Background: MK-8591 (4''-Ethynyl-2-Fluoro-2''-Deoxyadenosine; EFdA) is a potent and long-acting nucleoside RT translocation inhibitor (NRTTI) in clinical development for the treatment of HIV-1 infection. Single 10 mg doses of MK-8591 resulted in suppression of viremia in HIV-1 infected patients for at least 10 days as have weekly doses of 3.9 mg/kg or greater in SIV-infected rhesus macaques (RM).
Methods: Two groups of 8 male RM were given 5 mL/kg of 10% Tween80 with (treated) or without (placebo) 3.9 mg/kg MK-8591 by oral gavage on day 0, day 7 and weekly thereafter for a maximum of 14 doses or until SHIV infection was confirmed. All animals were challenged intrarectally (IR) with 1 ml of 50 TCID50 of SHIVC109P3, a viral stock derived from the third passage in RM of the molecular clone SHIVC109F.PB4, which contains an HIV Env initially derived from a newly HIV-infected Zambian. Challenges occurred on day 6 and weekly thereafter for a maximum of 12 challenges or until infection was confirmed. Prior to weekly challenge, blood was drawn to determine infection status and drug levels. Infection was confirmed by real-time RT PCR amplification of viral gag sequences in plasma on 2 consecutive samples. Proviral DNA was measured by PCR and virus-specific antibody responses were assessed. Intracellular levels of MK-8591-triphosphate (TP) were measured by LC/MS/MS.
Results: All placebo animals became infected after 1-4 challenges (median 1, mean 2). All treated animals remained uninfected after 12 challenges and were followed through week 24 without evidence of infection as determined by the absence of plasma viremia, proviral DNA and seroconversion. MK-8591-treated macaques had a 41.5-fold lower risk of infection (95% C.I 7.3, 237.9) compared with placebo macaques (p< 0.0001, log-rank test). Mean trough concentrations of the active MK-8591-TP at the time of challenge were 4.07 mM (range: 2.26-5.17) and compare favorably with the level achieved by a weekly oral dose of 10mg in HIV-1-infected humans.
Conclusions: MK-8591 is a potent NRTTI that completely protected against repeated low-dose IR challenge in this SHIVC109P3/RM model with intracellular active drug concentrations readily achieved in humans. These results support the potential use of MK-8591 for HIV prophylaxis.