Background: Oral pre-exposure prophylaxis trials have yielded disparate efficacy results attributed largely to variable adherence. Objective adherence benchmarks are needed. HPTN 066 was conducted to establish drug concentrations associated with 100% adherence by using directly observed tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) dosing with variable frequency. Methodology: Healthy, HIV- men and women were randomized 1:1:1:1 to 4 oral TDF 300 mg/FTC 200 mg regimens: 1 tab daily, 2 tabs twice weekly, 1 tab twice weekly, or 1 tab weekly, each for 5 weeks with all doses observed. Trough plasma TFV and FTC, peripheral blood mononuclear cell (PBMC) TFVdiphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) were assessed by UPLC-MS/MS from blood collected prior to the 2nd dose, weekly for 5 weeks, and 2 weeks after the final dose. Tissue biopsies for TFV, FTC, TFV-DP, and FTC-TP concentrations were collected on week 5 and 7 in half the participants. Results: Thirty-nine participants were evaluable. Steady-state concentrations (Table, median [interquartile range]) were achieved with the 2nd dose for plasma TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Colon tissue concentrations were greater than vaginal tissue concentrations for all moieties and arms except for FTC-TP. Two weeks following the final dose: only PBMC TFV-DP was detected in blood from weekly and twice weekly arms; all drug moieties were detected in blood in most participants in the daily arm; in tissue, detection of any drug moiety was rare except for the daily regimen and in colon tissue. Steady-state weekly-dose-adjusted concentrations did not demonstrate dose-proportionality for TFV-DP and FTC-TP (ANOVA p<0.05). Steady-state daily dosing inter- and intra-subject coefficient of variation (CV%) ranged from 33% - 63% and 14% - 34%, respectively, across all drug moieties and increased with less frequent dosing. Conclusions: Steady-state TFV-DP concentration was established earlier than predicted and dose-proportionality was not demonstrated in the phosphorylated moieties. Steady-state plasma TFV concentrations from daily dosing were consistent with concentrations reported in the Partners, TDF2 and Thai IDU PrEP studies (high levels of HIV protection); higher than in iPrEX (moderate protection), and far higher than in FEM-PrEP and VOICE (no protection). Therefore, HPTN 066 data can be used to benchmark adherence estimates in oral TFV PrEP trials, and assist in interpreting clinical outcomes.
CROI Conference
