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

12th World AIDS Conference

Abstracts 12208-12212 53

Cohort II). VL was profoundly suppressed in a biphasic manner. At 16 weeks, in
Cohort I mean VL reduction was 2.12 logs (range 1.18-2.71; n = 7); mean CD4
count increase was 202 cells/mm3 (SE = 44.017; n = 7). In Cohort II mean VL
reduction at week 16 was 2.71 logs (range 1.11-4.67; n = 8); mean CD4 count
increase was 37 cells/mm3 (SE = 44.071; n = 7). VL BQL at week 16 in Cohort
I was <20 = 1; <400 = 4; >400 = 2 and in Cohort II VL BQL at week 16 was
<20 = 1; <400 = 6; >400 = 1. Four patients in Cohort I and 1 in Cohort II were
withdrawn because of virologic failure (confirmed increase in VL > 1 log). Of the
15 remaining patients 12 elected to add RT inhibitors at wks 16-20. VL status
at time of addition of RT inhibitors for Cohorts I and II were as follows: VL < 20
copies/mL: 1, 2, respectively; VL 20-400: 3, 3; VL > 400: 0, 3. Of the 3 who
remained on RTV/NFV alone, 2 had VL < 20 (1 in each Cohort) and 1 had VL
20-400 (Cohort I).
Conclusion: RTV/NFV is a promising, well-tolerated dual-PI combination which
may need to be combined with additional agents to exert an optimal and durable
antiviral effect. Protease sequences are being evaluated in patients experiencing
virologic failure.
12208 | Selection of FTC dose based on viral kinetics and
pharmacokinetics in an accelerated clinical trial design
John Delehanty1, James Kahn2, M. Thompson3, D. Mildvan4, J. Pottage5,
D. Shepp6, C. van der Horst7. Triangle Pharmaceuticals Inc., 4611 University
Drive, Durham, NC; 2University California, San Francisco, CA; 3AIDS Res
Consortium-Atlanta, Atlanta, GA; 4Beth Israel Medical CTR, New York, NY;
5Chicago LTR Clin Res, Chicago, IL; 6North Shore University Hospital,
Manhasset, NY; 7University of North Carolina, Chapel Hill, NC, USA
Background: Phase 1/11 HIV monotherapy studies often pose a risk of selecting
for viral resistance. The design of an ongoing Phase 1I/l study of FTC ([1-/-L-FTC]
2',3'-didexoy-5-fluoro-3'thiacytidine) utilized information on HIV-1 dynamics and
observed rates of resistance to other cytidine nucleoside analogues to allow rapid
assessment of preliminary antiviral efficacy and minimize patient risk.
Methods: Over 14 days, five cohorts of eight patients each receive separate
escalating dose of FTC (25 mg bid, 100 mg qd, 200 mg qd, 100 mg bid or 200 mg
bid). Frequent plasma sampling for drug levels and HIV viral load determinations
occur throughout the study.
Results: The short plasma half-life of HIV-1 enabled measurement of HIV
suppression by FTC, which was 1.4 log1o in the 25 mg BID group and greater
than 2.0 loglo in the cohort receiving 200 mg once-daily. Differences in HIV suppression among cohorts allows for the initial selection of a dose for therapeutic
trials. Frequent plasma sampling for HIV RNA allows viral kinetic patterns to be
determined and compared between the dosing groups. Determination of plasma
and intracellular drug levels are used to correlate antiviral activity and nucleoside
pharmacology. HIV genotype analysis was performed for all the patients.
An accelerated clinical study design based upon knowledge of HIV-1 replication
kinetics was successfully used to preliminarily select a dose of FTC based on
antiviral activity and pharmacokinetics. A once-daily dose of 200 mg of FTC
appears to have potent antiviral activity in humans.
12209 1Tolerance and acceptability of vaginal cleansing with
benzalkonium chloride in HIV-infected African pregnant
women, 1996-1998: ANRS 049b clinical trial
Philippe Msellati1, N. Neda2, F. Dabis3, C. Welffens-Ekra4, P. Van De Perre2,
V. Leroy2, L. Mandelbrot5. 1Orston 04 BP 293 Abidjan 04; 4Chu Yopougon,
Abdijan, Cote D'lvoire; 2Centre Muraz Bobo Dioulasso, Burkina Faso; 3lnserm
330 Bordeaux; 5Clinique Port Royal-Hopital Cochin Paris, France
Different interventions are tested in Africa to reduce mother-to-child transmission
of HIV. Vaginal cleansing is one of these, with the advantage of low cost and high
feasibility. From a public health point of view, another interest is that HIV status
of the pregnant women is not required before the intervention.
Objectives: 1) to study the tolerance of vaginal cleansing by Benzalkonium
Chloride (BC) suppositories in HIV-infected pregnant women and of a bath with
BC of the newborn 2) to assess the acceptability of this intervention in urban
populations in West Africa.
Methods: After voluntary HIV testing and counselling to pregnant women in
prenatal care units of Abidjan (C6te d'lvoire) and Bobo-Dioulasso (Burkina Faso),
HIV-infected pregnant women, who gave their informed consent, were recruited in
a bicentric randomized phase II trial, BC versus placebo. They self-administered
daily a suppository of BC (1% concentration) from 36 weeks of pregnancy until
labor, and the last one intra partum (IP). The baby was washed with a BC solution
within 30' after birth. Placebo was given similarly. Women were followed weekly
with a speculum examination and wet mount and culture of cervico-vaginal secretions through 1 week post partum. Neonates were examined for irritations of
the skin, mucosae and eyes. Data will be unblinded in February 1998.
Results: 112 HIV-infected pregnant women were enrolled in the trial from
november 1996 to april 1997. They took the pre partum treatment for a mean

duration of 20 days. The IP treatment was done in 71% of them and 87% of
the babies were bathed with BC. The overall compliance was 91%. There were
no major clinical event during the follow-up period extending up to 45 days post
partum. In women, genital ulcers occurred in 1% and minor complaints in 17%.
12% of newborns presented with conjonctivitis and 2% with infectious dermatitis.
In two children, there was a cutaneous exfoliation.
Conclusions: Vaginal cleansing with BC is a feasible intervention in Africa.
It seems to be acceptable by the women. BC seems to have an acceptable

tolerance in women and children (to be confirmed after unblinding). These data
will help to determine whether BC can be considered for efficacy trials in the
prevention of vertical transmission of HIV.
112210 Activity of abacavir (1592, ABC) combined with protease
inhibitors (PI) in therapy naive patients
Dennise Kelleher1, John Mellors2, M. Lederman3, D. Haas4, E. Cooney5,
J. Horton6, J. Stanford7, R. Haubrich8. 1Glaxo Wellcome 5 More Drive RTP
NC27613 Antiviral CLinical Research; 2University of Pittsburgh/VAMC,
Pittsburgh PA; 3Case Western Research University Cleveland OH; 4 Vanderbilt
University, Nashville TN; 5 Yale University New Haven CT; 6Carolinas Medical
Center, Charlotte NC; 7Kansas City AIDS Research Consortium, Kansas City
MO; 8UCSD Treatment Center, San Diego CA, USA
Background: Therapy combining ABC with one of five different PI reduced viral
load to <400 cps/mL in 54-85% of antiretroviral therapy naive patients in each
treatment arm by 16 weeks.
Methods: In study CNAA2004 78 antiretroviral naive patients began therapy
with abacavir (300 mg q12h) combined with one of five different PI (indinavir,
ritonavir, nelfinavir, 141W94 (amprenavir, USAN approved], and saquinavir.sgc)
at standard dosing. HIV RNA was measured by Roche Amplicor standard (<400
cps/mL) and ultra-sensitive (<50 cps/mL) methodologies. Phenotypic resistance
(Antivirogram, Virco) of HIV clinical isolates was assessed at baseline and for
any 16 week sample containing RNA above threshold (>400 cps/mL). Where
possible, a sample of viral isolates from subjects with RNA < 400 copies/mL were
profiled.
Preliminary Results: Baseline and Change from Baseline - Plasma HIV Viral
RNA (log10 copies/mL)
Treatment 1592+ (N) Baseline WK8 WK16 WK24 WK32 WK16%<400 WK16%- 50
141 (13) 5.07 -2.38 -2.42 -2.55 * 85 60
Indinavir (13) 4.70 -1.98 -1.83 -1.84 * 70 50
Ritonavir (12) 4.57 -1.79 -1.63 -1.41 * 75 64
Saquinavir(14) 4.60 -1.77 -1.98 -1.39 * 54 40
Nelfinavir (12) 4.77 -2.14 -2.19 -2.06 * 78 60
Correlations between HIV RNA and susceptibility to ABC or randomized PI will
be presented.
Conclusions: Abacavir has substantial antiretroviral activity when combined
with PI in antiretroviral therapy naive, HIV infected subjects. These combinations
maintain viral RNA below 50 copies/mL in a majority of subjects for at least 24
weeks. The relationships between baseline susceptibility, resistance developing
while on study medication, and HIV RNA response patterns will be presented.
S12211il Oral PMPA prodrug: Relationship between clinical
pharmacokinetics, safety and anti-HIV activity
Kenneth C. Cundy, S. Safrin, R. Coleman, H.S. Jaffe. 1GILEAD Sciences, Inc.,
333 Lakeside Drive, Foster City CA, USA
Objectives: To examine the relationship between drug exposure and the safety
and antiviral activity of PMPA Prodrug monotherapy in HIV-infected patients.
Design: The pharmacokinetics, safety and efficacy of oral PMPA Prodrug
monotherapy were examined as part of a randomized, double-blind, placebocontrolled, dose escalation study in 36 subjects.
Methods: Serum pharmacokinetics of PMPA were determined following single
dose administration of the prodrug (75, 150, or 300 mg/day) (fed vs. fasted)
and following 8 and 28 days of daily dosing (fed only). Plasma HIV RNA was
determined by the Roche Amplicor" RT PCR assay.
Results: PMPA Prodrug was rapidly converted to the active drug PMPA following oral absorption. Oral bioavailability as PMPA was approx. 40% with food.
Systemic exposure to PMPA was dose-proportional and was not affected by
repeated dosing. Exposure at steady state (AUCss) correlated with decrease
in loglo HIV RNA after 28 days (R = 0.829, P < 0.001). Maximum observed
decrease in logio HIV RNA was 2.1 at AUCss = 6.05 /1g.hr/mL. Reversible
asymptomatic increases in creatine phosphokinase and serum transaminases
showed no relationship to drug exposure.
Conclusions: PMPA Prodrug displayed linear pharmacokinetics. Oral bioavailability as PMPA was substantial (40%) and was not affected by repeated dosing.
Antiviral activity was proportional to exposure over the dose range 75 to 300
mg/day. Changes in creatine phosphokinase and serum transaminases were not
related to drug exposure.
[ 12212 Abacavir (1592, ABC) in protocol CNAB 2002, provides
effective, long-term, 72 week, art for patients on triple
therapy regimens
Schlomo Staszewski1, C. Katlama3, T. Harrer2, P. Massip5, P. Yeni4, A. Cutrell6,
H.M. Steel7. 1 Universitats Klinikum Frankfurt, Theodor-Stern-Kai, Frankfurt;

2Dept. of Med III, Universitat Erlangen, Erlangen, Germany; 3Group Hospital
Lierpitie-Salpetrie, Paris; 4Group Hospital lerbichat-Claud Bernard, Paris;
5Hopital de Purpan, Toulouse, France; 6GlaxoWellcome, RTF NC, USA;
7GlaxoWellcome, London, UK
Objectives: To assess long term safety, tolerance and durability of antiviral activity
with open label abacavir (ABC) in triple combination with 3TC/ZDV.