HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention

Abstract

Background: Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence.

Methods: In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected.

Results: Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P < 0.001) for individuals receiving TDF and 91% (95% confidence interval: 47 to 98, P = 0.008) for individuals receiving FTC/TDF. Controls had consistent patterns of PrEP concentrations during follow-up; among the 81% with concentrations >40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations ≤40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner.

Conclusions: Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence.

FIGURE 1

Change in plasma level detected by visit in control and cases. Levels of tenofovir detected are grouped by undetectable (<0.31), detectable but less than daily dosing (0.31, 40.0) and consistent with steady-state dosing (>40) ng/mL in plasma. Figures 1a, 1b and 1c show individual patterns in control participants grouped by the levels of tenofovir quantified at the month 1 visit (green ≤0.31, orange = 0.31, 40.0, blue ≥40) ; each participant is represented by one line and lines terminate at each participant's last visit. Figure 1d shows the plasma levels of the 29 seroconverters; the final value shown corresponds to the tenofovir plasma level at first visit at which HIV infection was detected. Off drug means on clinical drug hold as a result of pregnancy, AE or other reason.

FIGURE 2

Pill count coverage and quantified tenofovir levels in plasma. Pill count coverage combines pill count and dispensing data to estimate the percentage of days since the previous visit that pills were taken.