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

BackgroundPre-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.MethodsA 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).ResultsOver 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.ConclusionsThis 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 RegistrationClinicalTrials.gov +NCT00903084.

Strong Correlation Between Concentrations of Tenofovir (TFV) Emtricitabine (FTC) in Hair and TFV Diphosphate and FTC Triphosphate in Dried Blood Spots in the iPrEx Open Label Extension: Implications for Pre-exposure Prophylaxis Adherence Monitoring

“…However, from the correlation data [11], we can estimate that hair TFV concentrations of 0.023 ng/mg (95% CI, .019-.025 ng/mg) and hair FTC concentrations of 0.37 ng/mg (95% CI, .28-.58 ng/mg) are likely to confer protective benefit in the context of PrEP. The TFV hair concentration estimated to confer protection in this study is similar to that achieved by volunteers taking 4 doses of TFV per week in a separate study (median value, 0.023 ng/mg) [12].…”

“…A qualitative study from South Africa on the acceptability of hair collection underscored this point [15]. Of note, TFV concentrations in pubic hair samples were not reliably associated with dose in another study [12], which corroborates other findings that pubic hair, with its erratic growth rates and urine contamination, is not an informative biomatrix.…”

“…After storage and shipment at ambient temperature to our University of California, San Francisco laboratory, the proximal 1.5 cm of each hair samples (representing approximately 6 weeks of exposure) was cut finely with scissors and 5 mg was processed and analyzed using LC/MS-MS as described elsewhere [3,12]. These assays have been validated from 0.002 to 0.400 ng/mg hair for TFV and from 0.02 to 4 ng/mg for FTC [12].…”

“…These assays have been validated from 0.002 to 0.400 ng/mg hair for TFV and from 0.02 to 4 ng/mg for FTC [12]. Of note, our assays for measuring TFV and FTC in hair samples have been peer reviewed and approved by the Division of AIDS Clinical-Pharmacology and Quality-Assurance (CPQA) program.…”

“…Hair collection is noninvasive, nonbiohazardous, and does not require phlebotomy or cold storage, and hair levels reflect uptake from the systemic circulation over weeks to months. Hair concentrations of TFV are strongly and linearly related to dose [12], and hair levels of both TFV and FTC correlate with plasma and PBMC concentrations [3]. Hair and DBS collection both provide feasibility advantages in resource-limited settings, and concentrations in these 2 matrices represent longer-term exposure, although the correlation between hair and DBS measures is unknown.…”