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

576 Abstracts 32279-32283

12th World AIDS Conference

334*/32279 Complete HIV polsequence in plasma and genital
tract of women: Genital reservoir and differential
drug resistance
Guowei Fang1, H. Burger1, K. Anastos2, C. Chappey3, D. Mayers4, W. Meyer5,
B. Weiser'. 1 Wadsworth Center, NYS Dept of Health, 120 New Scotland Ave,
Albany, NY 12208; 2Montefiore Medical Center, Bronx; 3Genbank, NIH
Bethesda MD; 4Naval Medical Research Institute, Bethesda MD; 5Quest
Diagnostics, Baltimore MD, USA
Background: Studies of HIV-1 in vivo after potent antiviral therapy has revealed
significant viral reservoirs outside the plasma and drug resistant virus in a portion
of individuals.
Methods: To study multi-drug related resistance and HIV-1 sequence variation
in different body compartments, we performed sequence analyses of the complete virion-derived HIV-1 pol gene from serial paired plasma and genital tract
samples. Four or more sets of serial samples were obtained from 2 participants
in the NIH Women's Interagency HIV Study, a longitudinal study of HIV disease
progression in women. Both women initiated multi-drug therapy after the first set
of samples were obtained, and both showed a reduction in plasma HIV-1 RNA
load. By history, one was infected heterosexually and the other had strong risks
for both sexual and parenteral transmission. Analysis of the serial sequences
focussed on genomic variation in cervicovaginal lavage (CVL) vs. plasma and
evolution of resistance mutations.
Results: Both subjects showed evidence for varying viral dynamics in plasma
vs. CVL. Response to antiviral therapy and patterns of antiviral drug resistance
differed in the two compartments, with viral load in CVL more effectively reduced than that in plasma and the evolution of HIV-1 resistance mutations far
more limited. Computational analyses showed that the sequences from different
compartments clustered separately when used to contsruct evolutionary trees.
Signature sequences such as specific insertions also distinguished virus obtained
from different sites. In both subjects, the level of diversity in virus derived from
CVL exceeded that in virus derived from plasma, suggesting that the infection in
CVL was established first and that both subjects were infected heterosexually.
The female gential tract can serve as reservoir of HIV-1 that is genetically
distinct from that in plasma. HIV-1 in the genital tract may display a different
pattern of drug resistance than that contemporaneous in plasma. The rarity of
antiviral drug resistance in HIV-1 from CVL as compared to that from plasma
discribed here may reflect different antiviral pharmokinetics and different HIV-1
replication dynamics in these two sites.
228* / 32280 Frequency of transmission of drug-resistant
variants in individuals with primary HIV-1 infection
Sabine Yerly', G. Schockmel', J.P. Bru2, B. Hirchel3, L. Perrin'. 'Laboratory of
Virology, University Hospital 1211, Geneva 14; 3Div. Infectious Diseases,
Geneva, Switzerland; 2Div. of Infectious Diseases, Geneva, France
Background: Transmission of ZDV-resistant variants has occurred in recent years
in up to 10% of newly infected individuals. We determined the frequency of
reverse transcriptase inhibitors (NRTI or NNRTI) and protease inhibitors (PI) in
individuals with primary HIV infection (PHI).
Methods: Population based sequencing of RT and protease genes of viruses
present in plasma were performed in 67 consecutive individuals with PHI followed
in our Center from January 1996 to December 1997.
Results: ZDV-resistance mutations (M41L, D67N, K70R, T215Y/F) were detected in 5/67 (7.5%) individuals. Other RTI or NNRTI-resistance mutations were
not detected, except for 1 individual (pt SGY) with M184V (3TC), T69D (ddC),
Y181C, G190A (NVP). Major PI-resistance mutations were detected in 6/57
(10.5%) individuals analyzed. Five individuals had V821/A mutation associated
with 1 to 3 minor PI-resistance mutations (K20R, 154V, M361, L63P, A71T) and
1 individual (pt SGY) had 2 major mutations (V82A, L90M) associated with 4
minor mutations (L101, L63P, A71T, V771). Minor PI-resistance mutations were
frequently detected (6 x L10I/V, 2 x K20R, 15 x M361, 1 x 154V, 29 x L63P, 4 x
A71T, 11 x V771). In individuals without major PI mutations, the number of minor
PI mutations was 4 in 1 individual, 3 in 3 individuals and 2 in 8 individuals.
Conclusions: ZDV-resistance mutations were detected in 5/67 individuals with
primary HIV infection in 1996 and 1997. A single individual had mutations associated with 3TC, ddC and nevirapine resistance. Major PI-resistance mutations
were detected in 6/57 individuals, in all of them minor PI-resistance mutations (1
to 4) were also detected. Sequencing of the RT and protease genes might help
to select appropriate treatment in drug-naive individuals.
32281 Virological response in patients switching from AZT/3TC
or AZT/ddC to other double NRTI combinations
Veronica Miller1, Axel Moller2, A. Phillips3, B. Morgenstern2, M. Kortenbusch4,
K. Hertogs5, T. Lutz2, S. Staszewski2. 1HAUS68/Infektionsambul Anz
Frankfurt/M. Universitatsklin Ikum Theodor- Stern-KAI 7, Germany; 2Dept. of Inf.
Dis. JW Goethe-University, Frankfurt/Main, Germany; 3Primary Care & Popul.

Sciences RFH SM, London, UK; 4Dept. of Virology JW Goethe - University
Frankfurt/Main, Germany; 5Virco Viro Logical/Laboratory, Mechelen, Belgium
Objective: To assess the virological response and identify predictors for response
in patients switching various double NRTI combinations.
Design and Methods: A retrospective analysis including all patients from the
Frankfurt HIV-Cohort who switched from 1) AZT/3TC to d4T/ddl, 2) AZT/3TC
to d4T/3TC, 3) AZT/ddC to d4T/ddl, 4) AZT/ddC to AZT/3TC or 5) AZT/ddC to

d4T/3TC prior to the availability of protease inhibitors. A multiple linear regression
analysis was used to assess the contribution of baseline viral load, CD4, phenotypic resistance to the new drugs, and prior use of 3TC to short-term change
in viral load. Phenotypic resistance was measured using the AntivirogramTM
recombinant virus assay. A total of 96 patients were available for this analysis;
drug resistance against all NRTI's was available for 39 samples. Resistance was
defined as a change in IC50 of >4-fold compared to wild-type.
Results: The overall change in viral load from baseline (using the last value
between week 4 and week 16) was - 0.25 log10 HIV-1 RNA copies/ml; there were
no significant differences among the groups. In a multiple regression analysis
adjusted for baseline viral load and CD4, the prior use of 3TC vs ddC resulted in
a difference in viral response of -0.12 log10 HIV-1 RNA copies/ml (ie, a better
response was observed in those previously on 3TC) but this was not significant (p
= 0.54). Looking at resistance, baseline viral load and CD4 count in an adjusted
analysis, the difference in viral response in patients with HIV-1 resistant to 1
out of 2 new NRTI's vs. those with HIV-1 susceptible to both new drugs was
not significant (-0.28 log10 copies/ml, p = 0.19). However, patients with HIV-1
resistant to 2/2 new NRTI's vs. 0/2 had a viral load response which was worse
by 0.65 log10 copies/ml (p = 0.04). The viral load response in patients with HIV-1
resistant to 2/2 of the new NRTI compared to those with HIV-1 resistant to 0/2 or
1/2, was worse by 0.74 log10 (p = 0.02). The contribution of baseline viral load
and CD4 was not significant when adjusted for resistance.
Conclusions: The overall virological response in patients switching from
AZT/3TC or AZT/ddC to other NRTI combinations was not high. Pre-treatment
with 3TC vs ddC did not influence the magnitude of the response significantly.
However, resistance to both NRTI in the new combinations was significantly associated with a poor response. These findings are important for the optimization
of the NRTI component in >3-drug combinations.
233*/32282 Detection of genotypic drug resistance to antiviral
nucleoside inhibitors in short-time pretreated and
drug-naive HIV-1 infected patients as predictor of
treatment failure in high acting antiretroviral
therapy (HAART)
Anja Masuhr', K. Arasteh', V. Simon', C. M6cklinghoff2, A. Moll3. 3For the
Racing- Trial Group; 'Auguste-Viktoria-Hospital II. Innere Abteilung, Rubensstr.
125, 12157 Berlin; 2HoffMann-La Roche, Clinical Research, Grenzach,
Germamy
Objective: To determine the development of genotypic drug resistance in shorttime pretreated and drug-naive HIV-1 infected patients and to assess the efficacy
of saquinavir SGC in combination with zidovudine and zalcitabine.
Design: Prospective, randomized controlled study.
Methods: Ninety-five HIV-infected adult patients with a viral load of more than
5000 copies/ml and no previous treatment with proteins inhibitors and pretreatment with nucleoside analogues for less than 6 months were included in the
study. All patients received treatment with saquinavir SGC in combination with
zidovudine and zalcitabine. To look for genotypic drug resistance at baseline,
blood samples were taken from all patients and tested with LiPA (Line probe
assay) which detects up to 90% of all the genetic motifs present in the HIV-1 RT
(genotype B) at codons 41, 70, 74, 184 and 215 that are associated with the
resistance against ZDV, ddl, ddC, and 3TC.
Results: Blood samples of 86 patients were available for analysis. Fifteen patients (17.4%) had preexisting mutations against nucleoside reverse transcriptase
(RT) inhibitors (ZDV = 11, 3TC = 1, and ddC = 1, and ZDV/3TC = 2) at baseline. Eight patients (53.3%) of these 15 patients were drug-naive and 7 patients
(46.7%) were pretreated with RT inhibitors for a mean of 2.4 months. Whereas
plasma viral load (limit of detection 400 copies/ml) decreased in all patients for
a mean of 2.3 log after 4 weeks of treatment with a triple therapy (saquinavir
SGC/zidovudine/zalcitabine), the decrease of plasma viral load in patients with
preexisting mutations (1.2 log) was significantly lower (p < 0.05). After 8 weeks,
the mean reduction of plasma viral load compared to screening values was only
0.8 log for all patients with preexisting mutations and 8 patients (53.3%) were
excluded from the study because of treatment failure.
Conclusion: Our results demonstrate a remarkable rate of genotypic drug
resistance in short-time pretreated and even drug-naive HIV-1 infected patients.
Since reduction of plasma viral load with HAART was significantly lower in patients
with preexisting mutations against RT inhibitors, determination of drug resistant
variants is necessary to choose the optimal algorithm of antiviral compounds for
each individual patient before treatment is initiated.
1232* / 32283 Correlation of phenotypic resistance and clinical
efficacy of abacavir in a phase III pediatric study
Susan C. Danehower', C.D. Mitchell2, C.A. Gilbert', A. Keller', M.L. Smiley',
S.V. Hetherington', E.R. Lanier'. 'Glaxo Wellcome Inc., 5 Moore Drive,
Research Triangle Park, NC; 2U of Miami School of Medicine, Miami, FL, USA
Background: Prolonged therapy of HIV-1 infection with nucleoside analogues

eventually results in diminished suppression of viral replication. The development of validated phenotypic assays would be a major advance in the clinical
management of HIV-1 infections.
Methods: 205 therapy-experienced patients were randomized to one of two
treatment arms. One treatment arm included 8 mg/kg 1592/180 mg/m2 ZDV/4
mg/kg 3TC (bid) and the second treatment arm was 180 mg/m2 ZDV/4 mg/kg
3TC (bid). Subjects were stratified prior to randomization by age <30 months