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.

Evaluation of a Multidrug Assay for Monitoring Adherence to a Regimen for HIV Preexposure Prophylaxis in a Clinical Study, HIV Prevention Trials Network 073

“…dosing regimen and a 4-dose/week regimen (13). That benchmark study found that the 90% sensitivity thresholds for TFV and FTC were 35.5 ng/ml and 49.1 ng/ml, respectively, for the daily dosing regimen and 4.2 and 4.6 ng/ml, respectively, for the 4-dose/week regimen (13).…”

“…That benchmark study found that the 90% sensitivity thresholds for TFV and FTC were 35.5 ng/ml and 49.1 ng/ml, respectively, for the daily dosing regimen and 4.2 and 4.6 ng/ml, respectively, for the 4-dose/week regimen (13). Results from the quantitative TFV-FTC assay were available for 163 of 165 HIV-uninfected men who accepted PrEP (end-of-study visits only; two participants did not have samples available for testing).…”

“…Antiretroviral (ARV) drug testing provides an objective biomedical measure of ARV drug use (12). ARV drug testing for evaluation of adherence to TDF-FTC regimens is often performed using quantitative assays based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) (13)(14)(15)(16)(17). Steady-state concentrations of tenofovir (TFV) in plasma are achieved after a few days of daily oral dosing.…”

“…In a placebo-controlled PrEP efficacy trial, plasma TFV concentrations of Ͼ40 ng/ml were shown to provide 91% risk reduction for individuals receiving daily TDF-FTC (16). HIV Prevention Trials Network [HPTN] 066 was a 5-week, directly observed TDF-FTC dosing study (13); the study included a daily dosing regimen and a 4-dose/week regimen. The ϳ90% sensitivity thresholds for serum TFV and FTC concentrations in HPTN 066 were 35.5 and 49.1 ng/ml, respectively, for daily dosing and 4.2 and 4.6 ng/ml, respectively, for the 4-dose/week regimen (13).…”

“…HIV Prevention Trials Network [HPTN] 066 was a 5-week, directly observed TDF-FTC dosing study (13); the study included a daily dosing regimen and a 4-dose/week regimen. The ϳ90% sensitivity thresholds for serum TFV and FTC concentrations in HPTN 066 were 35.5 and 49.1 ng/ml, respectively, for daily dosing and 4.2 and 4.6 ng/ml, respectively, for the 4-dose/week regimen (13). We previously developed a qualitative method based on high-resolution mass spectrometry (HRMS) (18) that is less costly than LC-MS/MS methods.…”