Background:  SPD754 is a cytidine analogue with activity against HIV-1, including isolates resistant to other available NRTI. SPD754 has predictable pharmacokinetics and shows low potential for cytotoxicity and mitochondrial toxicity in vitro. Introduction of a new NRTI brings the risk of resistance. Phase 2 monotherapy studies represent the first opportunity to evaluate the in vivo resistance profile of new antiretroviral agents.

Methods:  We randomized 63 HIV⁺ patients to receive either placebo or 1 of 6 regimens of SPD754 capsules, 200 mg twice daily, 400 mg twice daily, 600 mg twice daily, 800 mg twice daily, 800 mg daily, and 1200 mg daily as monotherapy for 10 days. Patient viruses were genotyped at baseline at the end of treatment and 1 and 2 weeks later. Genotypes were determined using the Trugene assay. Viral loads were determined using the Roche AMPLICOR assay version 1.5.

Results:  Genotyping was completed at baseline for all but 3 patients. At 10 days some samples (n = 30) were below the minimum sensitivity criteria for the genotypic analysis (1000 copies/mL). However genotyping at 10 days was unsuccessful in only 9 patients and sequences were characterized for the remaining 54. At baseline, 4 patients had known resistant mutations within reverse transcriptase (RT):  patient A (placebo) A98S, G190A, T215S; patient B (200 mg twice daily) M41L, L74V, L100I, K103N, T215F; patient C (200 mg twice daily) V75M/V; and patient D (400 mg twice daily) M41L. All 3 of the patients who received SPD754 responded to treatment with VL drops of -0.65, -1.61 and -0.94 (log₁₀ HIV1-RNA copies/mL) at 10 days for patients B, C, and D respectively. These observations compared favorably with the observed mean reductions of -1.07 for the 200 mg twice daily and -1.28 for the 400 mg twice daily dose groups. Baseline virus samples also contained a number of additional substitutions (A98S, K101R, K101Q, V179I, L210F) not normally associated with resistance to NRTI (NAM). No new NAM emerged after 10 days treatment with SPD754.

Conclusions:  SPD754 does not select for mutations in RT after 10 days of mono-therapy at doses between 400 and 1600 mg per day; 10 days treatment with SPD754 gave rise to substantial reductions in viral load for those patients whose virus contained NAMs at baseline. There results support the further evaluation of SPD754 for the treatment of NRTI resistant virus in combination with other agents.

Keywords: SPD754; Monotherapy; Genotype