Title: Once-weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques from Intrarectal SHIV109CP3 Challenge.

BACKGROUND MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine, EFdA) is a novel reverse transcriptase translocation inhibitor. METHODS We assessed MK-8591 as pre-exposure prophylaxis (PrEP) in the rhesus macaque (RM)-simian/human immunodeficiency virus (SHIV) intrarectal challenge model. In Study 1, 8 RMs received 3.9 mg/kg of MK-8591 orally on day 0 and weekly for 14 weeks. Eight controls were treated with vehicle. All RMs were challenged with SHIV109CP3 on day 6 and weekly for up to 12 challenges or until infection was confirmed. The dose of MK-8591 was reduced to 1.3 and 0.43 mg/kg/week in Study 2 and further to 0.1 and 0.025 mg/kg/week in Study 3. In Studies 2 and 3 each dose was given up to 6 times QW and animals challenged 4 times once a week with SHIV109CP3. RESULTS Control macaques were infected after a median of one challenge (range 1-4). All treated animals in Studies 1 and 2 were protected, consistent with a 41.5-fold lower risk of infection (P<0.0001, log-rank test). In Study 3, at the 0.1 mg/kg dosing level, two RMs became infected consistent with a 7.2-fold lower risk of infection (P=0.0003, log-rank test). The 0.025 mg/kg dose offered no protection. CONCLUSIONS These data support MK-8591's potential as a PrEP agent.