Hair as a Biomarker of Tenofovir Prophylactic Exposure

描述（由申请人提供）：暴露前预防（PrEP），或在潜在的艾滋病毒暴露之前开始使用抗逆转录病毒药物，已成为一种非常有前途的，但未经证实的生物医学艾滋病毒预防策略。正在进行或计划进行几项PrEP试验，以评估该方法在全球不同人群中的安全性和有效性。替诺福韦（TFV）是一种广泛用于艾滋病毒治疗的抗逆转录病毒药物，在目前的试验中是所有PrEP方案的组成部分。在这些研究中，每日给予TFV剂量的依从性和药物暴露将是预防效果的重要决定因素，并且假设可能需要一定的暴露阈值才能实现对艾滋病毒感染的保护。HIV病毒载量是HIV治疗中对治疗反应的明确标志，但PrEP预防领域缺乏类似的替代物来保护免受HIV传播。开发与预防艾滋病毒感染相关的患者依从性和药物暴露于TFV的准确生物标志物，将有助于解释当前PrEP疗效研究的主要科学结果，并有助于设计和开展未来的试验。该项目通过确定头发中的TFV水平是否与药物剂量相关，为实现这一目标迈出了重要的第一步。由于TFV的半衰期较长，理想的生物标志物应反映长时间的平均药物暴露。因此，单一的血液水平，只能提供一个短暂的时间快照，是不完美的暴露指标。由于药物会在几周到几个月的时间内从血液中吸收到头发中，因此头发分析已经成为一种很有前途的工具，可以测量长时间的药物暴露情况。头发收集起来也很便宜，可以在室温下长时间储存（几个月到几年）。我们已经开发了测量头发中TFV水平的方法，现在能够在动态范围内可靠地检测头发中的TFV。然而，目前尚不清楚这些不同的头发浓度是否准确地反映了TFV药物暴露的程度。为了解决我们理解中的这一差距，我们提出了一项开放标签交叉研究，以评估不同剂量模式对头发中TFV浓度的影响。我们将招募24名未感染艾滋病毒的男性和女性，他们将在1)完全（100%）依从性，2)服用4剂/周（57%依从性）和3)服用2剂/周（29%依从性）的条件下接受改良的直接观察每日替诺福韦剂量（目标1）。我们还将确定稳态下个体药代动力学参数如何影响TFV毛发浓度（目的2）。这将使我们能够评估药物剂量和生物变异对TFV毛发水平的影响。通过使用改进的直接观察剂量，我们将更可靠地在知情的低风险感染HIV-1的志愿者中建立不同的剂量条件。拟议中的研究将在验证头发作为替诺福韦依从性和药物暴露的生物标志物方面迈出重要的一步。一旦得到验证，TFV头发水平就可以在即将在世界各地进行的PrEP临床试验中作为预防艾滋病毒感染的替代品进行测试。公共卫生相关性：验证头发作为患者每日替诺福韦剂量依从性的生物学标记可以极大地帮助艾滋病毒预防领域。目前，几项暴露前预防（PrEP）的临床试验正在测试含有替诺福韦的抗艾滋病毒药物方案在预防未感染艾滋病毒的人感染艾滋病毒方面是否安全有效。由于药物依从性和由此产生的体内药物水平将是PrEP是否有效减少艾滋病毒感染的重要决定因素，因此开发患者依从性和药物暴露于替诺福韦的客观标记将极大地有助于解释这些研究的结果。

DESCRIPTION (provided by applicant): 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.