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Background:  Cross resistance limits the ability to construct effective antiretroviral regimens for persons failing current therapies. A5118 compared the use of amdoxovir (DAPD), a novel nucleoside analog to placebo in combination with enfuvirtide (ENF) plus optimized background therapy (OBT) in ENF-naïve subjects who had failed ≥ 2 antiretroviral (ARV) regimens including at least 2 nucleoside reverse transcriptase inhibitors (NRTI), 2 protease inhibitors (PI), and 1 non-NRTI (NNRTI).

Methods:  This randomized, prospective, double-blind, placebo-controlled study assessed the antiretroviral activity and safety of DAPD (300 mg by mouth twice a day) vs placebo with ENF (90 mg subcutaneously twice a day) plus OBT (3 to 5 agents selected based on genotypic and phenotypic testing at screening) in subjects described above. The primary endpoints were comparison between arms of time-averaged area under the curve minus baseline in plasma HIV RNA copies/mL (copies/mL) at 24 week and time to first serious (AACTG ≥ grade 3 or 4) adverse event. Planned sample size was 50 subjects, however study enrollment was terminated following an unplanned interim review convened when the long-term development plans for DAPD became uncertain. Subjects on study were unblinded and allowed to continue through 48 week; 24 week data on the 18 subjects (9 per arm) enrolled are reported here.

Results:  Median baseline CD4 cell count was 36 cells/mm³ (range, 11 to 537); HIV RNA was 4.8 log₁₀ copies/mL (range, 3.5 to 6.3). Baseline samples showed a median of 6 NRTI mutations and 8 PI mutations; NNRTI resistance was present in samples from 13 of 18 subjects: . 4 subjects discontinued therapy prior to week 24; 3 for poor virologic response (2 on DAPD; 1 on placebo); 1 subject on placebo discontinued for ENF injection site reactions; 2 subjects (one per arm) briefly interrupted therapy for decreased creatinine clearance. By intention-to-treat analysis, the of time-averaged area under the curve minus baseline was –1.1 log₁₀ copies/mL (95% CI = 0.19 to 2.01) in the DAPD arm and –0.8 log₁₀  copies/mL (95% CI = 0.15 to 1.45) in the placebo arm (p = 0.69). Mean CD4 increase was 70 cells/mm³ (95% CI = 35 to 105) in the DAPD arm and 54 (95% CI = 14 to 94) in the placebo arm (p = 0.45). Time to first serious adverse event did not differ between arms. ENF injection site reactions were the most common adverse events (5 subjects). Mild decreases in creatinine clearance were equal between arms, and no subject developed an increase in lens opacity score.

Conclusions: In this pilot study, the addition of DAPD to ENF with optimized background therapy in advanced and highly resistant subjects appeared safe. Further studies of DAPD in this setting are warranted.

Keywords: amdoxovir; salvage therapy; enfuvirtide