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

12th World AIDS Conference

Abstracts 12358-12362 85

S12358 (-)-3-D-2,6-diaminopurine dioxolane is a prodrug of
dioxolane guanosine a novel inhibitor of HIV-1 replication
Laura Lynn Kiefer1, Phillip A. Furman1, G.R. Painter1, I. Liberman2, E.L. Hill1,
K.B.E. Borroto1, C.K. Chu3, R.F. Schinazi2. 1 Triangle Pharmaceuticals Inc.,
4611 University Drive, Durham, NC; 2Emory University Decatur, GA; 3University
of Georgia, Athens, GA, USA
Objectives: To compare the anti-HIV-1 activity of (-)-/-D-2,6-diaminopurine dioxolane (DAPD) and dioxolane guanosine (DXG) and to determine the mechanism
of action of DAPD.
Results: DAPD and its metabolite DXG are inhibitors of HIV-1 replication in
vitro. The EC50 values against HIV-1 in MT2 cells for DAPD and DXG are 1.5
~ p/M and 0.005 ~ p M, respectively. DAPD is also active against hepatitis B
virus in vitro (EC5o = 0.024 i/M) and in the woodchuck model for hepatitis. The
concentration of both drugs that inhibit cell growth by 50% is >100 tM. We
have shown that DAPD is deaminated by adenosine deaminase to DXG and
that deamination is required for anti-HIV activity. Using purified calf adenosine
deaminase, DAPD has a Km of 11 pIM and a kcat of 0.25 s-1. In CEM cells
exposed to DXG, the compound is readily converted to the 5'- mono-, di-, and
triphosphate derivatives. DAPD, on the other hand, is not phosphorylated in CEM
cells, but is first deaminated to DXG and then converted to the nucleotide forms
of DXG. DXG 5'-triphosphate is a potent inhibitor of the HIV-RT giving a Ki of
0.019 ~ 0.002 p/M. In contrast, the 5'-triphosphate of DAPD is a weak inhibitor
of the HIV-RT with a Ki of 250 ~ 25/pM. Against the human a-DNA polymerase
both DXG- and DAPD-5'-triphosphate show weak inhibition with Ki values of 78
~ 17 M and 1200 ~ 100 pM, respectively.
Conclusions: DAPD, a novel prodrug that is converted to DXG, shows potent
and specific in vitro anti-HIV activity with little or no cytotoxicity. DAPD is currently
being developed for the treatment of disease due to HIV and hepatitis B virus.
12359 Durable clinical anti-HIV-1 activity (72 weeks) and
tolerability for efavirenz (DMP 266) in combination with
indinavir (IDV) [DMP 266-003, Cohort IV]
Sharon Riddler1, J. Kahn2, C. Hicks3, D. Havlir4, D. Stein5, J. Horton6, N. Ruiz7.
1University of Pittsburgh, Pittsburgh, PA; 2San Francisco General Hospital,
San Francisco, CA; 3Duke University, Durham, NC; 4 UCSD Treatment Center,
San Diego, CA; 5Albany Medical College, Albany, NY; 6Carolinas Medical Center,
Charlotte, NC; 7DuPont Merck Pharmaceutical Company, Wilmington, DE,
USA
Introduction: Efavirenz (EFV, Sustiva'", DMP 266) is an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI). Pharmacokinetic evaluation
supports once-daily administration.
Objectives: Evaluate the safety, tolerability, and long-term antiretroviral activity
of EFV (200 mg qd increased to 600 mg qd at 36 weeks) and IDV (800/1000 mg
q8h) given in combination compared with that of IDV (800/1000 mg q8h) alone in
asymptomatic or mildly symptomatic patients.
Dosing: Fifty-nine patients randomized to EFV + IDV initiated treatment with
both drugs simultaneously. Forty-two patients randomized to initiate treatment
with IDV alone subsequently added d4T and EFV after 12 weeks.
Methodology: Multicenter, blinded study (101 patients) with plasma samples taken at defined intervals. HIV-1 RNA (copies/mL) determined by RT-PCR
(Amplicor"); CD4 (cells/mm3) determined by flow cytometry.
Demographics: Men = 86%; age = 38.5 years (~8.0); prior NRTI therapy =
71%; mean years HIV+ = 5.0 + 3.6.
Baseline Values: Mean plasma HIV RNA = 5.06 log1o ~ 0.55; mean CD4 =
283 ~ 118 cells/mm3.
Preliminary Results: At 60 weeks, the percentage of patients with plasma
HIV RNA below quantifiable levels (BQL), (BQL = <400 copies/mL) was: EFV +
IDV = 89%; IDV + d4T + EFV = 68%. Mean loglo decrease in plasma HIV RNA
(truncated at 400 copies/mL) at 60 weeks: EFV + IDV = -2.5 ~ 0.09; IDV + d4T
+ EFV = 1.9 ~ 0.20. Mean increases at 60 weeks for CD4 count: EFV + IDV =
+267 (~26) cells/mm3; IDV + d4T + EFV = +210 (+36) cells/mm3. Seventy-two
(72) week updates of this data will be presented.
Tolerability. Both treatment arms were generally well tolerated out greater than
1 year at 72 weeks. Updated tolerability data will be presented.
Conclusion: EFV dosed once daily in combination with IDV provides sustained,
durable, viral suppression.
| 12360 Once-daily dosing of nevirapine: A retrospective,
cross-study analysis
Alex Dusek1, D. Hall2, M. Lamson2, M. Myers2. 1900 Ridgebury Rd, Ridgefield
Ct; 2Boehringer Ingelheim Pharmaceuticals, Rigdgfield Ct, USA
Background: Nevirapine (NVP) is a potent non-nucleoside reverse transcriptase
inhibitor. In pivotal clinical trials it was dosed as one 200 mg tablet x 14 days,
followed by one 200 mg tablet twice-daily (BID) thereafter, due to auto-induction
CYP450 enzymes. It is >90% bioavailable, widely distributed, and isn't affected

by food or antacids. Early trials of NVP used a 400 mg once-daily (QD) dose due
to NVP's 25-30 hr steady state (ss) life.
Methods: Pharmacokinetic (PK) data were analyzed from 4 clinical trials where
NVP was administered at a 400 mg QD dose. Patients in these trials were either
taking NVP or NVP+ zidovudine at the time of PK sampling. 52 patients are
included in the preliminary analysis (BI 744 n = 10, BI 1010 n = 19, BI 1011 n =
23). Analyses include descriptive summary of mean trough levels and review of

the adverse events AE's in each trial. The trough levels were then expressed as
a multiple of the IC90 of NVP for wild-type (WT) virus [60 nM].
Results: In preliminary analyses, the C troughs with 400 mg QD are compared
below to pivotal BID NVP trials.
Clinical Trial (n =) Dosing Regimen (ss) Mean Trough Levels (/;g/mL) NVP Cmin/IC90
ACTG 241 (n = 156) 200 mg BID 4.6 287
INCAS (n = 84) 200 mg BID 4.1 257
QD studies (n = 52) 400 mg QD 4.0 251
Further examination of the difference in PK of 200 mg BID and 400 mg QD
will characterize differences in both peak and tough. The AE's observed in the
400 mg QD trials did not differ greatly from 200 mg BID trials, except for a higher
incidence of rash in the patients who were not given a 2 week lead in at 200 mg
QD.
Conclusions: The plasma levels achieved by once-daily dosing of NVP were
251-fold above the IC90 of WT virus. These trough levels compare favorably
to pivotal NVP BID trials where potent and durable viral load suppression was
achieved. This suggests that a two tablet, 400 mg once-daily dosing regimen of
NVP after a 2 week 200 mg QD lead-in should provide adequate drug exposure in
combination therapy regimens designed to maximize adherence and convenience
for the patient.
S12361 Patients with higher baseline pVL are less likely to have a
virologic response in a meta-analysis of two trials of
ZDV/ddl vs ZDV/ddl/NVP
Janet Raboud1, J.S.G. Montaner2, S. Rae2, R. Bucciardini3, M. Floridio3,
D. Ricciardulli3, S. Vella3. 1620-1081 Burrard Street, Vancouver, BC VGZ 146;
2Canadian HIV Trials Network, Vancouver, Canada; 3lstituto Superior Di Sanita,
Rome, Italy
Objectives: To compare virologic response by baseline plasma viral load (pVL)
in a meta-analysis of two randomized trials of ZDV/ddl vs ZDV/ddl/NVP.
Methods: Original data from 170 antiretroviral naive patients with pVL and CD4
measurements at baseline in the INCAS and ISS047 trials were pooled together
in a single database and analysed together. 87 patients received ZDV/ddl and 83
received ZDV/ddl/NVP.
Results: At baseline, 82 patients had pVL < 50,000 copies/mL, 39 had pVL
50,000-250,000 copies/mL and 49 had pVL > 250,000 copies/mL. Among patients on ZDV/ddl, 28% of those with pVL < 50,000, 18% of those with pVL
50,000-250,000 and 0% of those with pVL > 250,000 at baseline had pVL <
400 copies/mL at 48 weeks (p =.02). Among patients on ZDV/ddl/NVP, 44% of
those with pVL < 50,000, 29% of those with pVL 50,000-250,000 and 22% of
those with pVL > 250,000 at baseline had pVL < 400 copies/mL at 48 weeks (p
=.16). In multivariate proportional hazards models, patients with pVL > 250,000
at baseline were 2.33 (95% CI = 1.1-4.9) times as likely to experience virologic
failure (pVL > 5000) as patients with pVL < 50,000 at baseline, after controlling
for treatment, compliance and pVL nadir.
Z DV.dd'N VP
1 -I Baseline pVL:
-- 25.000
S-...... 25.so -250C000
p *-- > 250.000

o0 24 40 45
n; Study Week
a83 72 -64- 59 58
Conclusions: Among patients on ZDV/ddl, baseline pVL > 250,000 copies/mL
was strongly predictive of a poor virologic response at 48 weeks. Although not
statistically significant, there was a trend for patients on ZDV/ddl/NVP with higher
pVL at baseline to have poorer pVL response.
S12362 Drug combination studies on MKC-442 with RT inhibitors
in long-term culture of HIV-1-infected cells
Satoshi Yuasa1, K. Nakade1, J. Piras2, M. Baba2. 1Mitsubishi Chemical
Corporation, 1000 Kamoshida, Aoba-Ku, Yokohama; 2Kagoshima University,
Kagoshima, Japan
Objective: MKC-442 is a potent nonnucleoside reverse transcriptase inhibitor
(RTI), and clinical trials of MKC-442 as combination therapies with nucleoside
RTIs are in progress. To investigate the profiles of MKC-442 in drug-resistance,
long-term cultivation of infected cells with wild-type and mutant HIV-1 were carried
out in combination of MKC-442 with one or two RTIs.
Methods: Drug-combination effects were evaluated in MT-4 cells infected with
HIV-1 III strain. Viral breakthrough was observed during long-term cultivation of
IIIB, A018A and A018C strains.
Results: MKC-442 synergistically suppressed the replication of III strain,
when combined with 3TC and AZT. A ratio of 10:100:1 for MKC-442: 3TC: AZT
showed the strongest synergism. This three-drug combination markedly delayed
or even completely suppressed HIV-1 replication at least for 40 days. In contrast,
viral breakthrough were observed in two-drug combinations, such as MKC-442 +
3TC or MKC-442 + AZT, after a 20-day cultivation period. Breakthrough viruses