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

摘要 非洲妇女感染艾滋病毒的比例更高，在怀孕期间感染艾滋病毒的风险更高。 暴露前预防(PrEP)是一种有效的HIV预防策略，但PrEP临床应用依从性不同 对女性的试验和有限的药理学数据导致了对PrEP程度的不清楚 在顺性妇女中使用艾滋病毒保护所需的。对于与男性发生性关系的美国男性来说，DOT-DBS和STRAND 作为直接观察疗法(DOT)的PrEP研究准确地确定了靶点替诺福韦二磷酸 (TFV-DP)每周不同剂量的PrEP产生的浓度(即每周2、4、7剂)； 这些数据随后被应用于Iprex试验队列，它们为男性定义了稳健的依从性-有效性阈值。 单剂量组织药理学研究表明，与女性相比，女性的生殖器组织较少 男性直肠集中，潜在意味着女性需要非常高的PrEP依从性才能实现 类似的艾滋病毒保护；然而，对坚持合理但不完美的PrEP的妇女的临床研究 建议采取高水平的艾滋病毒保护措施。这场争议的根源是缺乏将累积的PrEP与 剂量阈值与女性PrEP疗效的关系。最近，我们团队和IMPAACT 009研究的数据 从非洲女性的PrEP研究中产生的数据表明，链水平可能并不真正反映 PrEP在非洲环境中的药理学，一般情况下，特别是在怀孕期间：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TFV-DP的浓度，这是确定 观察到的水平是否会影响怀孕期间对艾滋病毒的保护。明确地说，遵守- 在美国人群中由DOT剂量制定的疗效阈值对非洲和 因此，解释女性在该晶状体中的PrEP依从性-浓度-功效关系将是错误的。 事实上，没有临床数据将替诺福韦的细胞内浓度与HIV保护联系起来 富马酸盐(TDF)PrEP阻止FDA延长替诺福韦丙氨酰胺(TAF)/恩曲他滨(FTC)的使用期限 准备给女性做指征。我们组建了一支真正具有多学科协同的强大团队，包括 PrEP领域的领导者，进行一项新的随机药理学研究，以确定女性特有的 依从性-根据不同频率的DOT TDF/FTC PrEP得出的浓度阈值(目标1)。我们会 采取全面的方法：点滴，从第一周到稳定状态，包括怀孕 多个生物基质(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和来自合作伙伴PrEP研究的未感染HIV的子集，我们将定义TFV-DP浓度 与妇女艾滋病毒保护有关(目标2)。最后，我们将基准应用于一套PrEP 执行研究，测试在现实世界环境中妇女特定遵守阈值的使用情况(目标3)。

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).