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过高，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临床治疗中的依从性不同。 在女性中进行的试验和有限的药理学数据导致缺乏关于PrEP程度的明确性 使用所需的艾滋病毒保护cisgender妇女。对于与男性发生性关系的美国男性，DOT-DBS和STRAND 作为直接观察治疗（DOT）提供的PrEP研究精确定义了靶向替诺福韦二磷酸 （TFV-DP）浓度由每周不同数量的PrEP剂量引起（即，2、4、7剂/周）;当 然后将这些数据应用于iPrEx试验组群，他们定义了男性的稳健的依从性-功效阈值。 单剂量组织药理学研究表明，女性的生殖器组织比男性低， 男性直肠浓度，可能意味着女性需要非常高的PrEP坚持，以实现 类似的艾滋病毒保护;然而，在合理但不完美的PrEP依从性的女性中进行的临床研究 这意味着高水平的艾滋病毒保护。这场争论的根源是缺乏将累积的PrEP 剂量阈值与PrEP在女性中的功效。最近，我们的团队和IMPAACT 009研究的数据显示， 从非洲妇女的PrEP研究中产生的结果表明，STRAND水平可能并不能真正反映 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水平的差异可高达30-40%。然而，在这方面， IMPAACT 009研究未测量PBMC中的TFV-DP浓度，而这是确定 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，坚持- 在美国人群中通过DOT给药开发的疗效阈值可能对非洲妇女不准确， 因此解释女性在该透镜中的PrEP粘附-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酯的细胞内浓度与HIV保护联系起来， 富马酸盐（TDF）PrEP阻止FDA延长替诺福韦艾拉酚胺（TAF）/恩曲他滨（FTC） PrEP指示女性。我们组建了一支强大的团队，具有真正的多学科协同作用，包括 PrEP领域的领导者，进行一项新的随机药理学研究，以确定女性特异性 从DOT TDF/FTC PrEP的不同频率得出的粘附浓度阈值（目的1）。我们将 采取全面的方法：DOT给药，从第一周到稳态采样，包括妊娠 群组和多种生物基质（血浆，全血，干血斑， PBMC和阴道组织）。然后，利用存档的样本，在一项对那些获得 HIV和Partners PrEP研究中剩余的未感染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，我们将把基准应用于一套PrEP 实施研究，测试在现实世界中使用妇女特有的遵守阈值（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).