11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th:Abstract No. 137

R L Murphy¹, D Schürmann², A Beard³, L Cartee³, R F Schinazi⁴, and M J Otto^3
1Northwestern Univ., Chicago, IL, USA; ²Charité Univ. Hosp., Berlin, Germany; ³Pharmasset, Inc., Tucker, GA, USA; and ⁴Emory Univ. Sch. Med. and VA Med. Ctr., Atlanta, GA, USA

BACKGROUND: Reverset (RVT, D-D4FC) is a NRTI with specific and potent in vitro activity against HIV-1 isolates resistant to AZT, 3TC, and other NRTI. In a single dose phase 1 study, the pharmacokinetic data were linear with dose from 25 to 200 mg and resulted in a 0.44 log₁₀ drop (p < 0.001) in mean HIV plasma RNA levels.

METHODS: A total of 30 HIV-positive treatment-naïve individuals with CD4+ cell counts > 50 cells/mm³ and plasma HIV-1 RNA levels > 5,000 copies/mL were enrolled in a 10-day mono-therapy dose escalation study. Subjects were randomized to 1 of 3 dose levels of RVT: 50, 100, or 200 mg or placebo (2/group), once daily for 10 days. Study medication was administered in a double-blind fashion; plasma samples were taken for HIV-1 RNA pre-dose and on days 1, 2, 4, 8, and 10 of treatment and on days 11, 14, 21, 28, and 38 in the follow-up phase. Plasma samples for virus genotyping were taken at baseline, end of treatment, and at follow-up visits. Pharmacokinetic samples were obtained over the first 24 hours of dosing and again on day 10.

RESULTS: Preliminary results from this fully enrolled ongoing study showed that plasma pharmacokinetic values were linear with dose on days 1 and 10. The mean viral load drop at the end of the treatment phase for the 50-mg dose level was 1.67 ± 0.24 log₁₀ with maximum viral load reductions ranging from 1.0 to 2.6 log₁₀. The mean viral load drop at the end of the treatment phase for the 100-mg dose level was 1.80 ± 0.34 log₁₀ with maximum drops ranging from 1.2 to 2.3 log₁₀. For subjects with viral load < 50 copies/mL the endpoint value was imputed as 1.69 log₁₀. Viral RNA levels slowly returned to baseline during the follow-up period. CD4+ cell counts increased during the treatment phase, but returned to pretreatment levels during the follow-up period. No serious adverse events were reported and all adverse events were mild or moderate and occurred at similar incidences in the active and placebo groups.

CONCLUSIONS: RVT was highly effective in HIV-1-infected individuals with more than 1.6 log₁₀ drop in viral load. The potent in vivo antiviral activity and safety in the current study coupled with the in vitro susceptibility of drug-resistant HIV to RVT warrants further investigation in treatment-experienced subjects for longer durations.

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Copyright © 2004 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.