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Antiretroviral Trials

Data from key trials of antiretroviral combination regimens were presented on Tuesday afternoon, 14 October 1997.

Ag-511
Dr A. Petersen (USA) presented 52-week data from study Ag-511 in which 297 antiretroviral-na�ve patients were randomised to ZDV+3TC plus either placebo or nelfinavir (NFV) 750mg tid or NFV 500mg tid. Response rates (2 consecutive HIV RNA measures <500 copies/mL) were >80% for the NFV arms compared with 55% in the ZDV+3TC arm. At 24 weeks, NFV-treated patients had a mean reduction in their plasma HIV RNA of 2 log₁₀copies/mL, with no apparent differences between the 2 NFV dosages. However, differences between the 2 dosages began to emerge after 6 months with the percentage of patients with HIV RNA <500 copies/mL at 12 months maintained at 80% in the 750mg arm but fallen to <60% in the 500mg arm. Diarrhoea was the most frequently reported adverse event, but its incidence appeared to decrease with time from 20% at 6 months to 9% at 12 months (NFV 750mg arm).

SPICE
The use of NFV in combination with the new soft gelatin formulation of saquinavir (SQV) was discussed by Dr A. Posniak (UK). He presented the 16-week interim analysis from SPICE (Studiy of Protease Inhibitors in Combination in Europe) in which 157 HIV-infected individuals (mean CD4 and HIV RNA at baseline of 307 cells/mm³ and 4.8 log₁₀copies/mL) were randomised in a 1:1:2:2 manner to NFV+2RTIs, SQV-SGC+2RTIs, NFV+SQV-SGC or NFV+SQV-SGC+2RTIs. Around 50% of patients were antiretroviral na�ve and all started at least 1 new RTI. The study was powered to show significance only between the dual PI arms. The study is planned to run for 48 weeks.

At the 16-week analysis, HIV RNA was below detection (<400 copies/mL) in 84% of patients on SQV+NFV+2RTIs compared with 57% of those receiving NFV+SQV without RTIs. The greatest benefit of quadruple therapy was observed in previously na�ve patients, with HIV RNA dropping to <400 copies/mL in over 90% by week 12. The mean reduction in HIV RNA at 16 weeks is summarised in the table below. All regimens were generally well tolerated although the incidence of diarrhoea tended to be highest in the double PI regimens.

* p=0.014 vs SQV+NFV

Previous pharmacokinetic work has shown that NFV increases SQV exposure by around 5-fold. Exploiting this positive interaction between NFV and SQV was further discussed by Dr R. Hoetelmans (Netherlands). He presented data from a pharmacokinetic substudy (n=5) of the ADAM trial which examines the concept of induction-maintenance therapy. In the induction phase of the study patients received the current hard gel capsule formulation (HGC) of SQV (600mg tid) + NFV (750mg tid) + d4T (40mg bid) +3TC (150mg bid). The mean SQV plasma AUC attained with this regimen was not significantly different from that attained in 10 patients receiving a 1200mg tid dosage of SQV HGC plus 2 nucleoside analogues (1.95 vs 1.74 h*mg/mL). 8-weeek data from the ADAM study, show a 3 log₁₀ reduction from baseline in HIV RNA and a 200 cells/mm³ increase in CD4 count.

CAESAR
Professor C. Katlama (France) presented post 52-week follow up data from CAESAR, in which 1840 patients were randomised to current treatment plus placebo, 3TC or 3TC+loviride (a discontinued NNRTI). At 12 months, 18% of patients in the 3TC arms had progressed to a new AIDS-defining event (ADE) or death compared to 31% in the placebo arm. After 52 weeks, patients were offered open label 3TC to which other antiretrovirals could be added. Approximately 50% of patients started treatment with a PI at this time. The benefit of 3TC was maintained post-52 weeks, with 22% of patients progressing to a new ADE or death during a median follow-up of 16 months compared with 36% of patients randomised to the placebo arm. 3TC was associated with a 45% reduction in disease progression at this time point (p<0.001).

The predictive value of HIV RNA and CD4 was evaluated in a subset of 806 patients in CAESAR, 180 of whom progressed to an ADE or death (Dr J. Montaner, Canada). The Prentice criteria were used to determine the proportion of the effect of 3TC that could be explained by changes in HIV RNA or CD4 cell counts. CD4 and HIV RNA were found to be independent predictors of disease progression, the 2 parameters together explained an estimated 100% of the treatment effect. Dr Montaner concluded that these data support the use of HIV RNA and CD4 as surrogate markers of disease progression, although these results need to be repeated in trials of other antiretrovirals and for longer-term follow-up.

AVANTI 2
The AVANTI 2 trial randomised 100 antiretroviral na�ve patients (median HIV RNA 4.5-4.7 log₁₀copies/mL) to ZDV+3TC or ZDV+3TC+IDV. The median reduction in HIV RNA over the 52 week study period was 2.6 log₁₀copies/mL in the triple therapy arm compared to 1.3 log₁₀copies/mL in the ZDV+3TC arm (p<0.001). At 52 weeks, the proportion of patients with HIV RNA <500 copies/mL was 75 % in the IDV group and 23% in the dual therapy arm (on-treatment analysis). The percentage of patients with HIV RNA <20 copies/mL at 52 weeks was approximately 60% and 5%, respectively. The greatest benefit of triple therapy was in those patients with low initial viral load (<20,000 copies/mL). Approximately 60% of this subgroup had undetectable HIV RNA (<20 copies/mL), as compared to only 40% of those with initial HIV >20,000 copies/mL. These results suggest that more potent regimens may be required in patients with higher initial viral loads.

PISCES (SV 14604)
Results from the PISCES study (SV 14604) were summarised by Dr H-J Stellbrink (Germany). PISCES is the largest clinical endpoint study of HIV therapy to date, and included 3485 patients from 25 countries. The study included patients who were either antiretroviral na�ve or had received ZDV for � 16 weeks. Patients were randomised to one of 4 groups: i) ZDV; ii) ZDV+ddC; iii) SQV+ZDV; or iv) SQV+ZDV+ddC. Randomisation to the ZDV monotherapy arm was stopped in October 1995 after the release of data from Delta and ACTG175, and patients initially assigned to this group were switched to the triple regimen. Patients were treated for approximately 14 months (mean) and followed for 17 months (mean).

Treatment with SQV+ddC+ZDV was associated with a 50% reduction in the risk of progression to a first ADE or death compared with ZDV+ ddC (8% vs 15.1%, p=0.001).

Using a Cox proportional hazard model, 56% of the treatment effect could be explained by HIV RNA. CD4 count appeared to be a poor predictor of response accounting for only 8% of the treatment effect.

An exploratory analysis comparing clinical outcome in patients who switched from ZDV monotherapy to triple therapy with that of patients initially randomised to triple therapy revealed a significant clinical and survival advantage of using triple therapy from the outset. This study is the first to demonstrate the clinical benefit of a triple combination regimen as initial therapy for HIV infection.

Quality of life data from this study were presented in the latebreaker session by Dr D. Revicki (USA). Over 48 weeks, SQV+ddC+ZDV was associated with a maintenance in physical health summary scores (measure by the MOS-HIV Health Survey Scale) from baseline whereas patients in the ddC+ZDV arm experienced a substantial decline in this parameter (p<0.05).

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