Similar tenofovir hair concentrations in men and women after directly observed dosing of tenofovir disoproxil fumarate/emtricitabine: implications for preexposure prophylaxis adherence monitoring

Abstract

Objectives: Women likely require higher adherence than men to preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for similar efficacy. Pharmacologic metrics of adherence predict efficacy better than self-report, but expected drug levels (adherence benchmarks) must be established using directly observed therapy. We sought to evaluate whether tenofovir hair concentrations differ between women and men receiving directly observed TDF/FTC.

Methods: We assessed tenofovir hair concentrations in HIV-uninfected volunteers randomized to receive 100%, 67%, or 33% of daily dosing of TDF/FTC for 12 weeks (DOT-DBS, NCT02022657). Hair samples were collected at dosing weeks 4, 8, and 12 and every 3 weeks during a 12-week washout. Tenofovir concentrations in the proximal 1.5 cm of hair (representing ∼6 weeks of exposure) were analyzed using liquid chromatography/tandem mass spectrometry. Linear regression was used to model tenofovir hair concentrations in terms of sex, doses over the prior 6 weeks, and number of days since last dose.

Results: A total of 264 hair samples were analyzed from 23 female and 24 male participants. Female participants had similar tenofovir hair concentrations to men (estimated fold-difference 0.92, 95% CI 0.75-1.13, P = 0.43). The estimated fold-difference in tenofovir levels for female versus male participants did not appreciably change when age (0.93, 95% CI 0.76-1.15), weight (0.89, 95% CI 0.71-1.11), or race/ethnicity (0.95, 95% CI 0.77-1.17) were added to the model.

Conclusion: Women and men have similar adherence benchmarks for tenofovir in hair samples. As pharmacokinetic metrics are increasingly used for PrEP monitoring, these findings provide guidance for assessing adherence via hair concentrations.

Conflict of interest statement

Potential conflicts of interest: Gilead Sciences donated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as study drug, but had no other role in the design or conduct of the study or the analysis or interpretation of data. C.A.K. has received grant support paid to her institution from the Gilead Sciences Research Scholars Program in HIV. P.L.A. has received grant and contracts from Gilead Sciences, paid to his institution. A.Y.L. has led studies in which Gilead Sciences has donated study drug.

Figures

Figure 1.. Schema for directly-observed administration of TDF/FTC and collection of hair samples from study participants.

Blue bars indicate doses given during each randomized study arm. Intermittent doses were separated by days (e.g. 1 day on/2 days off for 33% intermittent dosing) and holiday doses were separated by weeks (e.g. 1 week on/2 weeks off for 33% holiday dosing). Gray bars represent ~6 weeks of hair growth (reflecting drug exposure over that time) prior to hair collection (indicated by red arrows). Hair was collected at weeks 4, 8, and 12 during dosing and every 3 weeks during a 12-week washout period. Following a 12-week washout period, participants received 12 additional weeks of a different dosing regimen and hair collection.

Figure 2.. Estimated fold-difference in hair concentrations of tenofovir by female versus male sex