Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine after Directly Observed Dosing in Healthy Volunteers to establish Adherence Benchmarks (HPTN 066).

Publication Type:

Journal Article

Source:

AIDS research and human retroviruses (2015)

Abstract:

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC).

METHODS: Healthy, HIV uninfected men and women were randomized to 1 of 4 oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: 1 tablet weekly (1/wk), 1 tablet twice weekly (2/wk), 2 tablets twice weekly (4/wk), or 1 tablet daily (7/wk). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC) and CD4+ TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants.

RESULTS: The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP pre-dose concentrations demonstrated dose-proportionality: 1/wk 1.6 fmol/106 PBMCs, 2/wk 9.1, 4/wk 18.8, 7/wk, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the >4/wk regimens. Adherence benchmarks were identified using receiver operating characteristic curves which had areas under the curve > 0.93 for all analytes in serum and PBMC. Inter- and intra-subject coefficients of variation (%CV) ranged from 33% - 63% and 14% - 34%, respectively, for all analytes in serum and PBMCs.

CONCLUSIONS: Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating pre-dose concentration dose-proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes.