Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men

Abstract

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.

Fig 1

Observed TFV-DP concentrations from STRAND and iPrEx. The values observed in the STRAND study are shown on the left for 2 doses/week (open circles), 4 doses/week (light-toned circles), and 7 doses/week (dark-toned circles). iPrEx values on the right included those from the visit with first evidence of HIV infection in cases (red triangles) and the matched study visit in HIV-negative controls (dark-toned triangles). The bars represent the medians. The numbers of participants tested, the proportion of vPBMC tested with detectable TFV-DP; the median concentrations among values in the detectable range; and the interquartile ranges are listed below the x-axis.

Fig 2

Longitudinal drug detection relative to the time of first HIV-1 detection. The % of case and control time points with any drug detection in plasma or PBMC including TFV, FTC, TFV-DP, or FTC-TP, at the time of first laboratory evidence of HIV in cases or the matched time point in controls (dashed vertical line), and at pre- and post-HIV infection time points. The pre- and post-HIV infection time points were divided into those within 3 months (90 days) before or after HIV infection, and those within 6 month intervals distal to these time points. The number of time points with either plasma or vPBMC available for testing is listed for each time period.

Fig. 3

Estimated HIV incidence from exponential regression model of TFV-DP concentrations (fmol/M vPBMC) in iPrEx. The placebo HIV infection rate is shown as a horizontal line at 3.9 infections per 100 person years, with the relative rate in the active arm according to TFV-DP concentrations (x-axis). Dashed lines represent the 95% confidence intervals. The IQR of TFV-DP concentrations associated with directly observed dosing in STRAND are provided as colored panels overlying the curves.

Fig 4

The % of case and control time points with TFV-DP ≥ 16 fmol/M viable PBMC (estimated EC90). Dark-toned circles represent HIV-negative controls, and red circles represent HIV infected cases. The x-axis represents time relative to the visit with first evidence of HIV infection in the case and the matching time point in controls. Pre- and post-HIV infection time points were divided into those within 3 months (90 days) before or after HIV infection, and those within 6 month intervals distal to these time points. The number of time points with vPBMC tested for TFV-DP is listed for each time period. *indicates significant differences between cases and controls (P<0.05).