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

12th World AIDS Conference

Abstracts 41174-41178 777

Conclusion: Our study shows that HIV-1 subtypes circulating in Burkina Faso
do not appear as having any impact on five currently used commercial HIV
screening tests responses.
557*/41174 Anti-HIV activity, biochemistry, and
pharmacokinetics of 3-D-2',3'-didehydro2',3'-dideoxy-5- fluorocytidine (D-D4FC)
Raymond Schinazi1, L. Ma1, J. Shi1, D. Liotta2, A. Faraj3, J.P. Sommadossi3.
1 VAMC/Emory University Medical Rsch 151 1670 Clairmont Rd Decatur, GA
3003; 2Emory University Atlanta GA; 3 University of Alabama Birmington AL, USA
Introduction: The antiviral, biochemical, and pharmacological profile of a new
chiral /-D-cytosine nucleoside was determined in vitro and in vivo.
Methods and Results: D-D4FC is a potent and selective inhibitor of HIV-1,
HIV-2 and SIV in vitro with an EC50 in human peripheral blood mononuclear (PBM)
cells of <0.07 pM and no cytotoxicity in human cells up to 100 ptM. Surprisingly
and in contrast to the toxic L-D4FC enantiomer, D-D4FC had no in vitro toxicity,
and had no effect on human bone marrow cells or mitochondrial DNA synthesis. D-D4FC was not cross-resistant with AZT, DDC, DDI, D4T, 3TC, (-)-FTC,
L-D4FC, DXG, various protease and non-nucleoside RT inhibitors, and was effective against cloned viruses with single and multiple mutations in the reverse
transcriptase region (41L, 65R, 67N, 70R, 103N, 184V, 215Y, 219Q, 210W). Combination studies in acutely infected human PBM cells indicated that the interaction
between D-D4FC and AZT or D4T was not antagonistic. D-D4FC-5'-triphosphate
was a potent and selective inhibitor of recombinant HIV-1 RT with an IC50 of 0.1
pM and no effect on cellular polymerases up to >50 pM. D-D4FCTP was a more
effective DNA chain terminator than either 3TCTP or L-D4FCTP when either
wild-type RT or 184V-mutated RT was used. D-D4FC was also highly effective in
a SCID-hu HIV-1 mouse model at 60 mg/kg per day when given intraperitoneally
for 6 days. Pharmacokinetic studies in rhesus monkeys indicated that the DD4FC had a terminal oral tl/2 of 4.0 ~ 0.9 hr, was orally bioavailable (F = 48%),
and was primarily cleared unchanged by the kidney.
Conclusions: D-D4FC is different from related cytosine nucleosides such as
3TC and (-)-FTC, where the greater potency and lack of cytotoxicity resides
with the /-L-enantiomers. D-D4FC has favorable virological and pharmacological
properties for advanced preclinical development for HIV infections. (Supported
by NIH grant AI-41980, AI-28731, RR00165, and VA)
554*/41175 1 Cellular pharmacology of the antiviral agents
PMPA and PMEA in vitro and in vivo
Arnold Fridland1, B. Robbins1, J. Rodman1, C.C. Tsai2, N. Bischofberger3. 1St
Jude Childrens Research Hospital, 332 N. Lauderdale, Memphis, TN; 2Univ of
Washington, REGPRIMATE Center, Seattle, WA; 3GILEAD Sciences, Foster
City, CA, USA
Background: The acyclic nucleotide analogs PMPA and PMEA (adefovir) have
shown potent anti-SIV activity in macaques and anti-HIV activity in Phase II/111
clinical trials. The efficacy of these agents is dependent on their intracellular
activation to their diphosphate derivatives.
Objective: To investigate the phosphorylation of the two drugs in vitro in human
PBMC and in vivo in macaques following systemic administration to develop a
kinetic model of their intracellular metabolism that may guide further clinical trials.
Design: Four long-tailed macaques were administered either PMEA or PMPA
(30 mg/kg) as short (~0.1 h) intravenous infusion and serial measurements (over
48 h) of plasma drug concentrations, and their mono- and diphosphate derivatives
in PBMC, red blood cells and lymph nodes was determined.
Results: The peak plasma PMPA and PMEA concentrations in the macaques
were 30-52 uM; elimination of PMEA and PMPA from plasma was monophasic
with terminal t1/2 of 7.6 h. The active intracellular metabolites of PMPA and
PMEA in PBMCs in these animals reached level of 0.3-0.5 uM, which persisted in
cells for >48 h. These intracellular metabolites of PMEA and PMPA also showed
prolonged half-lives in human PBMC with t1/2 of -15 and 49 h in stimulated
quiescent and cells, respectively.
Conclusions: These results show that PMPA and PMEA have very favorable
cellular kinetic properties in vivo, as well as in vitro, which may permit maintenance of effective levels of these analogs with infrequent dosing for the treatment
and prophylaxis of HIV and HBV infections.
293*/41176 The safety, tolerance, pharmacokinetics, and
efficacy of PNU-140690, a new non-peptidic HIV
protease inhibitor, in a phase I/II study
Yenyun Wang1, C.M. Tutton2, M.T. Borin1, C.L. Daenzer1, H. Li1, R.M. Wurtz2,
A.A. Piergies2, W.W. Freimuth1. 1Pharmacia & Upjohn, 7000 Portage RD
9155-243-148 Kalamazoo M 49001; 2Evanston Hospital Evaston IL, USA
Background: PNU-140690 is a new nonpeptidic HIV protease inhibitor (PI)
effective against ritonavir/indinavir resistant HIV isolates in vitro.

Methods: Open-label, multiple-doses (900, 1200 and 1500 mg TID) of PNU140690 were administered to 24 PI naive patients, who had CD4 cell >50 cells/
mm3, HIV RNA > 4000 copies/mL, and were on stable dual nucleoside reverse
transcriptase inhibitors (NRTIs) for >2 months (median - 10 months). Pharmacokinetic parameters were estimated from steady-state profiles obtained on study
day 10. Primary immunological and virological parameters for efficacy were CD4
and plasma HIV-1 RNA measured by Roche's Amplicor and ultrasensitive assay.

Results: Data collected up to 4 weeks showed that PNU-140690 was well tolerated. No serious adverse events (AE) reported. Primary AEs were gastrointestinal
(GI) tract related including diarrhea, nausea and vomiting that were managed by
taking study drug with light snacks, although 37% were treated symptomatically.
Steady-state trough PNU-140690 concentrations on day 10 averaged 1.2 ~ 0.6,
1.9 ~ 1.2, and 2.8 ~ 1.6 pM in the 900, 1200, and 1500 mg TID groups, respectively. Adding PNU-140690 to dual NRTI therapy resulted in mean HIV RNA
reductions of 1.0, 1.3 and 1.2 log on day 11 in the 900, 1200, and 1500 mg TID
groups, respectively. At week 4 the corresponding average RNA reductions were
0.5, 1.1, and 0.9 logs in these groups. No genotypic changes observed at week
4. Clinical records suggested compliance was correlated with the changes in HIV
RNA levels.
Conclusions: PNU-140690, a new nonpeptidic HIV protease inhibitor with
potent antiretroviral effect has been well tolerated in PI naive patients in this
study at doses of 900 to 1500 mg TID. There were no significant adverse effects
of PNU-140690 observed when PNU-140690 was added to stable dual NRTI
therapy. The pharmacokinetics of PNU-140690 taken with two NRTIs in HIV-1
infected patients were similar to those observed in healthy volunteers receiving
PNU-140690 alone.
179*/41177 Peripheral insulin resistance leading to impaired
glucose tolerance in HIV-1 infected patients treated
with protease inhibitors
Ravi K. Walli1, O. Herfort1, G.M. Michl1, T. Demant2, S. Maus3, C. Dieterle1,
F.D. Geobel1. 1Nedizinische Poliklinik, University of Munich, Pettenkofer Str. 8a,
80336 Munich; 2Klinikum Grosshadern, University of Munich, Munich;
3Kuratorium fOr Immunschwaache, Munich, Germany
Objectives: The use of protease inhibitors in antiretroviral therapy for HIV-1
infection has been linked with the occurrence of both transient and irreversible
hyperglycemia and manifest diabetes mellitus. It is unclear whether these findings
are coincidental or whether they reflect a causative effect of protease inhibitors.
Design: Cross-sectional controlled study.
Methods: Insulin sensitivity (IS) was determined in 27 patients treated with
protease inhibitors, 7 therapy naive patients and 18 HIV-negative controls by
regression analysis from an intravenous insulin tolerance test (ITT). In addition,
20 of the treated patients underwent an oral glucose tolerance test (OGTT).
Results: 9 of the treated patients showed normal glucose tolerance (NGT),
and 11 impaired glucose tolerance (IGT; 7 of these diabetic). In all therapy naive
patients and controls, IS was normal. Whereas all 11 patients with IGT revealed
a peripheral insulin resistance, in patients with NGT IS was normal (n = 5),
inadequate (n = 3) or borderline (n = 1). Of the 7 treated patients not subjected
to OGTT, 2 had a normal, and 5 a pathological IS: Median IS was significantly
highest in controls (177 /Imol/l/min) and therapy naive patients (150 tpmol/l/min),
as compared to treated patients with NGT (121 p/mol/l/min; p < 0.01) or IGT (55
/imol/l/min; p < 0.001). Median IS in patients with NGT was significantly higher (p
< 0.01) than in patients with IGT. C-peptid values in OGTT showed no significant
differences between patient groups.
Conclusion: Antiretroviral therapy for HIV-infection with protease inhibitors is
associated with impaired glucose tolerance by inducing peripheral insulin resistance Further investigation is needed to confirm the causative role of protease
inhibitors, and to elucidate underlying pathophysiological mechanisms.
339*/41178 Triple combination therapy and change in
peripheral blood T-cell subset composition during
asymptomatic HIV-infection
Milos Opravill, Leslie R. Bisset2, R. Con1, W. Huber1, M. Battegay3,
P. Vernazza4, P.J. Grob5, R. Luethy1. Ilnfectious Diseases University Hospital
CH-8091 Zuerich; 2Clinical Immunology University Hospital Zuerich; 3Outpatient
Clinic University Hospital Basel;4 Medical Clinica Cantonal Hospital St Gallen;
Objectives: To evaluate the influence of triple combination anti-retroviral therapy
on disease-induced T-cell activation and maturation abnormalities during early
asymptomatic HIV-infection.
Design: A prospective open-label trial of AZT, 3TC and ritonavir in treatmentnaive asymptomatic HIV-infected individuals with >400 CD4+ T-cells/pl.
Methods: Peripheral blood CD4+ and CD8+ T-cells derived from 15 asymptomatic HIV-infected individuals (baseline: 534 + 41 CD4+ T-cells/pl, 1124 ~ 171
CD8+ T-cells/pl, 3.74 ~ 0.21 loglo HIV-RNA copies/mi) undergoing therapy with
AZT (2 x 300 mg/day), 3TC (2 x 150 mg/day) and ritonavir (2 x 600 mg/day)
were assessed for change in expression of phenotypic markers of T-cell activation
(HLA-DR and CD38) and maturation (CD45RA and CD45RO). At weeks 0, 2, 4,
8, 12, 16, 20 and 24, T-cell subsets were quantified by flow cytometry and plasma
viral load determined using a commercial reverse-transcription polymerase chain
reaction (RT-PCR) assay.
Results: After 24 weeks of triple combination therapy, all but one participant
(with poor compliance) exhibited plasma HIV-RNA levels below assay detection

limits. This decrease was observed to coincide with significant reduction in activated CD4+/HLA-DR+ (change: 17 ~ 4 cells/pl), CD8+/HLA-DR+ (change: 345
~ 75 cells/pl) and CD8+/CD38+ (change: 375 ~ 81 cells/opl) T-cell numbers.
A concomitant significant increase in naive CD4+/CD45RA+ (change: 94 ~ 16
cells/pl) and memory CD4+/CD45RO+ (change: 41 ~ 5 cells/pl) T-cell numbers was evident, which contrasted with the significant diminishment in memory
CD8+/CD45RO+ (change: 241 ~ 50 cells/p/) T-cell levels also observed.