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

58 Abstracts 12232-12235

12th World AIDS Conference

resistant (NVP-r) HIV isolates; and the response to PI Rx of plasma viral load
(pVL) and CD4+ cells in patients who failed to control pVL on NVP/nuc.
Methods: Susceptibility testing: 17 highly NVP-r isolates from patients who
received NVP/nuc Rx were tested for susceptibility to PIs using a modified
recombinant phenotypic methodology (VIRCO).
Clinical Study: Investigators provided follow-up on patients who received
NVP/nuc Rx in international NVP trials. Criteria for evaluability: patients treated
with NVP/nuc and subsequently treated with PI Rx; no intervening change in Rx
between NVP and the start of PI Rx; <6 mo. between NVP and the start of PI
Rx. Evaluable for RNA: BL (start of PI Rx) HIV RNA > 1000 copies/ml and >
one other HIV RNA result within 6 mo. of starting PI (Response: RNA nadir at
least 50% below BL). Evaluable for CD4+: BL CD4+ result plus > one other value
obtained within 6 mo. (Response: zenith >40 cells/mm3 or 33% above BL)
Results: Susceptibility All NVP-r isolates were fully susceptible to IND, NFV,
SAQ and RIT (IC50 Range: (0.002-0.1 ptM). All IC50s were <4-fold greater than
WT virus IC50.
Clinical: 40 adults and 19 children were evaluable for RNA and/or CD4+
analyses. 50 of the 51 (98%) RNA evaluable patients responded to PI Rx (mean
decrease in HIV RNA: 1.52 loglo copies/ml). 50 of the 55 (90.9%) CD4+ evaluable
patients responded to PI Rx (mean increase in CD4+ cells: 144 cells/mm3).
Conclusion: The susceptibility results and clinical RNA and CD4+ responsiveness in the clinical study demonstrate that therapy with NVP/nuc combinations
does not render patients unresponsive to subsequent PI therapy. These results
support the PI sparing strategy of using NVP/nuc combinations as primary therapy.
12232 Aggressive vs sequential therapy in experienced HIV
patients: The MASTER study (Standardized Management
of Antiretroviral Therapy)
Giampiero Carosi1, F. Castelli2, G. Carnevale3, F. Maggiolo4, A.M. Orani5,
M. Andreoni6, G.M. Vigevani7. 1Clinica Malattie Infettive Tropicali, PZa Spedali
Civili; 2Clinica Malattie Infettive-Universita Brescia; Div. Malattie Infettive - Osp.
3Cremona, Cremona; 4Busto Arsizio, Busto Arsizio; 5Lecco, Lecco; 6Biella,
Biella; 7Como, Como, Italy
Background: HAART has modified HIV infection to a chronic status requiring
long-term Rx and high compliance to avoid drug holidays leading to viral resistance. Antiretroviral potency of available protease inhibitors is inversely related to
tolerability (i.e. compliance) in a HIV+ population largely coinfected with hepatitis
viruses (i.e. drug addicts) as in the Italian situation. A strategy-led, field based
study (MASTER study) was then designed to verify the long-term clinical benefit
of aggressive (IDV or RTV based) vs sequential (HGC-SQV based) HAART. The
results obtained in experienced pts are reported here.
Methods: Multicentric, randomized, open label study comparing efficacy and
tolerability of AZT (or d4T) + 3TC + HGC-SQV (sequential Rx arm - A) vs AZT (or
d4T) + 3TC + IDV or RTV (aggressive Rx arm - B) in RTI experienced HIV pts with
less than 500 CD4+. Patients were switched to the other Rx arm in case of WHO
4 grade toxicity, clinical progression or virological failure (HIV-RNA decrease less
than 1 log at month 4). Results are analysed on an intention to treat basis.
Results: Three hundred fifty-seven (357) pts were enrolled in the study (Rx
A = 178, Rx B = 179). Baseline immunological parameters (CD4+ cells, median
HIV-RNA) were comparable in the two groups. At month 8 of follow-up (Rx A
= 24 pts, Rx B = 19 pts), virological efficacy was significantly higher (HIV-RNA
undetectability = 70% vs 22%) and clinical success compared favourably in the
aggressive Rx B arm (cumulative disease progression 4 vs 8 pts). On the contrary
cumulative self driven drug-holidays episodes (21 vs 44) were significantly less
and toxicity episodes tended to be less (WHO 4 grade = 3 vs 9) in the sequential
Rx A arm.
Conclusions: In our experience, IDV and RTV were significantly more active
and less tolerated than HGC-SQV as components of triple HAART in the shortterm in experienced HIV patients. A longer observation is needed to verify if low
tolerability (possibly leading to drug holidays) will vanish the higher virological
potency of IDV/RTV based HAART in the long term in the real clinical setting.
The 12 month follow-up results will be presented.
1 12233 | Lack of clinical or immunologic disease progression with
transient use of zidovudine (ZDV) to reduce perinatal
HIV-1 transmission in PACTG 076
Arlene D. Bardeguez1, L.M. Mofenson2, C. Spino3, D.E. Shapiro3,
M.G. Fowler4, R. Sperling5, R. Boyer6. 1New Jersey Medical School 185 South
Orange Avenue E-506 NWK NJ; 2NICGD-NIH, Rockville, MD; 3Harvard
University, Boston, MA; 4NIAID-NIH, Bethesda, MD; 5MOunt Sinai Medical
School, New York City, NY; 6UCLA School of Medicine, Los Angeles, CA, USA
Objective: Evaluate and compare postpartum clinical and immunologic HIV disease progression and survival among women who received ZDV or placebo (PL)
in the perinatal trial PACTG 076.
Methods: After completion of PACTG 076 study [6 months postpartum] women
were enrolled in a three year follow up study, PACTG 288. Study visits were sched
uled 12 months postpartum, and yearly thereafter. Each visit included HIV-related
history, physical exam, lymphocyte subset analysis and stored plasma for future
virologic assays. The primary endpoint was time from delivery to AIDS [defined
as CDC Category C disease or CD4 count <200/mm3] or death. Comparisons
were based on PACTG 076 randomization [ZDV vs PL]. This interim analysis
describes 18 months of follow-up in this cohort. Chi-square, t-test, product-limit
estimators and logrank test were used in the analysis.

Results: 226/513 [44%] of the women who enrolled in PACTG 076 were enrolled to PACTG 288. 112/226 [49%] were originally randomized to the ZDV arm.
No significant differences were observed among women who had received ZDV
or PL in age at enrollment, baseline CD4 count or length of follow-up in PACTG
288; mean follow-up was 2.4 years. More women in the PL arm received antiretroviral therapy postpartum [38% ZDV vs 52% PL, p = 0.01]. 48 [21%] women had
disease progression or death during the follow-up period [27 in ZDV vs 21 in PL
arm, p = 0.42]. 8 women progressed to CDC Category C [5 ZDV vs 3 PL arm], 41
had CD4 < 200 [24 ZDV vs 17 PL arm], and 2 patients died [1 each group]. There
was no significant difference in time to AIDS or death between the two arms.
Conclusions: Transient use of ZDV during pregnancy to prevent perinatal
transmission in PACTG 076, which enrolled healthy women with CD4 > 200, was
not associated with increased risk of clinical or immunologic disease progression
following delivery. "Women for who therapy is optional (low HIV RNA/high CD4)
& who wish to reduce fetal exposure to multiple drugs may consider use of ZDV
alone during pregnancy to reduce perinatal transmission."
12234 Immunologic and virologic markers as indicators of
clinical outcome in patients enrolled in the alpha ddl trial
Paul McQueen1, N.N. Zheng2, S. Simasathiansophon3, D.G. Smith3,
M.G. Law4, S.F. Delaney3, D.A. Cooper4. 1P+S Sciwrite PO Box 74 Pacific
Palms NSW 2428; 2Centre for Immunology Sydney; 3Dept Biotechnology
University NSW Sydney; 4 University NSW NCHECR Sydney, Australia
Objectives: The aim of the study was to determine the relationship of virologic, immunologic and genotypic factors to clinical progression in a subgroup of
subjects enrolled in the Alpha ddl trial.
Design: Studies were preformed on the sequential isolates of 142 participants
who enrolled in the MRC/INSERM Alpha ddl Trial at St Vincent's Hospital, Sydney,
Australia. The trial was a randomised, double-blind trial testing the efficacy and
safety of high-dose (HD; 750 mg daily) versus low-dose (LD; 200 mg daily) ddl in
humans infected with HIV-1 who were intolerant or resistant to ZDV.
Methods: Plasma HIV RNA concentrations (viral load), biologic phenotype,
and genotype at position 215 of RT, both at entry and throughout follow-up were
evaluated.
Results: Clinical data were correlated with these virologic and genotypic markers, as well as immunological markers observed during the trial. The immunologic
and virologic data showed that HD ddl significantly increased CD4 cell count,
decreased viral load at week 12 and was active against syncytium-inducing (SI)
strains compared to LD ddl. The initial plasma HIV-1 RNA concentration, CD4 cell
count and stage of disease were all independently predictive of survival. Neither
the length of prior ZDV treatment nor the ZDV resistance mutation at codon 215
associated with survival.
Conclusion: The present study serves to illustrate that the conclusion in the Alpha International Coordinating Committee (AICC) report that there was little or no
difference in clinical benefit ascribable to ddl based on parameters not including
analysis of viral load, could be an oversimplification of the actual situation.
S287*/12235 Hydroxyurea in combination regimens for the
treatment of antiretroviral naive, HIV-infected
adults
Marianne E. Federici1, Sergio Lupo2, P. Cahn3, I. Cassetti4, R. Pedro4,
G. Ruiz-Palacios5, J.S.G. Montaner6, T. Kelleher1. 15 Research Parkway,
Bristol-Myers Squibb Dept. 102, Wallingford, CT, USA; 2Caica, Rosario;
3Huesped, Buenos Aires, Argentina; 4Unicamp, Campinas; 5Cei, Buenos Aires,
Brazil; 6lnnsz, Mexico City, Mexico; 7St. Paul's Hospital, Vancouver, Canada
Introduction: Hydroxyurea (Hydrea"', HU) has been shown in-vitro to enhance
the anti-HIV activity of ddl and there are clinical reports of potent antiviral activity
of this combination.
Objective: To assess the antiviral effects and safety profile of HU in combination regimens for the treatment of antiretroviral naive, HIV-infected adults in a
controlled study.
Methods: We enrolled 183 antiretroviral naive subjects at 8 study centers in
Argentina, Brazil, Canada and Mexico. In this on-going, randomized trial, subjects
received full recommended doses of ddl + d4T + ZDV placebo (PBO) vs ddl +
ZDV + d4T PBO vs ddl + d4T PBO + HU vs ddl + d4T + HU. HU dose was
500 mg BID. Preliminary data are presented for 120 subjects comparing pooled
HU arms (59 subjects) vs pooled non HU arms (61 subjects). Demographic data
for the two groups appeared balanced. Trial duration is scheduled for 6 months
after randomization of the last subject. HIV RNA measurements are obtained at
baseline, week 2, 4, 8, 12, 16, 20 and 24. Data are available for a total of 41
subjects at 24 weeks.
Results: At baseline mean plasma HIV RNA (log1o copies/ml) were 4.47 (HU
group) and 4.35 (non HU group). Week 12 and 24 mean plasma HIV RNA declines
were 1.59 loglo and 1.76 loglo (HU group); 1.59 logio and 1.45 loglo (non HU
group). The proportions of patients with undetectable (<400 copies/ml) HIV RNA
at week 12 and 24 were 56% and 60% (HU group); 58% and 43% (non HU group).

Mean CD4 counts (cells/mm3) change from baseline at week 12 and 24 were 4
and -6 (HU group); 89 and 91 (non HU group). The CD4 changes may reflect a
mild leukopenia in the HU group. There were no clinically significant differences
in adverse events between the two groups. Only one subject receiving HU (1.6%)
experienced a grade 3 neutropenia while on-study.
Conclusion: In this first randomized, controlled trial, the addition of HU to the
ddl containing regimens provides a safe, cost effective alternative for the treat