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Objective To study the prognosis of HIV-infected patients with virological failure after exposure to three classes of antiretroviral drugs (ARVs).Design Cohort study. Setting: French Hospital Database on HIV.Patients Patients previously exposed to at least two nucleoside reverse transcriptase inhibitors (NRTIs), two protease inhibitors and one non-NRTI, with viral load (VL) values of >5000 copies/ml after the exposure criteria were met and a new treatment initiated between 1998 and 2001 with VL >5000 copies/ml.Main outcome measures Risk of new AIDS-defining-events (ADEs) or death from first introduction of a drug never used before occurring between 1998 and 2001 defined as baseline.Results The main baseline characteristics of the 1092 patients were: previous ADE in 49% of cases, median CD4 cell count 181 µl, median VL 4.9 log10copies/ml, median duration of ARV therapy 5.0 years and previous exposure to a median of nine ARVs. The crude progression rates were 20.1/100 patient-years among patients included in 1998, 15.1 in 1999, 11.1 in 2000 and 8.6 in 2001. After adjustment for baseline characteristics, the calendar year of inclusion was associated with the risk of clinical progression (P<0.001). When the types of newly available drugs used at baseline or during follow-up were introduced into the model, year of inclusion was no longer associated with the risk of clinical progression (P=0.42), while exposure to amprenavir/r, lopinavir/r, abacavir or tenofovir was associated with a lower risk.Conclusions The clinical prognosis of heavily pretreated patients experiencing virological failure improved between 1998 and 2001, mainly thanks to the use of newly available drugs with more favourable resistance profiles.

Objectives To compare the antiviral efficacy of a salvage therapy combining lopinavir and amprenavir with 200 mg/d or 400 mg/d ritonavir, together with nucleoside reverse transcriptase inhibitors, over a 26-week period in HIV-infected patients in whom multiple anti-retroviral regimens had failed.Design Phase IIb, randomized, open-label, multicentre trial. Patients were eligible if they had <500 CD4+ cells/mm3and >4 log10copies/ml HIV-RNA after treatment with at least two protease inhibitors (PIs) and one non-nucleoside reverse transcriptase inhibitor.Results At baseline (n=37), the median CD4+ cell count was 207/mm3and the median plasma HIV-1 RNA level was 4.7 log10copies/ml; the median number of PI mutations was seven and the median decrease in phenotypic susceptibility to lopinavir and amprenavir was 9.7 and 2.6, respectively. The mean number of antiretrovirals received prior to randomization was 7.7. The fall in the median HIV-1 RNA level at week 26 was -1.4 log10copies/ml in the 200 mg/d ritonavir group and -2.5 log10copies/ml in the 400 mg/d group (P=0.02). Viral load fell below 50 copies/ml in 32% and 61% of patients, respectively (P=0.07). After adjustment for the ritonavir dose, a smaller number of PI mutations was the only baseline characteristic associated with a better virological response at week 26. Amprenavir concentrations were significantly lower in presence of lopinavir. The lopinavir inhibitory quotient at week 6 correlated weakly with the change in the HIV-RNA level at week 26.Conclusion Combination of amprenavir, lopinavir and 400 mg/d ritonavir shows significant virological efficacy without increased toxicity in HIV-infected patients in whom multiple antiretroviral regimens have failed.

We evaluated the impact of genetic changes within p6Gaggene on the virological response (VR, mean decrease in plasma viral load at week 12) to unboosted amprenavir (APV). Gag-protease fragments, including gag p2, p7, p1, p6 regions and whole protease (PR) were sequenced from baseline plasma specimens of 84 highly pre-treated but APV-naive patients included in the NARVAL (ANRS 088) trial. The correlation between baseline p6Gagpolymorphism, PR mutations, baseline characteristics and VR to APV was analysed in univariate analysis. Insertions (P459Ins) within p6 protein, leading to partial or complete duplication of the PTAPP motif, were significantly associated with a decreased VR (P459Ins versus wild-type; –0.3 ±0.8 vs –1.1 ±1.2 log copies/ml, P=0.007) and were more frequent when the V82A/F/T/S PR mutation was present (P=0.020). In multivariate analysis, after adjustment on the predictive factors of the VR in the NARVAL trial and on the PR mutations linked with response, there was a strong trend to an association (P=0.058) between the presence of P459Ins and an altered VR. In conclusion, these results suggest that insertions in the p6 region of HIV-1 gag gene may affect the VR, in highly pre-treated patients receiving an unboosted APV-containing regimen.

Objective To compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy (ART) in HIV-1-infected patients.Design Open-label study in HIV-1-infected ART-naive adults, randomized to receive either Combivir® (lamivudine 150 mg/zidovudine 300 mg twice daily) + abacavir (300 mg twice daily), or Combivir® + nelfinavir (750 mg every 8 h) for 48 weeks. Plasma HIV-1 RNA, CD4 cell count and adverse events were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48.Results 195 subjects (131 men, 64 women), median age 34 years, were randomized: 98 received combivir/abacavir and 97 combivir/nelfinavir. Baseline median plasma HIV-1 RNA was 4.2 log10copies/ml [Interquartile range (IQR): 3.7-4.5.2] and 4.1 log10copies/ml (IQR: 3.8–4.6), respectively. Baseline median CD4 cell count was 387 cells/mm3(IQR: 194–501) and 449 cells/mm3(IQR: 334–605), respectively. Nine patients (3 vs 6, respectively) did not start treatment or did not have any available efficacy data. At week 48, using the intent to treat analysis (switch/missing equals failure), plasma HIV-1 RNA was <50 copies/ml in 54/95 (57%) and 53/91 (58%) of subjects, respectively. Median CD4 increase was +110 and +120 cells/mm3, respectively. Possible hypersensitivity reactions to abacavir were reported in four subjects (4%).Conclusion The triple nucleoside combination combivir/abacavir is well tolerated as a first-line ART regimen in HIV-1-infected adults, with comparable antiviral activity to a nelfinavir-containing regimen at week 48.