PrEP adherence-concentration thresholds associated with HIV protection among African women

非洲妇女中与艾滋病毒保护相关的 PrEP 坚持浓度阈值

• 批准号: 10560498
• 负责人: PETER L. ANDERSON
• 金额: $ 85.82万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560498
• 关键词: AIDS prevention; Adherence; Affect; Africa; African; Age; Anti-Retroviral Agents; Archives; Benchmarking; Biological; Blood; Blood specimen; Classification; Clinical; Clinical Data; Clinical Pharmacology; Clinical Research; Clinical Trials; Cohort Studies; Data; Data Pooling; Data Set; Development; Diphosphates; Directly Observed Therapy; Dose; Drug Exposure; Drug Kinetics; Dryness; Exposure to; Frequencies; Fumarates; Future; Genital; Genitalia; HIV; HIV Infections; HIV Seropositivity; HIV risk; Human immunodeficiency virus test; Injectable; International Maternal Pediatric Adolescent AIDS Clinical Trials; Intervention; Link; Measurement; Measures; Methods; Modality; Oral; Pattern; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Plasma; Population; Postpartum Women; Pregnancy; Pregnant Women; Prevention Research; Prevention strategy; Randomized; Rectum; Risk; Risk Factors; Route; Sampling; Site; Spottings; Study Subject; Tenofovir; Testing; Time; Tissues; Vagina; Visit; Whole Blood; Woman; Work; active control; case control; cis-female; clinical epidemiology; cohort; design; emtricitabine; follow-up; implementation study; infection rate; lens; male; men; men who have sex with men; multidisciplinary; novel; pharmacologic; pre-exposure prophylaxis; prevent; rectal; sample archive; scale up; seroconversion; sex; standard of care; success; synergism

ABSTRACT African women are disproportionately affected with HIV and have elevated risk of acquiring HIV in pregnancy. Pre-exposure prophylaxis (PrEP) is a potent HIV prevention strategy, but variable adherence in PrEP clinical trials among women and limited pharmacologic data have resulted in lack of clarity about the degree of PrEP use required for HIV protection in cisgender women. For US men who sex with men, the DOT-DBS and STRAND studies of PrEP delivered as directly-observed therapy (DOT) defined precisely the target tenofovir diphosphate (TFV-DP) concentrations arising from varying number of PrEP doses per week (i.e., 2, 4, 7 doses/ week); when these data were then applied to the iPrEx trial cohort, they defined robust adherence-efficacy thresholds for men. Single-dose tissue pharmacology studies have suggested that women have lower genital tissue compared with male rectal concentrations, potentially implying women need extraordinarily high PrEP adherence to achieve similar HIV protection; however, clinical studies in women with reasonable-but-imperfect PrEP adherence suggest high levels of HIV protection. At root of this controversy is the lack of data that link cumulative PrEP dosing thresholds with PrEP efficacy in women. Recently, data our team and the IMPAACT 009 Study have generated from PrEP studies in African women suggest the STRAND levels may not truly reflect the pharmacology of PrEP in African settings, both in general and particularly in pregnancy: These data suggest differences in TFV-DP levels may be as great as 30-40% between pregnant and postpartum women. However, the IMPAACT 009 study did not measure TFV-DP concentrations in PBMCs which are required to ascertain whether the observed levels may compromise HIV protection in pregnancy. To state it explicitly, the adherence- efficacy thresholds developed by DOT dosing in US populations may not be accurate for women in Africa and thus interpreting women's PrEP adherence-concentration-efficacy relationships in that lens will be erroneous. Indeed, the absence of clinical data linking intracellular concentrations to HIV protection for tenofovir disoproxil fumarate (TDF) PrEP prevented the FDA from extending the tenofovir alafenamide (TAF) / emtricitabine (FTC) PrEP indication to women. We have assembled a strong team with truly multidisciplinary synergy, including leaders in the PrEP field, to conduct a novel randomized pharmacologic study to define women-specific adherence-concentrations thresholds derived from varying frequency of DOT TDF/FTC PrEP (Aim 1). We will take a comprehensive approach: DOT dosing, sampling from week one to steady-state, including a pregnancy cohort, and pharmacologic measurement in multiple biologic matrices (plasma, whole blood, dried blood spots, PBMC, and vaginal tissue). Then, leveraging archived samples, in a case-cohort study of those who acquired HIV and a subset remaining HIV-uninfected from the Partners PrEP Study, we will define TFV-DP concentrations associated with HIV protection for women (Aim 2). Lastly, we will apply the benchmarks to a suite of PrEP implementation studies, testing use of women-specific adherence thresholds in real-world settings (Aim 3).

抽象的 非洲妇女受到艾滋病毒的影响不成比例，并且在怀孕中获得艾滋病毒的风险升高。 暴露前预防（PREP）是一种有效的艾滋病毒预防策略，但在PrEP临床上的依从性可变 妇女的试验和有限的药理学数据导致缺乏对PREP程度的清晰度 在Cisgender妇女中保护艾滋病毒所需的使用。对于我们与男人发生性关系的男人，点db和strand 针对直接观察疗法（DOT）的PREP的研究精确定义了目标替诺福韦二磷酸 （TFV-DP）浓度是由每周的预备剂量数量变化（即2、4、7剂量/周）；什么时候 然后将这些数据应用于IPREX试验队列，它们定义了男性的鲁棒性效能阈值。 单剂组织药理学研究表明，与 男性直肠浓度，可能意味着女性需要特别高的准备依从性才能实现 类似的艾滋病毒保护；但是，对具有合理但强大的准备依从性的女性的临床研究 建议高水平的艾滋病毒保护。这一争议的根源是缺乏连接累积准备的数据 剂量阈值具有女性的准备功效。最近，我们的团队和Inmaact 009研究的数据已有 非洲妇女的准备研究产生的 一般，尤其是怀孕的非洲设置中的PREP药理学：这些数据表明 TFV-DP水平的差异可能高达怀孕和产后妇女的30-40％。然而， Incract 009研究未测量PBMC中的TFV-DP浓度，这是确定的 观察到的水平是否可能损害怀孕的HIV保护。要明确陈述它的依从性 - 美国人口中点剂量开发的功效阈值可能对非洲妇女和 因此，解释妇女的依从性 - 浓度效能关系的关系将是错误的。 实际上，缺乏将细胞内浓度与HIV保护的临床数据 富马酸盐（TDF）准备阻止FDA延长替诺福韦抗烯酰胺（TAF） / Emtricitabine（FTC） 对女性的准备指示。我们已经组建了一支强大的团队，以真正的多学科协同作用，包括 准备领域的领导者，进行一项新的随机药理研究，以定义女性特异性 从点TDF/FTC准备的不同频率得出的依从性浓度阈值（AIM 1）。我们将 采用全面的方法：点剂量，从第一周到稳态进行抽样，包括怀孕 多种生物基质（血浆，全血，干血点， PBMC和阴道组织）。然后，在一项案例研究中，利用存档的样品对那些获得的人的研究 艾滋病毒和剩余的艾滋病毒从合作伙伴准备研究中未直接的艾滋病毒，我们将定义TFV-DP浓度 与妇女保护的艾滋病毒保护有关（AIM 2）。最后，我们将将基准应用于一套准备 实施研究，在现实环境中测试妇女特定依从性阈值的使用（AIM 3）。