Weekly Oral Prophylaxis With MK-8527 Protects Rhesus Macaques From Intrarectal Challenge With Simian-Human Immunodeficiency Virus.

Abstract

MK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor being evaluated for prevention of HIV-1 acquisition. MK-8527 is phosphorylated intracellularly to its active form, MK-8527-triphosphate, which inhibits HIV-1 replication. This study evaluated the efficacy of oral MK-8527 as pre-exposure prophylaxis in rhesus macaques challenged intrarectally with simian-human immunodeficiency virus (SHIV). Two groups of male macaques (n = 8 per group) received weekly oral doses of MK-8527 for 12 weeks. Starting 1 week after treatment initiation, the macaques received weekly intrarectal challenge with SHIV162P3 for 10 weeks. Each group was treated in 3 dosing panels: Group 1 received MK-8527 6, 1, and 0 mg/kg (vehicle only), whereas Group 2 received MK-8527 2, 0.3, and 0.1 mg/kg. A washout period of ≥4 weeks followed each dosing panel. A control group (n = 8) was challenged without receiving MK-8527. Plasma viral loads were monitored weekly, with infection confirmed by 2 consecutive measurements of SHIV RNA >100 copies/mL. Concentrations of MK-8527 phosphorylated forms were quantified using liquid chromatography-tandem mass spectrometry. Once-weekly doses of MK-8527 ≥ 0.1 mg/kg for 12 weeks conferred complete protection against intrarectal SHIV acquisition, and 7/8 untreated control macaques and 5/8 vehicle-only macaques became infected. The rate of infection for macaques receiving MK-8527 was at least 11.1-fold (P = .009) lower compared with the control or vehicle group. MK-8527-triphosphate trough concentrations at 0.1 mg/kg resulted in a mean inhibitory quotient of 2.2. Prophylaxis with MK-8527 completely protected macaques from SHIV infection, supporting its further clinical development for prevention of HIV-1 acquisition.