Background:  Among heterosexual men and women in the Partners PrEP Study, pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxyl fumarate (TDF) and combination emtricitabine (FTC/TDF) decreased HIV-1 acquisition risk by 67% and 75%, respectively. Plasma levels of PrEP medications could provide a biological marker of adherence to PrEP and important ancillary information about protective efficacy.

Methods:  We enrolled 4758 HIV-1-uninfected members of HIV-1 serodiscordant couples from Kenya and Uganda in a phase III, randomized, placebo-controlled trial of daily oral TDF and FTC/TDF PrEP. To assess the relationship between detectable levels of drug in plasma and HIV-1 protective effects, we conducted a case-cohort study comparing TDF drug levels in patients who acquired HIV-1 to a cohort who did not acquire HIV-1. Cases were those from the TDF and FTC/TDF arms who acquired HIV-1 after randomization (n = 17 for TDF; n = 12 for FTC/TDF); plasma from the HIV-1 seroconversion visit was tested. The comparison cohort was 198 randomly selected subjects from the TDF and FTC/TDF arms; plasma from months 1, 3, 6, 12, 18, 24, 30, and 36 was tested (n = 902 samples). Ultra-performance liquid chromatography–mass spectrometry assay was used; the limit of quantification was 0.3 ng/mL. TDF, the common medication between the 2 active study arms, was tested.

Results:  Among 29 subjects who acquired HIV-1, 35% (6 of 17) of those assigned to the TDF and 25% (3 of 12) of those assigned to the FTC/TDF arm had TDF detected in plasma at the seroconversion visit. In comparison, 83% (363 of 437) of samples from uninfected controls in the TDF and 81% (375 of 465) from the FTC/TDF arm had detectable TDF. Median TDF concentrations in the uninfected cohort were 70 ng/mL (IQR 33 to 111) in the TDF arm and 67 ng/mL (IQR16 to 99) in the FTC/TDF arm. For those randomized to TDF, having a detectable level of TDF, as compared to an undetectable level, was associated with an 86% (95%CI 67% to 94%, p <0.001) reduction in HIV-1 risk; for the TDF/FTC arm, the HIV-1 risk reduction was 90% (95%CI 58% to 98%, p = 0.002).

Conclusions:  Among persons taking TDF and FTC/TDF PrEP, detection of TDF in plasma was strongly predictive of high protection from HIV-1 acquisition. Drug detection and levels over multiple visits in the control cohort suggest that a majority consistently used PrEP, supporting the high level of protection for HIV-1 acquisition observed in the Partners PrEP Study.