HPTN 066
Dose-Proportionality and Intra-Individual Variability of Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate in Healthy Volunteers
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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.
Protocol Status
Concluded
Study Purpose
Describe the dose-proportionality and intra-individual variability of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) at steady-state in healthy human participants taking Truvada® (FTC 200mg/TDF 300 mg) under direct observation.
Study Design
Phase 1, multi-site, open label, randomized, 4-arm, dose-ranging, pharmacokinetic (PK) study.
Study Population
HIV-uninfected, healthy, sexually-active volunteers, including both men and women recruited from two sites in the United States (U.S.).
Study Size
32 participants distributed into four 8-person cohorts with 4 men and 4 women per cohort. 16 of the original 32 participants (2 men, 2 women per dosing cohort), will undergo intensive tissue sampling.
Study Duration
Approximately 12 months total. Accrual will require approximately 6 months. Each participant will be followed for approximately 2 months (screening, treatment, and follow-up).
Treatment Regime
Research participants will receive doses under the direct observation of study personnel for 5 weeks. Research participants will be enrolled randomly into one of four study arms:
(1) FTC 200 mg/TDF 300 mg, one tablet orally once weekly for 5 weeks;
(2) FTC 200 mg/TDF 300 mg, one tablet orally twice weekly for 5 weeks;
(3) FTC 200 mg/TDF 300 mg, two tablets orally twice weekly for 5 weeks;
(4) FTC 200 mg/TDF 300 mg, one tablet once daily for 5 weeks.
Primary Objectives
(1) Assess dose-proportionality of intracellular TFV-DP and FTC-TP from weekly to daily dosing;
(2) Describe intra-individual variability in intracellular TFV-DP and FTC-TP concentrations at steady-state (comparison of Day 28 and Day 35).
Secondary Objectives
(1) Describe the relationship between pre-dose (C_tau) and decaying concentrations of TFV, FTC, and their phosphorylated derivatives (TFV-DP and FTC-TP) in blood serum, peripheral blood mononuclear cells (PBMCs), CD4+ blood cells, total tissue cells, CD4+ tissue cells, tissue homogenate, semen, and luminal fluid at steady-state (Day 35 [pre-dose] and Day 49 [decaying, greater than one half-life for TFV-DP];
(2) Describe differences in intracellular TFV-DP and FTC-TP steady-state C_tau between men and women;
(3) Characterize the safety profiles of four different TDF/FTC regimens for pre-exposure chemoprophylaxis (PrEP).