Emtricitabine-Tenofovir Concentrations and Pre-Exposure Prophylaxis Efficacy in Men Who Have Sex with Men

PrEP drug concentrations associated with ≥90% reduction in HIV acquisition in men who have sex with men are achieved with daily dosing. PrEParing to Stop HIV Acquisition Pre-exposure prophylaxis (PrEP) using the antiretroviral drugs emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a recently proven strategy for preventing HIV acquisition. These drugs require phosphorylation in mononuclear cells to the pharmacologically active triphosphate moieties, called emtricitabine-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP). The iPrEx study was a randomized placebo-controlled trial of daily oral doses of FTC-TDF as PrEP in HIV-negative men who have sex with men. Participants all received a comprehensive package of HIV prevention services. HIV infections were reduced by 44% overall in the FTC-TDF arm relative to placebo. HIV risk was reduced by more than 90% among those having detectable drug in blood, indicating that adherence was a powerful determinant of drug efficacy at preventing HIV acquisition. A new study by Anderson et al. estimates specific drug concentrations and adherence levels associated with protection from HIV-1 acquisition in the iPrEx trial. A regression analysis predicted that a TFV-DP concentration of 16 fmol/106 peripheral blood mononuclear cells (PBMCs) (95% confidence interval, 3 to 28) was associated with a 90% reduction in HIV acquisition relative to placebo in the iPrEx study. To determine the number of tablets required to achieve this drug concentration, TFV-DP concentrations from another study called STRAND were used to establish expected TFV-DP concentrations. TFV-DP was detected in the blood at all dosing levels in all participants with a median (interquartile range) TFV-DP concentration of 11 fmol/106 PBMCs (6 to 13) after two doses per week, 32 fmol/106 PBMCs (25 to 39) after four doses per week, and 42 fmol/106 PBMCs (31 to 47) after seven doses per week. When the iPrEx study’s regression model was used to analyze the STRAND TFV-DP concentrations, the predicted HIV risk reductions were 76, 96, and 99% for two, four, and seven doses per week, respectively. These findings suggest that PrEP using oral FTC-TDF tablets is a robust intervention for preventing HIV acquisition among men who have sex with men. Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.