title: Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066).
abstract: Oral preexposure 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). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). 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. 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 predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/10(6) PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose 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.
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Andrade
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Namandjé N
authors.initials: NN
authors.lastname: Bumpus
authors.affiliation: 2 University of North Carolina-Chapel Hill , Chapel Hill, North Carolina.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Marzinke
authors.affiliation: 3 FHI 360, Durham, North Carolina.
authors.forename: Ayana
authors.initials: A
authors.lastname: Moore
authors.affiliation: 4 University of Colorado , Denver, Colorado.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.affiliation: 4 University of Colorado , Denver, Colorado.
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fuchs
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Ilene
authors.initials: I
authors.lastname: Wiggins
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Christine
authors.initials: C
authors.lastname: Radebaugh
authors.affiliation: 2 University of North Carolina-Chapel Hill , Chapel Hill, North Carolina.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Prince
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Bakshi
authors.affiliation: 2 University of North Carolina-Chapel Hill , Chapel Hill, North Carolina.
authors.forename: Ruili
authors.initials: R
authors.lastname: Wang
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: 1 Johns Hopkins University , Baltimore, Maryland.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Shieh
authors.affiliation: 5 SCHARP , Seattle, Washington.
authors.forename: Laura
authors.initials: L
authors.lastname: McKinstry
authors.affiliation: 5 SCHARP , Seattle, Washington.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: 5 SCHARP , Seattle, Washington.
authors.forename: Deborah
authors.initials: D
authors.lastname: Donnell
authors.affiliation: 6 National Institutes of Health Division of AIDS , Rockville, Maryland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Elharrar
authors.affiliation: 7 Fenway Health , Boston, Massachusetts.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Mayer
authors.affiliation: 2 University of North Carolina-Chapel Hill , Chapel Hill, North Carolina.
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D019985:Benchmarking; D001826:Body Fluids / Q000737:chemistry; D004334:Drug Administration Schedule; D000068679:Emtricitabine / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010349:Patient Compliance / Q000706:statistics & numerical data*; D065129:Pre-Exposure Prophylaxis; D012372:ROC Curve; D013607:Tablets; D000068698:Tenofovir / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D013607:Tablets; D000068698:Tenofovir; D000068679:Emtricitabine