Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP)

Albert Y Liu, Qiyun Yang, Yong Huang, Peter Bacchetti, Peter L Anderson, Chengshi Jin, Kathy Goggin, Kristefer Stojanovski, Robert Grant, Susan P Buchbinder, Ruth M Greenblatt, Monica Gandhi, Albert Y Liu, Qiyun Yang, Yong Huang, Peter Bacchetti, Peter L Anderson, Chengshi Jin, Kathy Goggin, Kristefer Stojanovski, Robert Grant, Susan P Buchbinder, Ruth M Greenblatt, Monica Gandhi

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.

Trial registration: ClinicalTrials.gov NCT00903084.

Conflict of interest statement

Competing Interests: Robert Grant received 3 grants to support meals and lodging for study personnel to attend annual investigator meetings and 1 grant to support a study video project. Monica Gandhi received payment for participating in a one-time advisory board meeting of Gilead (March 2012). This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT flowchart for STRAND study.
Figure 1. CONSORT flowchart for STRAND study.
Figure 2. Dosing scheme for the STRAND…
Figure 2. Dosing scheme for the STRAND Study.
Figure 3. Spaghetti plot of tenofovir (TFV)…
Figure 3. Spaghetti plot of tenofovir (TFV) concentrations.
Hair TFV concentrations for each subject are shown for each dosing period. Each line represents drug concentration data from one participant (at 2, 4, and 7 doses/week). The red line distinguishes between hair scalp concentrations for 2 vs. 7 doses/week. ng/mg = nanogram/milligram.

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