A Randomized, Double-blind, Placebo-controlled, Short-term Monotherapy Study of MK-6186, an HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), in Treatment-Naïve HIV-Infected Participants.

Abstract

OBJECTIVE To assess the antiviral activity, pharmacokinetics, and safety of MK-6186 in NNRTI-naïve, HIV-1-infected male participants. DESIGN Double-blind, randomized, two-panel study. METHODS In 2 sequential panels, 18 participants received MK-6186 (40 mg [Panel A] or 150 mg [Panel B]) or matching placebo once daily for 7 days. Plasma samples were collected for measurement of HIV-1 RNA levels and MK-6186 pharmacokinetics. RESULTS For the mean change from baseline in HIV-1 RNA (log10 copies/mL) at 24 hours post Day 7 dose, the mean difference (90% confidence interval) between MK-6186 and placebo was 1.54 (-1.73, -1.34) in the 40-mg group and -1.28 (-1.81, -0.75) in the 150-mg group. One participant in the 150-mg group had viral rebound at 24 hours after Day 6 dosing (Day 7 predose) associated with outgrowth of the V106A minority variant. Ultra-deep sequencing confirmed expansion of this predose minority variant from 0.26% to 63.67%. No outgrowth and rebound was seen in another participant in whom a V106A minority variant was also detected. MK-6186 was generally well tolerated. MK-6186 was rapidly absorbed with peak concentrations at 2 hours followed by a biphasic decline. The effective t½ of MK-6186 was 43.9 to 48.7 hrs. Steady state was not achieved. CONCLUSIONS Daily monotherapy with MK-6186 demonstrated robust antiviral activity with maximal antiviral activity at a dose of 40 mg. One participant in the 150-mg group exhibited viral rebound with outgrowth of the resistant V106A minority variant, demonstrating a risk of resistance development typical of NNRTIs. The reason for this outgrowth remains unclear as no outgrowth occurred in a participant in the 40-mg group in whom the V106A minority variant was also detected. MK-6186 may be an alternative next-generation NNRTI in combination therapy, in that combination antiretroviral therapy could prevent outgrowth of resistant minority variants.