Characterization of determinants of genotypic and phenotypic resistance to enfuvirtide in baseline and on-treatment HIV-1 isolates.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These data identify the importance of HIV-1 gp41 aa 36-45 in the emergence of resistance to ENF.

A phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy.

OBJECTIVES: The primary objective was to determine the long-term safety of the subcutaneous self-administration of enfuvirtide. Secondary objectives included the determination of enfuvirtide pharmacokinetics and antiviral activity and the immunological response to the enfuvirtide-containing regimen. METHODS: A multicenter 48-week uncontrolled open-label rollover study was conducted on 71 HIV-infected adults recruited from previous enfuvirtide clinical trials. Patients with extensive previous use of protease and reverse transcriptase inhibitors received a twice-daily dose of 50 mg enfuvirtide subcutaneously (45 mg deliverable) combined with two or more antiretroviral drugs selected for each individual, guided by resistance testing and previous treatment history. RESULTS: The mean baseline plasma HIV-RNA level was 4.81 log(10) copies/ml and the mean CD4 cell count was 134.8 cells/microl. The majority (86.9%) of treatment-emergent adverse events were grade 2 or less in severity. Injection site reactions were common, but no patients discontinued treatment. A mean HIV-RNA change of -1.33 log(10) was achieved within 14 days of treatment initiation. At week 48, approximately one-third of all patients in the intent-to-treat population maintained significant suppression of plasma HIV RNA, with either less than 400 copies/ml or more than a 1.0 log(10) decline from baseline. The mean gain in absolute CD4 cell counts at 48 weeks was 84.9 cells/microl. Trough plasma concentrations of enfuvirtide were consistently higher than target concentrations. CONCLUSION: Self-administration of enfuvirtide is not associated with unexpected toxicities for up to one year, and combined with oral antiretroviral drugs was associated with a significant decrease in HIV RNA and an increase in CD4 cell counts.

The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults.

Enfuvirtide (T-20) is a novel antiretroviral agent that blocks HIV-1 cell fusion. A 28-day randomized dose-comparison study was conducted to determine the safety, pharmacokinetics, and antiviral activity of enfuvirtide in 78 HIV-infected adults, most with extensive treatment experience. Patients received enfuvirtide, added to a failing regimen, either by continuous subcutaneous infusion (CSI: 12.5, 25, 50 or 100 mg/day) or by subcutaneous (SC) injection (50 or 100 mg twice daily). Dose-related decreases in viral load were observed, with a maximum mean reduction from baseline of 1.6 log(10) copies/ml (p< 0.001) seen in the 100 mg bid SC group. Most responses diminished by 28 days. Plasma pharmacokinetics and antiviral responses were more consistent for SC injection than for CSI because of technical difficulties experienced with CSI. Injection site reactions were common but generally mild. These results indicate that enfuvirtide is a promising new therapeutic agent for HIV-infected patients, including those with prior antiretroviral treatment.