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: 10155163
• 负责人: PETER L. ANDERSON
• 金额: $ 74.94万
• 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/10155163
• 关键词: AIDS prevention; Adherence; Affect; Africa; African; Age; Anti-Retroviral Agents; Archives; Benchmarking; Biological; Blood; Blood specimen; 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; 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; Plant Roots; Plasma; Population; Postpartum Women; Pregnancy; Pregnant Women; Prevention Research; Prevention strategy; Randomized; Risk; Risk Factors; Route; Sampling; Site; Spottings; Study Subject; Tenofovir; Testing; Time; Tissues; Vagina; Visit; Whole Blood; Woman; Work; active control; base; 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; pre-exposure prophylaxis; preclinical trial; 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 非洲妇女受艾滋病毒影响尤为严重，并且在怀孕期间感染艾滋病毒的风险较高。 暴露前预防 (PrEP) 是一种有效的 HIV 预防策略，但 PrEP 临床的依从性参差不齐 在女性中进行的试验和有限的药理学数据导致 PrEP 的程度缺乏明确性 顺性别女性艾滋病毒保护所需的使用。对于与男性发生性行为的美国男性，DOT-DBS 和 STRAND 作为直接观察疗法 (DOT) 进行的 PrEP 研究精确定义了目标替诺福韦二磷酸盐 (TFV-DP) 每周不同数量的 PrEP 剂量（即每周 2、4、7 剂）产生的浓度；什么时候 然后将这些数据应用于 iPrEx 试验队列，他们为男性定义了稳健的依从功效阈值。 单剂量组织药理学研究表明，与男性相比，女性的生殖器组织较少 男性直肠浓度，可能意味着女性需要极高的 PrEP 依从性才能实现 类似的艾滋病毒保护；然而，针对 PrEP 依从性合理但不完美的女性的临床研究 表明高水平的艾滋病毒保护。这场争议的根源在于缺乏将累积 PrEP 联系起来的数据 女性 PrEP 疗效的剂量阈值。最近，我们的团队和 IMPAACT 009 研究的数据 对非洲妇女进行的 PrEP 研究表明，STRAND 水平可能无法真正反映 非洲环境中 PrEP 的药理学，无论是一般情况还是特别是妊娠期：这些数据表明 孕妇和产后妇女之间 TFV-DP 水平的差异可能高达 30-40%。然而， IMPAACT 009 研究没有测量 PBMC 中的 TFV-DP 浓度，而需要确定这一浓度 观察到的水平是否会损害怀孕期间的艾滋病毒保护。明确地说，遵守- DOT 剂量在美国人群中制定的疗效阈值对于非洲和非洲的女性可能不准确 因此，从这个角度解释女性的 PrEP 依从性-浓度-功效之间的关系将是错误的。 事实上，缺乏将替诺福韦二吡呋酯的细胞内浓度与 HIV 保护联系起来的临床数据 富马酸盐 (TDF) PrEP 阻止 FDA 延长替诺福韦艾拉酚胺 (TAF)/恩曲他滨 (FTC) 的有效期 女性 PrEP 适应症。我们组建了一支真正具有多学科协同作用的强大团队，包括 PrEP 领域的领导者，进行一项新颖的随机药理学研究来定义女性特异性 从 DOT TDF/FTC PrEP 的不同频率得出的依从浓度阈值（目标 1）。我们将 采取综合方法：DOT 给药，从第一周到稳态采样，包括怀孕 多种生物基质（血浆、全血、干血斑、 PBMC 和阴道组织）。然后，利用存档的样本，对那些获得 HIV 和合作伙伴 PrEP 研究中未感染 HIV 的子集，我们将定义 TFV-DP 浓度 与女性艾滋病毒保护相关（目标 2）。最后，我们将把基准应用于一套 PrEP 实施研究，测试在现实环境中使用特定于女性的遵守阈值（目标 3）。