analysis (<40 copy/mL cut-off), the triple therapy
group had a significantly greater mean decrease in HIV-1 RNA levels (-2.2
loglocopies/mL) than the ZDV+3TC group (-1.3 loglocopies/mL) at week 24.
The ZDV+3TC arm had a greater HIV-1 RNA reduction than the DLV+ZDV (-0.6
loglocopies/mL) treatment arm. The triple therapy group had a significantly greater
percentage of patients below the limit of detection (%BLD, <400 copies/mL) than
the ZDV+3TC group at all timepoints from week 8 through week 52. In the triple
therapy group, the %BLD remained at 68% after 52 weeks. In the ZDV+3TC
group only 22% were BLD at 52 weeks. For weeks 24 to 52, the mean increase
from baseline in CD4 cell count was 88-122, 72-77, and 13-18 cells/mm3 for the
DLV+ZDV+3TC, ZDV+3TC, and DLV+ZDV groups respectively. The percentage
of patients who remained free from virologic failure (at both the <400 and <40
copies/mL cutoff) was significantly greater with the triple drug therapy than either
dual therapy.
Conclusion: The DLV+ZDV+3TC therapy demonstrated a superior and significant reduction in viral burden as measured by mean change from baseline and
by percent of patients with RNA levels below detection limit than either of the dual
therapies.
S12220 Combivir" (lamivudine (3TC) 150 mg/zidovudine (ZDV)
300 mg) given BID plus a protease inhibitor (PI) compared
to 3TC 150 mg BID and ZDV 200 mg TID plus a PI
Mark Shaefer1, J. Eron2, E. Yetzer3, P. Ruane4, S. Becker5, G. Sawyerr1,
N. Graham1. 1 Glaxo Wellcome Inc., Five Moore Drive Research Triangle Park,
NC; 2UNC-Chapel Hill, RTP, NC; 3Pacific Oaks Research Beverly Hills, CA;
5Pacific Horizon Medical Group, San Francisco, CA, USA
Objectives: To show that in HIV-infected patients Combivir BID in combination
with a PI is not different than a conventional regimen of 3TC, ZDV and a PI as
measured by HIV-1 RNA levels over time. To compare the number of patients
that attain undetectable HIV-1 RNA levels below the limit of detection, <400
copies/mL.
Design: An open-label, randomized, parallel-group study to enroll 240 patients
stable on a regimen of 3TC 150 mg BID, ZDV 600 mg daily and a PI, with HIV
RNA < 10,000 c/mL and CD4+ cell count >300/mm3. Patients are stratified by
their current PI and then randomized to receive their PI and either Combivir or
3TC and ZDV separately. Patients will be followed for 16 weeks, or until they
reach a study endpoint defined as an HIV-1 RNA increase of >0.51ogio above
baseline. Compliance data will be collected and correlated with viral load results.
Results: To date, 97 patients have been randomized to Combivir and 95 to
3TC and ZDV (88% male). PI's on entry were as follows: 62% indinavir, 18%
nelfinavir, 10% saquinavir and 9% ritonavir. Four patients reached a viral load
endpoint, HIV-1 RNA increase of >0.51og0o above baseline, one in the Combivir
+ PI arm and three in the 3TC, ZDV + PI arm.

Combivir + PI 3TC, ZDV + PI
n Median VL (range) --400 n Median VL (range) -400
Wk 0 97 400 (<400-8,977) 70% 95 400 (<400-17,822) 75%
Wk 4 81 400 (-400-24,503) 73% 81 400 (-400-23,167) 75%
Wk 8 62 400 (<400-17,901) 81% 63 400 ( 400-51,299) 68%
Wk 16 24 400 (<400-3613) 96% 25 400 ( 400-18806) 72%
*P value for comparison of percentage of subjects with HIV-1 RNA - 400 copies/mL

p
0.998
0.006
0.038

Conclusion: Preliminary data suggest that subjects taking Combivir + a PI
were more likely to have HIV-1 RNA viral load below the limit of detection than
subjects taking 3TC and ZDV separately with a PI. Correlation of compliance data
with viral load will be presented.
126*/12221 Saquinavir/ritonavir may have better antiviral
efficacy than either ritonavir or indinavir in HIV
infected antiretroviral naive patients
Court Pedersen, J. Gerstoft, J.O. Lunnogren, L. Mathiesen, O. Kirk, H. Nielsen,
T. Katzenstein. Department Infectious Diseases C Odense University Hospital
5000 Odense; Department Infectious Diseases Rigs Hospital, Copenhagen
Denmark, 2Dept. infectious Aaborg, denmark Sygehus, Denmark
Background: The efficacy of a protease inhibitor in combination with two nucleoside analogues has been established. However, it is not known which protease
inhibitor or combination hereof, that is the best. In a randomised, controlled trial
we compared the efficacy and safety of three different protease inhibitor regimens.
Methods: A total of 257 patients not previously treated with protease inhibitors
were randomly assigned to one of three daily protease inhibitor regimens: 800
mg indinavir t.i.d., or 600 mg ritonavir b.i.d., or a combination regimen with 400
mg ritonavir b.i.d. and 400 mg saquinavir b.i.d. All patients received additional
treatment with two nucleoside analogues. 161 patients were previously treated
with nucleoside analogues. The primary end-point was the proportion of patients
with HIV-RNA <200 copies/ml at 6 months (Roche Amplicor). In the drug naive
patients efficacy was also determined using HIV-RNA <20 copies/ml as endpoint
at 6 months.
Results: By 1st December 1997 177 patients had completed 6 months of treatment. The proportion of patients with HIV-RNA < 200 copies/ml was 79% in the
indinavir group, 72% in the ritonavir group, and 86% in the combination group (p =