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

美国 PrEP 疗效的修改

• 批准号: 8448509
• 负责人: MARLA J KELLER
• 金额: $ 89.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448509
• 关键词: AIDS prevention; AIDS/HIV problem; Accounting; Address; Adherence; Adolescent; Adult; Affect; Africa South of the Sahara; African; Aftercare; Age; Anaerobic Bacteria; Anti-Retroviral Agents; Bacterial Vaginosis; Biological Assay; Biological Response Modifiers; Biopsy; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Clinical Research; Coitus; Communities; DNA; Deoxyadenosines; Development; Diagnosis; Diphosphates; Dose; Drug Kinetics; Environment; Epithelial; Exposure to; Female; Futility; Gel; Genetic Transcription; Genital system; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; HIV risk; HIV-1; Half-Life; Heterosexuals; High Risk Woman; Hormonal; Hydrogen Peroxide; Immune; Immune Cell Activation; Immunity; Infection; Inflammation; Inflammatory Response; Instruction; Irrigation; Knowledge; Lactobacillus; Lymphocyte; Measures; Mediator of activation protein; Medroxyprogesterone 17-Acetate; Metabolism; Mucosal Immunity; Oral; Organic Anion Transporters; Outcome; Participant; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma; Play; Population; Predisposition; Prevention strategy; Prophylactic treatment; Rest; Risk; Risk Factors; Role; Seminal fluid; Sexual Transmission; Swab; T-Cell Activation; T-Lymphocyte; Tenofovir; Tenofovir disoproxil fumarate; Tissues; Vagina; Vaginal Gel; Vaginal Ring; Woman; aged; antileukoprotease; cervicovaginal; cohort; cytokine; hormonal contraception; human SLPI protein; immune activation; innovation; prevent; pyrosequencing; rectal; restoration; sexually active; social; tripolyphosphate; vaginal lactobacilli; vaginal microbicide; young woman

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

项目摘要(见说明)：年轻妇女迫切需要女性控制的艾滋病毒预防战略，包括用于局部或口服暴露前预防的抗逆转录病毒药物(PrEP)。每天两次口服ARV PrEP研究和一次阴道凝胶研究证明了在预防妇女感染HIV-1方面的有效性。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新陈代谢和宫颈免疫细胞群存在差异，但生殖器粘膜环境中可能影响ARV药代动力学(PK)、药效学(PD)和疗效的具体差异研究不足。我们假设，年轻、细菌性阴道病(BV)、精液暴露和使用醋酸甲羟孕酮(DMPA)与CD4-I-T细胞激活增加、可溶性免疫改变和阴道乳酸菌丢失有关，这些因素增加了HIV感染的风险，改变了局部ARV PK/PD。在项目3中，将通过四项临床研究来研究已知的艾滋病毒风险影响PK/PD的机制：在BV诊断和成功治疗后，在无保护的阴道性交环境中，在DMPA开始之前和之后，通过比较性行为活跃的青少年和成年女性来研究妇女。最终目标是利用艾滋病毒感染风险潜在机制的知识，推动选择有效的、由女性控制的PrEP战略。我们还建议在美国和非洲HIV高危妇女中进行一项替诺福韦富马酸二异丙酯(TDF)阴道环(IVR)1期前研究，以评估与激素效应相关的粘膜免疫变化和/或阴道微生物区系变化调节TDF的PK/PD的假设。在TDF环使用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特定物种的定量PCR分析，以检查可能调节TDF的PK/PD的阴道微生物区系的变化。这些研究将利用创新的方法为局部ARV PrEP策略的发展提供信息，并将调查关键假设，即不同的高危女性人群可能需要不同的预防策略