Hair Extensions: Using Hair Levels to Interpret Adherence, Effectiveness and Pharmacokinetics with Real-World Oral PrEP, the Vaginal Ring, and Injectables

项目摘要/摘要 PrEP(暴露前预防)临床试验的三个教训--坚持对有效性至关重要， 药物依从性措施比自我报告更可靠，而且每天服药很困难 -必须应用于下一阶段的艾滋病毒预防研究。此阶段将调查口服PrEP的推广情况 和高发环境下的优化，以及预防艾滋病毒感染的新的长效方法， 例如注射剂或阴道环。在最近的两项试验中，阴道环阻止了艾滋病毒的感染，但效果不佳 坚持一致的环插入降低了整体效果。注射用长效PrEP 卡替格列韦是有意义的，但需要足够的药物水平才能有效，特别是在服药结束时 间隔时间和错过访问的情况。药理计量学将生物学(药代动力学，PK)和行为相结合 (依从性)，并将是解释真实世界口服PrEP、环和注射剂有效性的关键。 我们的团队帮助开创了使用小头发样本(易于收集、存储和运输)的先河 监测暴露(PK)和坚持使用抗逆转录病毒药物(ARV)。在本次R01的第一个资金期内， 我们在最初的目标上取得了重大进展，证明了监测抗逆转录病毒药物的毛发水平 长期接触，比自我报告的依从性(或血浆)更能预测治疗成功 在感染艾滋病毒的孕妇、儿童和成人中)。我们还展示了头发的初步用途 监测口服PrEP依从性和毒性的替诺福韦(TFV)/恩曲他滨(FTC)水平。 这项提案将利用三个重要的试验来探索将在 艾滋病毒预防工作的下一阶段：东非社区卫生可持续研究(SEARCH) 试验(Havlir博士，主席兼联合-I)刚刚启动了一项大型研究，为16年的高危人群提供口服PrEP 非洲的社区。杀微生物剂试验中HIV开放标签预防推广(HOPE)研究 网络(MTN)(主席兼第一协办Baeten博士)将评估达匹韦林阴道环的开放标签使用。这个 非依从性HIV感染者的长效抗逆转录病毒治疗试验(A5359，Castillo博士- Mancilla，共同主席和联合主席)在艾滋病临床试验小组(ACTG)将检查长效注射剂 有不良依从性病史的艾滋病毒感染者。所有三项试验都将收集头发和血浆中的药物水平， 并跟踪稳健的结果，使我们能够1)调查头发水平作为阴道依从性的衡量标准 在非洲进行听诊和口试，并检查坚持的模式(例如，每天、在风险时期前后、在 访问)通过结合血浆和头发中的数据；以及2)检查头发水平作为PK的易于收集的指标 使用注射剂进行监测。这次更新的总体目标是开发一个完整的 跨越PrEP给药的高度预测性生物依从性和药代动力学措施包 方法和优化策略。定义口服PrEP和环的依从性的预测因素和模式，如下 以及监测注射用PK的指标，将为预防艾滋病毒的公共卫生干预措施提供信息。

PROJECT SUMMARY/ ABSTRACT Three lessons of the PrEP (pre-exposure prophylaxis) clinical trials - that adherence is critical to effectiveness, that pharmacologic adherence measures are more reliable than self-report, and that daily pill-taking is difficult –must be applied to the next phase of HIV prevention research. This phase will investigate oral PrEP roll-out and optimization in high incidence settings, as well as novel long-acting methods for preventing HIV infection, such as injectables or vaginal rings. The vaginal ring prevented HIV acquisition in two recent trials, but poor adherence to consistent ring insertion dampened overall effectiveness. Injectable PrEP with long-acting cabotegravir is of interest, but will require adequate drug levels to be effective, especially at the end of dosing intervals and with missed visits. Pharmacologic metrics integrate biology (pharmacokinetics, PK) and behavior (adherence) and will be crucial to interpreting effectiveness with real-world oral PrEP, rings and injectables. Our group has helped pioneer the use of small hair samples (which are easy to collect, store and ship) to monitor exposure (PK) and adherence to antiretrovirals (ARVs). During the first funding period of this R01, we made significant progress on our original aims, demonstrating that hair levels of ARVs, which monitor long-term exposure, are stronger predictors of treatment success than self-reported adherence (or plasma levels) in HIV-infected pregnant women, children, and adults. We have also shown preliminary utility of hair levels of tenofovir (TFV)/emtricitabine (FTC) to monitor adherence and toxicities with oral PrEP. This proposal will leverage three important trials to explore key knowledge gaps that will arise in the next phase of HIV prevention work: The Sustainable East Africa Research in Community Health (SEARCH) trial (Dr. Havlir, chair and co-I) has just launched a large study providing oral PrEP to at-risk individuals in 16 communities in Africa. The HIV Open-Label Prevention Extension (HOPE) study in the Microbicide Trials Network (MTN) (Dr. Baeten, chair and co-I) will assess open-label use of the dapivirine vaginal ring. The Long-Acting Antiretroviral Therapy in Non-adherent HIV-Infected Individuals Trial (A5359, Dr. Castillo- Mancilla, co-chair and co-I)) in the AIDS Clinical Trials Group (ACTG) will examine long-acting injectables in HIV-infected patients with a history of poor adherence. All 3 trials will collect hair and plasma for drug levels, and track robust outcomes, to allow us to 1) investigate hair levels as metrics of adherence with the vaginal ring and oral PrEP in Africa and examine patterns of adherence (e.g. daily, around periods of risk, just prior to visits) by combining data in plasma and hair; and 2) examine hair levels as easy-to-collect metrics for PK monitoring with the use of injectables. The overarching goal of this renewal is to develop an integrated package of highly predictive biologic adherence and pharmacokinetic measures spanning PrEP delivery methods and optimization strategies. Defining predictors and patterns of adherence to oral PrEP and rings, as well as metrics to monitor PK with injectables, will inform public health interventions in HIV prevention.