Immunologic changes associated with three progestin-based contraceptives: characterizing immune profiles over one year and identifying factors that may alter HIV risk

与三种孕激素避孕药相关的免疫学变化：描述一年内的免疫特征并确定可能改变艾滋病毒风险的因素

• 批准号: 10440378
• 负责人: Lisa Blake Haddad
• 金额: $ 75.79万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440378
• 关键词: 16S ribosomal RNA sequencing; AIDS/HIV problem; Adherence; Affect; African ancestry; Area; Bacterial Vaginosis; Biological Assay; Blood specimen; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Chronic; Clinical; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Counseling; Cytometry; Data; Decision Making; Disease; Dose; Drug Kinetics; Epidemiology; Escherichia coli; Estrogen Antagonists; Estrogens; Etonogestrel; Exposure to; Female; Female genitalia; Flow Cytometry; Formulation; Genital; Genitalia; Gonadal Steroid Hormones; HIV; HIV Infections; HIV risk; Immune; Immune Targeting; Immune response; Immunologic Factors; Immunologic Markers; Immunologics; Implant; Incidence; Individual; Intrauterine Devices; Lead; Levonorgestrel; Link; Mediating; Medroxyprogesterone 17-Acetate; Menorrhagia; Methods; Mucous Membrane; Nature; Outcome; Outcome Study; Patients; Pharmacology; Polycystic Ovary Syndrome; Predisposition; Prevention; Progestins; Provider; Public Health; Publishing; Recommendation; Reporting; Reproductive Health; Research; Research Design; Research Project Grants; Risk; Risk Factors; Role; Sample Size; Sexually Transmitted Diseases; Testing; Time; Tissues; Translational Research; Vagina; Visit; Woman; aged; base; cohort; comparative; cytokine; endometriosis; epidemiology study; follow-up; global health; hormonal contraception; infection risk; modifiable risk; novel; personalized decision; prospective; recruit; reproductive; reproductive tract; response; translational potential; unintended pregnancy; vaginal microbiome; vaginal microbiota; volunteer

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year translational research project to explore the mechanisms underlying the HIV risk associated with pharmacologic doses of exogenous sex hormones (via hormonal contraceptives). Emerging data suggests that certain hormonal contraceptives may induce mucosal and systemic immune changes that could increase the risk of infection with HIV. While several studies have aimed to characterize immunologic changes in women using hormonal contraceptives, the nature and the magnitude of these immune changes have not been adequately defined due to limitations in study design rigor, and small and statistically underpowered sample sizes. There is limited comprehensive data or comparative data on the effect of different types of contraceptives on innate and adaptive immunologic markers of HIV susceptibility. Without this research, we cannot effectively counsel our patients on contraceptive selection. Characterization of potential individual-level factors, such as the presence of bacterial vaginosis (BV), that may alter a woman's risk profile with contraceptive use, could lead to individualized decision-making about contraceptive choice and would have profound implications for global health especially in HIV-endemic areas. We propose to prospectively recruit cohorts of HIV-uninfected women initiating hormonal contraception to characterize systemic and lower genital track innate and adaptive immunologic changes that occur over the course of 1 year. This study will test the overarching hypothesis that hormonal contraceptives induce systemic and mucosal immune changes capable of altering susceptibilities and/or responses to diseases including HIV infection, and that these effects vary markedly in nature and magnitude by contraceptive type and will be modified by the vaginal microenvironment. The aims are: 1) To determine the immunologic alterations in female genital and systemic immune profile associated with depot medroxyprogesterone acetate (DMPA), Etonogestrel impant (Eng-Implant) and Levonorgestrel IUD (Lng-IUD). We hypothesize that HIV target immune cells within the female genital tract of HIV-uninfected at-risk women will increase following contraceptive initiation. Further, because the anticipated mucosal immune changes with progestin-only contraceptives are, to a large extent, mediated via estrogen suppression, we hypothesize the impact of the Lng-IUD (with minimal to no anti-estrogen effect) and Eng-Implant (with milder anti-estrogen effect) will be significantly less pronounced compared with that of DMPA. 2) To evaluate the vaginal microenvironment as a moderator of genital and systemic immune profile changes and changes in tissue infectivity following exposure to these three commonly used hormonal contraceptives. Based on our earlier findings, we hypothesize that immunologic changes induced with hormonal contraception will be more pronounced in the setting of BV. The outcomes of the proposed study could have significant global clinical implications for safe individualized contraceptive counseling and decision-making for women at risk for HIV/AIDS.

项目总结/摘要 该提案概述了一个为期5年的转化研究项目，以探索艾滋病毒的潜在机制。 与外源性性激素（通过激素避孕药）的药理剂量相关的风险。 新的数据表明，某些激素避孕药可能会诱导粘膜和全身免疫 这些变化可能会增加感染艾滋病毒的风险。虽然有几项研究旨在描述 使用激素避孕药的妇女的免疫变化，这些变化的性质和程度 由于研究设计严格性的限制，免疫变化尚未充分定义， 统计学上效力不足的样本量。关于影响的综合数据或比较数据有限 不同类型的避孕药对HIV易感性的先天性和适应性免疫标志物的影响。没有 这项研究，我们不能有效地咨询我们的病人避孕选择。表征 潜在的个人水平的因素，如细菌性阴道病（BV）的存在，可能会改变妇女的 使用避孕药具的风险状况，可能导致关于避孕药具选择的个性化决策， 将对全球健康产生深远影响，特别是在艾滋病毒流行地区。我们建议 前瞻性招募开始使用激素避孕的未感染艾滋病毒的女性队列， 系统性和下生殖道的先天性和适应性免疫变化，发生在1 年这项研究将测试总体假设，即激素避孕药诱导全身和 能够改变对包括HIV在内的疾病的易感性和/或应答的粘膜免疫变化 感染，这些影响的性质和程度因避孕类型而异， 被阴道微环境改变目的是：1）确定免疫学改变， 与长效醋酸甲羟孕酮（DMPA）相关的女性生殖器和全身免疫特征， 依托孕烯植入物（Eng-Implant）和左炔诺孕酮IUD（Lng-IUD）。我们假设艾滋病病毒的目标免疫 未感染艾滋病毒的高危女性生殖道内的细胞在避孕后会增加， 初始化。此外，由于仅孕激素避孕药的预期粘膜免疫变化， 在很大程度上，通过雌激素抑制介导，我们假设Lng-IUD的影响（最小到 无抗雌激素作用）和Eng-Implant（抗雌激素作用较轻）的显著性较低 与DMPA相比。2)评估阴道微环境作为生殖器和 在暴露于这三种常见的病毒后，全身免疫特征的变化和组织感染性的变化 使用激素避孕药。基于我们早期的发现，我们假设免疫变化 在BV的情况下，激素避孕引起的不良反应将更加明显。的成果 拟议的研究可能对安全的个体化避孕药具有重要的全球临床意义 为有感染艾滋病毒/艾滋病风险的妇女提供咨询和决策。

项目成果

Evaluating the impact of three progestin-based hormonal contraceptive methods on immunologic changes in the female genital tract and systemically (CHIME Study): a prospective cohort study protocol.

• DOI: 10.1186/s12905-022-02053-w
• 发表时间: 2022-11-18
• 期刊: BMC WOMENS HEALTH
• 影响因子: 2.5
• 作者: Haddad, Lisa B.;Herring, Gina Bailey;Mehta, C. Christina;Staple, Tyree;Young, Marisa R.;Govindaraj, Sakthivel;Velu, Vijayakumar;Smith, Alicia K.
• 通讯作者: Smith, Alicia K.

Interactions between Hormonal Contraception and Anti-Retroviral Therapy: An Updated Review.

激素避孕与抗逆转录病毒疗法之间的相互作用：更新的评论。

• DOI: 10.1007/s13669-020-00289-7
• 发表时间: 2020-09
• 期刊: Current obstetrics and gynecology reports
• 影响因子: 0.5
• 作者: Krishna GR;Haddad LB
• 通讯作者: Haddad LB