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.

Keywords: Reverset; DD4FC; Monotherapy