Pre-exposure prophylaxis (PrEP), or the use of antiretroviral medication initiated prior to a potential HIV exposure, has emerged as a highly promising, but unproven biomedical HIV prevention strategy. Several PrEP trials are underway or being planned to evaluate the safety and efficacy of this approach in diverse populations globally. Tenofovir (TFV), an antiretroviral medication used extensively in HIV treatment, is a component of all PrEP regimens in current trials. Adherence and drug exposure to daily TFV dosing will be important determinants of prophylactic efficacy in these studies, and it has been hypothesized that there may be a certain exposure threshold required to achieve protection from HIV infection. HIV viral loads serve as a clear marker of response to therapy in HIV therapeutics, but the PrEP prevention field lacks an analogous surrogate for protection from HIV transmission. The development of an accurate biomarker of patient adherence and drug exposure to TFV which correlates with protection from HIV acquisition would aid both the interpretation of primary scientific outcomes of current PrEP efficacy studies and the design and conduct of future trials. This project provides an essential first step toward this goal by determining if levels of TFV in hair correlate with drug dose. Due to TFV's extended half-life, an ideal biomarker would reflect average drug exposure over long periods of time. Therefore, single blood levels, which provide only a brief snapshot of time, are imperfect indicators of exposure. Because drug is incorporated from blood into hair over weeks to months, hair analysis has emerged as a promising tool for measuring drug exposure over long periods of time. Hair is also cheap to collect and can be stored at room temperature for prolonged periods (months to years). We have developed methods for the measurement of TFV levels in hair and are now able to reliably detect TFV in hair over a dynamic range. However, it is currently unknown whether these varying hair concentrations accurately reflect the degree of drug exposure to TFV. To address this gap in our understanding, we propose an open label cross-over study to evaluate the impact of varying dosing patterns on concentrations of TFV in hair. We will enroll a cohort of 24 HIV-uninfected men and women who will receive modified directly observed daily tenofovir dosing under conditions of 1) perfect (100%) adherence, 2) taking 4 doses/week (57% adherence), and 3) taking 2 doses/week (29% adherence) (aim 1). We will also determine how individual pharmacokinetic parameters at steady-state impact TFV hair concentrations (aim 2). This will allow us to assess the influence of both drug dose and biologic variability on TFV hair levels. By using modified directly observed dosing, we will more reliably establish different dosing conditions in well-informed volunteers at low risk for acquiring HIV-1. The proposed research will take an essential next step in validating hair as a biomarker of adherence and drug exposure to tenofovir. Once validated, TFV hair levels can then be tested as a surrogate of protection from HIV acquisition in upcoming PrEP clinical trials around the world. PUBLIC HEALTH RELEVANCE: Validating hair as a biological marker of patient adherence to daily tenofovir dosing could greatly assist the HIV prevention field. Currently, several clinical trials of pre-exposure prophylaxis (PrEP) are testing whether anti-HIV medication regimens containing tenofovir are safe and effective in preventing HIV infection among HIV-uninfected people. Since medication adherence and the resulting levels of drug in the body will be an important determinant of whether PrEP is effective in reducing HIV infections, developing an objective marker of patient adherence and drug exposure to tenofovir will greatly help the interpretation of results from these studies.

R21MH085598

2009-03-19

2011-08-28