HPTN 066

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

Study Summary
Study Documents - Study Details - Key Study Personnel - Study Sites Publications

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.


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.

Study Details

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 Regimen:

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).

Key Study Personnel

Cheryl Blanchette, Protocol Team Member
Kevin Bokoch, CORE Protocol Specialist
Ying Q. Chen, Protocol Team Member
Susan Eshleman, Protocol Team Member
Rebecca Guzman, Protocol Team Member
Craig Hendrix, Protocol Chair
Angela Kashuba, Protocol Team Member
Kenneth H. Mayer, Protocol Co-Chair
Laura McKinstry, SDMC Project Manager
Ayana Moore, CORE Protocol Specialist
Paul Richardson, Protocol Team Member
Jim Rooney, Protocol Team Member
Katie Shin, DAIDS Pharmacist