Modifies of PrEP Efficacy in US & African Women: Age, Hormones, Sex & Microbiota

项目摘要（见说明）：年轻女性迫切需要女性控制的艾滋病毒预防策略，包括抗逆转录病毒（ARV）药物用于局部或口服暴露前预防（PrEP）。两项每日口服ARV PrEP研究和一项阴道凝胶研究证明了预防女性HIV-1感染的有效性。然而，另外两项每日口服PrEP和一项每日替诺福韦（TFV）凝胶的研究因无效而提前停止。先前的研究表明，在其他方面相似的美国和撒哈拉以南非洲妇女之间，ARV代谢和宫颈免疫细胞群存在差异，但生殖器粘膜环境的具体差异可能会影响ARV药代动力学（PK），药效学（PD）和疗效。我们假设年轻、细菌性阴道病（BV）、精液暴露和长效醋酸甲羟孕酮（DMPA）的使用与CD 4-i-T细胞活化增加、可溶性免疫改变和阴道乳酸杆菌丢失相关，这些因素增加了HIV感染风险并改变了局部ARV PK/PD。在项目3中，将在4项临床研究中研究已知HIV风险影响PK/PD的机制：将在BV诊断时和成功治疗后、在无保护阴道性交的情况下、在开始DMPA之前和之后以及通过比较性活跃的青少年与成年女性来研究女性。最终目标是利用知识的机制，艾滋病毒感染的风险，以推进有效的，女性控制的PrEP策略的选择。我们还提出了一项在美国和非洲有HIV风险的女性中进行的1期前替诺福韦酯（TDF）阴道环（IVR）研究，以评估与激素效应相关的粘膜免疫变化和/或阴道微生物群变化调节TDF的PK/PD的假设。使用TDF环14天后，将测量血浆、生殖道分泌物和上皮组织中的药物水平（核心B）。将进行焦磷酸测序和物种特异性定量PCR测定，以检查可能调节TDF PK/PD的阴道微生物群的变化。这些研究将利用创新方法为局部ARV PrEP策略的制定提供信息，并将调查不同高危女性人群可能需要不同预防策略的关键假设

PROJECT SUMMARY (See instructions): Young women are in urgent need of female-controlled HIV prevention strategies, including antiretroviral (ARV) drugs for topical or oral pre-exposure prophylaxis (PrEP). Two daily oral ARV PrEP studies and one vaginal gel study demonstrated efficacy in preventing HIV-1 infection in women. However, two other studies of daily oral PrEP and one of daily tenofovir (TFV) gel were stopped early for futility. Prior studies suggest differences in ARV metabolism and cervical immune cell populations between otherwise similar U.S. and sub-Saharan African women, but specific differences in the genital mucosal environment that may impact ARV pharmacokinetics (PK), pharmacodynamics (PD) and efficacy are understudied. We hypothesize that young age, bacterial vaginosis (BV), semen exposure, and depot medroxyprogesterone acetate (DMPA) use are associated with increased activation of CD4-i- T cells, changes in soluble immunity, and loss of vaginal lactobacilli, which increase HIV acquisition risk and alter topical ARV PK/PD. In Project 3, mechanisms by which known HIV risks impact PK/PD will be investigated in four clinical studies: women will be studied at BV diagnosis and after successful treatment, in the setting of unprotected vaginal sexual intercourse, before and after initiation of DMPA, and by comparing sexually active adolescents to adult women. The ultimate goal is to utilize knowledge of the mechanisms underlying HIV acquisition risk to advance selection of effective, female-controlled PrEP strategies. We also propose a pre-Phase 1 tenofovir disoproxil fumarate (TDF) intravaginal ring (IVR) study in U.S. and African women at risk for HIV to assess the hypothesis that changes in mucosal immunity related to hormonal effects and/or changes in vaginal microbiota modulate PK/PD of TDF. Drug levels will be measured in plasma, genital tract secretions and epithelial tissue following 14 days of TDF ring use (Core B). Pyrosequencing and species-specific quantitative PCR assays will be performed to examine changes in vaginal microbiota that may modulate PK/PD of TDF. These studies will utilize innovative approaches to inform the development of topical ARV PrEP strategies and will investigate the key hypothesis that distinct populations of high risk women may require differential preventative strategies