Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy

Antimicrob Agents Chemother. 2017 Dec 21;62(1):e01710-17. doi: 10.1128/AAC.01710-17. Print 2018 Jan.

Abstract

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.).

Keywords: HIV; adherence; intracellular; nucleoside analog; pharmacokinetics; preexposure prophylaxis.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / blood
  • Adenine / pharmacokinetics
  • Adenine / therapeutic use
  • Adult
  • Anti-HIV Agents / blood*
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Cross-Over Studies
  • Directly Observed Therapy / methods*
  • Dried Blood Spot Testing*
  • Emtricitabine / blood*
  • Emtricitabine / pharmacokinetics*
  • Emtricitabine / therapeutic use
  • Female
  • HIV Infections / blood*
  • HIV Infections / prevention & control*
  • Humans
  • Male
  • Middle Aged
  • Organophosphates / blood*
  • Organophosphates / pharmacokinetics*
  • Organophosphates / therapeutic use
  • Patient Compliance
  • Pre-Exposure Prophylaxis
  • Prospective Studies
  • Sexual and Gender Minorities
  • Young Adult

Substances

  • Anti-HIV Agents
  • Organophosphates
  • tenofovir diphosphate
  • Emtricitabine
  • Adenine

Associated data

  • ClinicalTrials.gov/NCT02022657