Amdoxovir versus placebo with enfuvirtide plus optimized background therapy for HIV-1-infected subjects failing current therapy (AACTG A5118)

Background: Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside Reverse Transcriptase Inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses.

Methods: ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade > or = 3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks.

Results: Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI = -2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI = -1.1, -0.1) in the placebo arm (P = 0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI =1, 115) in the DAPD arm and 60 (95% CI =1, 101) in the placebo arm (P = 0.45). Time to first serious AE did not differ between arms (P = 0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities.

Conclusions: Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.