Hair as a Biomarker of Tenofovir Prophylactic Exposure

头发作为替诺福韦预防性暴露的生物标志物

• 批准号: 7622701
• 负责人: Albert Ying-Hwa Liu
• 金额: $ 13.89万
• 依托单位: PUBLIC HEALTH FOUNDATION ENTERPRISES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-19 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622701
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Adherence; Anti-Retroviral Agents; Area Under Curve; Biological Availability; Biological Markers; Biological Markers; Blood; Cessation of life; Chemoprophylaxis; Clinical Trials; Cross-Over Studies; Data; Development; Directly Observed Therapy; Dose; Drug Exposure; Drug Kinetics; Enrollment; Equation; Exposure to; Frequencies; Future; Goals; HIV; HIV Infections; HIV prevention trial; HIV-1; Hair; Half-Life; Highly Active Antiretroviral Therapy; Hour; Individual; Measurement; Measures; Methods; Modeling; Monitor; Oral; Outcome; Participant; Patients; Pattern; Pharmaceutical Preparations; Plasma; Population Heterogeneity; Prevention; Prevention strategy; Prophylactic treatment; Protease Inhibitor; RNA; Research; Research Design; Research Project Grants; Risk; Safety; Staging; Temperature; Tenofovir; Testing; Therapeutic; Time; Treatment Protocols; Viral Load result; Woman; base; cohort; compliance behavior; innovation; insight; interest; medication compliance; men; novel; open label; preclinical study; prevent; prophylactic; public health relevance; response marker; tool; transmission process; volunteer

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.

描述（由申请人提供）：暴露前预防（PrEP），或使用抗逆转录病毒药物在潜在的艾滋病毒暴露之前开始，已成为一个非常有前途的，但未经证实的生物医学艾滋病毒预防策略。几项PrEP试验正在进行或计划进行，以评估这种方法在全球不同人群中的安全性和有效性。泰诺福韦（TFV）是一种广泛用于艾滋病毒治疗的抗逆转录病毒药物，是目前试验中所有PrEP方案的组成部分。在这些研究中，每日TFV给药的依从性和药物暴露将是预防疗效的重要决定因素，并且假设可能需要一定的暴露阈值来实现对HIV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物，但PrEP预防领域缺乏类似的替代品来保护免受HIV传播。开发一种准确的生物标志物，用于评估患者依从性和药物暴露于TFV（与预防HIV感染相关），将有助于解释当前PrEP疗效研究的主要科学结果，以及未来试验的设计和实施。该项目通过确定头发中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的半衰期延长，理想的生物标志物将反映长期的平均药物暴露。因此，单次血液水平只能提供一个短暂的时间快照，并不是暴露的完美指标。由于药物从血液中进入毛发需要数周到数月的时间，因此毛发分析已成为测量长期药物暴露的一种有前途的工具。收集头发也很便宜，可以在室温下长时间储存（数月至数年）。我们已经开发出测量头发中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毛发浓度是否准确反映了药物暴露于TFV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，以评估不同给药模式对毛发中TFV浓度的影响。我们将招募24名未感染HIV的男性和女性，他们将在以下条件下接受改良的直接观察每日替诺福韦给药：1）完美（100%）依从性，2）每周服用4剂（57%依从性），3）每周服用2剂（29%依从性）（目标1）。我们还将确定稳态时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性对TFV毛发水平的影响。通过使用改良的直接观察给药，我们将在获得HIV-1低风险的知情志愿者中更可靠地建立不同的给药条件。拟议的研究将采取必要的下一步，验证头发作为坚持和药物接触替诺福韦的生物标志物。一旦得到验证，TFV毛发水平就可以在世界各地即将进行的PrEP临床试验中作为预防艾滋病毒感染的替代品进行测试。公共卫生关系：验证头发作为患者坚持每日替诺福韦给药的生物标志物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治疗方案是否安全有效地预防未感染艾滋病毒的人感染艾滋病毒。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HIV感染的重要决定因素，因此开发患者依从性和替诺福韦药物暴露的客观标志物将极大地有助于解释这些研究的结果。