title: Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP).
abstract: BACKGROUND
  Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.
  
  
  METHODS
  A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).
  
  
  RESULTS
  Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.
  
  
  CONCLUSIONS
  This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00903084.
authors.affiliation: Bridge HIV, San Francisco Department of Public Health, San Francisco, California, United States of America ; Department of Medicine, University of California San Francisco (UCSF), San Francisco, California, United States of America.
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Liu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Qiyun
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, San Francisco, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Bacchetti
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado, Aurora, Colorado, United States of America.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, San Francisco, California, United States of America.
authors.forename: Chengshi
authors.initials: C
authors.lastname: Jin
authors.affiliation: Children's Mercy Hospital and Clinics, University of Missouri-Kansas City, Kansas City, Missouri, United States of America.
authors.forename: Kathy
authors.initials: K
authors.lastname: Goggin
authors.affiliation: Bridge HIV, San Francisco Department of Public Health, San Francisco, California, United States of America.
authors.forename: Kristefer
authors.initials: K
authors.lastname: Stojanovski
authors.affiliation: Gladstone Institutes, San Francisco, California, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Grant
authors.affiliation: Bridge HIV, San Francisco Department of Public Health, San Francisco, California, United States of America ; Department of Medicine, University of California San Francisco (UCSF), San Francisco, California, United States of America ; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, San Francisco, California, United States of America.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Buchbinder
authors.affiliation: Department of Medicine, University of California San Francisco (UCSF), San Francisco, California, United States of America ; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, San Francisco, California, United States of America ; Department of Clinical Pharmacy, University of California San Francisco, San Francisco, San Francisco, California, United States of America.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Greenblatt
authors.affiliation: Department of Medicine, University of California San Francisco (UCSF), San Francisco, California, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Gandhi
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000284:Administration, Oral; D000328:Adult; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control*; D006197:Hair / Q000378:metabolism*; D006801:Humans; D008297:Male; D055118:Medication Adherence; D063065:Organophosphonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000068698:Tenofovir
chemical_list: D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine