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

了解低剂量醋酸甲羟孕酮对女性生殖道微生物组和免疫学的影响

• 批准号: 10179439
• 负责人: Jennifer Caraway Deese
• 金额: $ 60.1万
• 依托单位: FAMILY HEALTH INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179439
• 关键词: Address; Africa South of the Sahara; Bacteria; Biological; Biological Response Modifiers; CCR5 gene; CCR6 gene; CD4 Positive T Lymphocytes; CXCL10 gene; Cells; Cervix Uteri; Complex; Conflict (Psychology); Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Copper Intrauterine Devices; Counseling; DEFB1 gene; Data; Depo Provera; Development; Dose; Eligibility Determination; Environment; Epithelial; Female genitalia; Formulation; Frequencies; Future; GPR2 gene; Genital; Genitalia; HIV; HIV Infections; HMGB1 gene; High Risk Woman; Hormones; Human; Immune; Immune response; Immunity; Immunology; Implant; Inflammation; Inflammatory; Injectable; Intramuscular; Intrauterine Devices; Levonorgestrel; Medical; Medroxyprogesterone 17-Acetate; Methodology; Mucous body substance; Observational Study; Outcome; PPBP gene; Parasites; Policies; Policy Maker; Predisposition; Progestins; Proteins; Proteomics; RANTES; Randomized; Randomized Clinical Trials; Research; Resolution; Risk; SLPI gene; Safety; Sampling; Surveys; Time; Uncertainty; Vagina; Validation; Virus; Visit; Woman; World Health Organization; antimicrobial; base; beta-Defensins; cost; cost efficient; cytokine; epidemiology study; fungus; hormonal contraception; implantable device; inflammatory marker; innovation; metagenomic sequencing; metaproteomics; microbial; microbiome; microorganism; novel; pharmacokinetics and pharmacodynamics; phase I trial; rRNA Genes; randomized trial; receptor; recruit; repaired; reproductive tract; subcutaneous; unintended pregnancy; vaginal lactobacilli; vaginal microbiome; vaginal mucosa

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.

项目摘要 仅含孕激素的避孕药Depo-Provera 150 mg肌肉注射（150-IM）， 在世界范围内使用注射避孕药，与许多国家艾滋病毒感染增加有关。 观察性研究随机临床试验缺乏因果关系证据， 不确定所观察到的相关性是由于方法学限制还是由于真实的生物学原因 效果由于这种不确定性，以及与计划外怀孕有关的风险，世界卫生组织 该组织建议，艾滋病毒高风险妇女可以继续使用注射用雷公藤多甙与咨询。 关于其他长效避孕药具对艾滋病毒感染的影响的数据，如植入和宫内避孕 装置（宫内节育器）甚至更稀缺;并且没有关于Sayana® Press（DMPA-SQ 104 mg， 下文称为104-SQ）和其它开发中的较低剂量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，创新和具有成本效益的研究，以评估 多种避孕药的影响-包括150-IM，左炔诺孕酮（LNG）植入物，铜IUD，104- SQ和新的低剂量DMPA制剂-对女性生殖道（FGT）的微生物和免疫 环境本研究的目的是：1）利用16 S rRNA基因分析女性阴道微生物群 用于细菌、病毒、真菌和寄生虫高分辨率分析的调查和宏基因组测序 在开始150-IM、104-SQ、LNG植入物或Cu-IUD之前和之后; 2）评估阴道细胞因子水平 在开始150-IM、104-SQ、LNG植入物或Cu-IUD之前和之后的抗微生物蛋白; 3）评估 CCR 5+、CCR 6+、CCR 10-（Th 17样）和α4β7 CD 4 + T细胞的频率和活化的变化 使用150-IM，104-SQ，LNG植入物或Cu-IUD的妇女中的宫颈; 4）评估阴道的变化 使用较低MPA剂量（45、75和105 mg）的微生物组、细胞因子和抗菌蛋白， 150-IM，以及全身和生殖器内源性和外源性激素水平对这些的影响 结果;以及5）进行发现元蛋白质组学分析以评估阴道人类和 开始150-IM、104-SQ、LNG植入物或Cu-IUD后的微生物蛋白。这项研究将澄清 避孕暴露、内源性和外源性激素与FGT之间的复杂关联 微生物组，免疫和炎症标志物，HIV靶细胞的募集和这些细胞的活化 和上皮屏障修复的标志物。这些数据将为避孕药具的使用和政策提供信息， 未来避孕药开发的目标和安全终点。这些数据将提供 FGT微生物组和免疫变化的第一个证据，发生在其他MPA启动后 避孕药，包括104-SQ和新的低剂量MPA制剂， 如果ECHO试验确定150-IM使用者中艾滋病毒感染增加，则需要使用ECHO。