Understanding the Impact of Lower Dose Medroxyprogesterone Acetate on Female Genital Tract Microbiome and Immunology

项目摘要 仅含孕激素的避孕药Depo-Provera 150 mg肌肉注射(150-IM)，是应用最广泛的 在全球范围内使用注射避孕药，与许多人感染艾滋病毒的增加有关 观察性研究。随机临床试验缺乏因果关系的证据导致了 不确定所观察到的关联是由于方法限制还是真正的生物学原因 效果。由于这种不确定性，以及与意外怀孕相关的风险，世界卫生组织 该组织建议，艾滋病毒高危女性可以在咨询的同时继续使用孕激素注射剂。 其他长效避孕药对艾滋病毒感染的影响的数据，如植入物和宫内避孕药 装置(宫内节育器)更加稀缺；而且没有关于Sayana®Press的数据(DMPA-SQ 104 mg， 此后104-SQ)和其他正在开发的较低剂量的DMPA制剂。这项研究将利用 三项正在进行的随机试验，以进行及时、创新和成本效益高的研究，以评估 多种避孕药的影响--包括150-IM、左旋诺孕酮(LNG)植入物、铜质宫内节育器、104- SQ和新型低剂量DMPA制剂--对女性生殖道(FGT)微生物和免疫的影响 环境。本研究的目的是：1)利用16S rRNA基因对女性阴道微生物组进行分析 用于高分辨率分析细菌、病毒、真菌和寄生虫的调查和元基因组测序 150-IM、104-SQ、LNG植入或放置铜-IUD前后：2)评估阴道细胞因子水平 150-IM、104-SQ、LNG植入物或Cu-IUD植入前后的抗菌蛋白；3)评价 T细胞CCR5、CCR6CCR10-(Th17样)和α-4-β-7CD4T细胞频率和活化的变化 使用150-IM、104-SQ、LNG植入物或铜-IUD的妇女的宫颈；4)评估阴道的变化 微生物组、细胞因子和抗菌蛋白与使用较低剂量的MPA(45、75和105 mg)的比较 至150-IM，以及全身和生殖器内源性和外源性激素水平对这些激素水平的影响 结果；以及5)进行发现的代谢蛋白质组分析，以评估阴道人类和 150-IM、104-SQ、LNG植入物或铜IUD植入后的微生物蛋白。这项研究将澄清 避孕措施暴露、内源性和外源性激素与FGT之间的复杂关系 微生物组、免疫和炎症标志物、HIV靶细胞的招募和这些细胞的激活 和上皮屏障修复的标志物。这些数据将为避孕用法和政策提供信息，并提供 未来避孕药具发展的目标和安全终点。此外，这些数据将提供 FGT微生物群和免疫变化的第一个证据发生在其他MPA启动之后 以避孕药为基础的，包括104-SQ和新的低剂量MPA配方，这将是至关重要的 如果ECHO试验在150-IM用户中发现HIV感染增加，则需要。

Project Summary The progestin-only contraceptive Depo-Provera 150mg delivered intramuscularly (150-IM), the most widely used injectable contraceptive worldwide, has been associated with increased HIV acquisition in many observational studies. The absence of causal evidence from randomized clinical trials has resulted in uncertainty about whether the observed association is due to methodological limitations or a real biological effect. Due to this uncertainty, and the risks associated with unplanned pregnancies, the World Health Organization advises that women at high risk of HIV can continue to use progestin injectables with counseling. Data on the effects of other long-acting contraceptives on HIV acquisition, such as implants and intrauterine devices (IUDs) are even more scarce; and there are no data on Sayana® Press (DMPA-SQ 104mg, hereafter 104-SQ) and other lower dose DMPA formulations in development. This study will leverage three ongoing randomized trials to conduct timely, innovative, and cost efficient research to evaluate the impact of multiple contraceptives – including 150-IM, the levonorgestrel (LNG) implant, the copper IUD, 104- SQ, and novel low dose DMPA formulations - on the female genital tract (FGT) microbial and immune environment. The aims of this research are to: 1) analyze the vaginal microbiome of women by 16S rRNA gene survey and metagenomic sequencing for high-resolution analysis of bacteria, viruses, fungi, and parasites before and after initiation of 150-IM, 104-SQ, LNG implant or Cu-IUD; 2) evaluate levels of vaginal cytokines and antimicrobial proteins before and after initiation of 150-IM, 104-SQ, LNG implant or Cu-IUD; 3) evaluate changes in the frequency and activation of CCR5+, CCR6+CCR10- (Th17-like) and α4β7 CD4+ T cells in the cervix among women using 150-IM, 104-SQ, LNG implant or Cu-IUD; 4) evaluate changes in the vaginal microbiome, cytokines and antimicrobial proteins with use of lower MPA doses (45, 75 and 105mg) compared to 150-IM, and the effect of systemic and genital endogenous and exogenous hormone levels on these outcomes; and 5) conduct a discovery metaproteomics analysis to evaluate alterations in vaginal human and microbial proteins following initiation of 150-IM, 104-SQ, LNG implant or Cu-IUD. This research will clarify the complex associations between contraceptive exposure, endogenous and exogenous hormones and the FGT microbiome, markers of immunity and inflammation, recruitment of HIV target cells and activation of those cells and markers of epithelial barrier repair. These data will inform contraceptive use and policy as well as provide targets and safety endpoints for the development of future contraceptives. Moreover, these data will provide the first evidence of FGT microbiome and immune changes that occur following initiation of other MPA based contraceptives, including 104-SQ and novel low dose MPA formulations which will be critically needed if the ECHO trial identifies increased acquisition of HIV among 150-IM users.