HPTN 066

Dose-Proportionality and Intra-Individual Variability of Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate in Healthy Volunteers

Study Summary
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What is HPTN 066?

HPTN 066 was a study conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC).

Who participated in the study?

The study enrolled 49 HIV-uninfected men and women in Chapel Hill, North Carolina and Baltimore, Maryland.

What happened during the study?

Study participants 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). Serum, peripheral blood mononuclear cell (PBMC) and CD4+ drug 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 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. Inter- and intra-subject coefficients of variation (%CV) ranged from 33% - 63% and 14% - 34%, respectively, for all analytes in serum and PBMCs. Colon TFV and TFV-DP concentrations were quantifiable in all regimens. FTC analytes were rarely quantifiable in tissue. Neither drug was consistently quantifiable in vaginal tissue.

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 PrEP trials to assist interpreting outcomes.