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Enfuvirtide (ENF) is the first of a novel class of drugs that block HIV gp41-mediated viral fusion to host cells. Viruses with mutations at positions 36-38 in HIV-1 gp41 and/or reduced susceptibility to ENF have been selected both in vitro and in vivo.An analysis of baseline and on-treatment ENF susceptibility in virus samples from Phase II clinical trial patients treated with ENF as functional monotherapy for 28 days (TRI-003) or in combination with oral antiretrovirals for/= 48 weeks (T20-205, T20-206 and T20-208). Population sequencing identified amino acid (aa) substitutions at positions 36-45 of gp41 in plasma HIV-1. ENF susceptibility of virus isolates was tested in the cMAGI assay and viral DNA was sequenced for selected isolates.HIV-1 gp41 aa 36-45 were highly conserved in virus from ENF-naive patients, except for a 15% incidence of N42S which did not reduce sensitivity to ENF. Virus from patients experiencing viral load rebound exhibited reduced susceptibility to ENF and substitutions in gp41 aa 36-45. The most common substitutions observed on treatment were at positions 36, 38, 40, 42 and 43. On-treatment changes in the phenotypic susceptibility of virus isolates to ENF were generally associated with genotypic changes in aa 36-45. There was a relatively lower incidence of ENF resistance in patients with baseline sensitivity to more oral antiretrovirals in comparison to patients sensitive to fewer antiretrovirals.These data identify the importance of HIV-1 gp41 aa 36-45 in the emergence of resistance to ENF.

AIM To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. METHODS A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. RESULTS Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). CONCLUSIONS The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Context: There is little information available on the correlation between HIV-1 RNA level, CD4 cell count and the risk of progression to AIDS or death during treatment with reverse transcriptase inhibitors. Objectives: To define the correlation between HIV-1 RNA level, CD4 cell count and the 1 year risk of progression to AIDS or death. Design: Pooled analysis of six randomized clinical trials of zidovudine/lamivudine versus control treatments. Setting: Investigational sites in Europe, North America, Australia and South Africa. Patients: The trials recruited 1488 adult HIV-1-infected male and female patients aged ≥ 18 years, with inclusion CD4 cell count between 25 and 500 x 10 6 cells/l. Patients were either nucleoside analogue-naive or pre-treated, and at all stages of HIV-1 disease. Main outcome measures: Progression (defined as all new and recurrent AIDS-defining events or death) was correlated with the HIV-1 RNA level and CD4 cell count during the first 8 to 52 weeks of treatment. Results: During a median 1 year follow up, progression was largely restricted to patients with both low CD4 cell count (≤ 200 x 10 6 cells/l) and high HIV-1 RNA level (> 5000 copies/ml). There was an increase in the incidence of progression events with rises in HIV-1 RNA level > 5000 copies/ml and reductions in CD4 cell count under 200 x 10 6 cells/l. The events occurring with HIV-1 RNA ≤ 5000 copies/ml were generally atypical. Conclusions: Progression to AIDS or death is rare for patients with HIV-1 RNA ≤ 5000 copies/ml, particularly when CD4 cell count is more than 200 x 10 6 cells/l.