Biological effects, hormone levels and mechanisms relevant to HIV-1 infection for women randomized to the injectable contraceptives depo-medroxyprogesterone acetate or norethisterone enanthate.

随机注射避孕药醋酸甲羟孕酮或庚酸炔诺酮注射避孕药的女性与 HIV-1 感染相关的生物效应、激素水平和机制。

• 批准号: 10162497
• 负责人: Janet Patricia Hapgood
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10162497
• 关键词: Address; Affect; Africa South of the Sahara; Androgens; Area; Behavioral; Biological; Biological Markers; Biometry; Blood specimen; CCR5 gene; Cell model; Cells; Clinical; Clinical Data; Clinical Trials; Contraceptive Agents; Contraceptive methods; Data; Development; Disadvantaged; Discrimination; Dose; Enzymes; Epidemic; Epidemiology; Estrogens; Exhibits; Genes; Glucocorticoid Receptor; Guidelines; HIV-1; Health; Health Policy; Heptanoates; High Prevalence; Horizontal Disease Transmission; Hormones; Immune; Immune Targeting; Immunologic Markers; Immunology; Implant; In Vitro; Individual; Infection; Injectable; Injections; Institutes; Interdisciplinary Study; International; Intramuscular; Intramuscular Injections; Investigation; Knowledge; Levonorgestrel; Measures; Medroxyprogesterone 17-Acetate; Norethindrone; Observational Study; Pathogenesis; Population; Predisposition; Progestins; Proteins; Public Health; Randomized; Regulation; Relative Risks; Research; Research Personnel; Risk; Sampling; Series; Serum; Sex Bias; South Africa; South African; Steroid Receptors; Steroids; Technology; Time; Tissue Model; Vertical Disease Transmission; Woman; Women' s Health; aged; androgenic; black women; clinical practice; contraceptive efficacy; estrogenic; head-to-head comparison; high risk; high risk population; hormonal contraception; immune function; in vivo; infection rate; insight; inter-individual variation; novel; peptide hormone; randomized trial; receptor; reproductive tract; response; sample archive; sexually active; side effect; steroid hormone; steroid metabolism; young woman

The proposed research seeks to understand plausible biological mechanisms whereby different injectable contraceptives may or may not affect susceptibility to infections such as HIV-1. High usage of injectable contraceptives correlates with high prevalence of HIV-1 infection in sub-Saharan Africa and South Africa. A strong gender bias for HIV-1 infection occurs towards young women in sub-Saharan Africa. Depo- medroxyprogesterone acetate (DMPA-IM), a three-monthly, intramuscular (IM) injection of 150 mg MPA is the most commonly used, while Norethisterone enanthate (NET-EN), a two-monthly, IM injection of 200 mg NET- EN is widely used in South Africa, especially among young women. Higher quality observational clinical data show a significant 40-50% increased risk of HIV-1 acquisition compared to no hormonal contraception for DMPA-IM. Limited observational studies found no significant increased risk for HIV-1 acquisition compared to no hormonal contraception for NET-EN, while two head-to-head comparisons found a potential 32-40% increase in HIV-1 risk for DMPA-IM versus NET-EN users. Recent results from the randomized ECHO trial do not inform on the risk of HIV-1 infection of DMPA-IM compared to NET-EN, or for DMPA-IM compared to no hormonal contraception. However, they do suggest progestin-specific effects with a best estimate of 23-29% increased risk for DMPA-IM compared to a levonorgestrel-containing implant over only 18 months. It is possible that a 32-40% difference in HIV-1 risk between DMPA-IM and NET-EN, taking into account both vertical and horizontal transmission, may have an important impact on the epidemic over a longer time period in high risk populations and may be highly relevant for individual women who desire informed choice. Given the potential for confounding factors in observational studies, a definitive answer as to the relative HIV-1 risks of DMPA-IM and NET-EN remains elusive. Another approach to gaining insights into the relative risks of DMPA- IM versus NET-EN is to obtain and evaluate high quality clinical biological data on responses strongly implicated in HIV-1 acquisition from women randomized to DMPA-IM and NET-EN. We will obtain archived samples from such a randomized trial (The WHICH (part 1) trial), and measure biomarkers of immune function and other potential markers of HIV-1 susceptibility. We will also perform a series of in vivo and ex vivo mechanistic studies to investigate plausible biological mechanisms for MPA and NET for HIV-1 acquisition and determine how those results correlate with the clinical data. The results will provide insight into whether and how DMPA-IM and NET-EN exert different biological effects, with implications for HIV-1 acquisition in women. The results will contribute significantly to scientific knowledge in the contraception and HIV-1 fields. They are likely to impact on clinical practice, health policy and international guidelines, to either reassure the interchangeable use or suggest preferential use of one of these injectable contraceptives over the other in populations at high risk of HIV-1 infection.

拟议的研究旨在了解不同注射剂的合理生物学机制 避孕药可能会也可能不会影响对 HIV-1 等感染的易感性。注射剂使用率高 在撒哈拉以南非洲和南非，避孕药具与 HIV-1 感染率高相关。一个 撒哈拉以南非洲地区的年轻女性对 HIV-1 感染存在强烈的性别偏见。德波- 醋酸甲羟孕酮 (DMPA-IM)，每三个月一次，肌肉注射 (IM) 注射 150 毫克 MPA 最常用的是庚酸炔诺酮 (NET-EN)，每月两个月肌内注射 200 毫克 NET- EN 在南非被广泛使用，尤其是在年轻女性中。更高质量的观察性临床数据 与没有激素避孕的患者相比，感染 HIV-1 的风险显着增加 40-50% DMPA-IM。有限的观察性研究发现，与 NET-EN 没有激素避孕，而两次头对头比较发现潜在的 32-40% 与 NET-EN 用户相比，DMPA-IM 用户的 HIV-1 风险增加。随机 ECHO 试验的最新结果确实 未告知 DMPA-IM 与 NET-EN 相比的 HIV-1 感染风险，或 DMPA-IM 与无 HIV-1 感染的风险相比 激素避孕。然而，他们确实提出了孕激素特异性效应，最佳估计为 23-29% 与仅 18 个月内含左炔诺孕酮的植入物相比，DMPA-IM 的风险增加。这是 考虑到两者，DMPA-IM 和 NET-EN 之间的 HIV-1 风险可能存在 32-40% 的差异 垂直传播和水平传播，可能在较长时期内对疫情产生重要影响 在高风险人群中，可能与渴望知情选择的女性个体高度相关。鉴于 观察性研究中潜在的混杂因素，关于 HIV-1 相对风险的明确答案 DMPA-IM 和 NET-EN 仍然难以捉摸。另一种深入了解 DMPA 相对风险的方法- IM 与 NET-EN 的比较是为了获得和评估有关反应的高质量临床生物学数据 与随机分配至 DMPA-IM 和 NET-EN 组的女性的 HIV-1 感染有关。我们将获得存档的 来自此类随机试验（WHICH（第 1 部分）试验）的样本，并测量免疫功能的生物标志物 以及 HIV-1 易感性的其他潜在标记。我们还将进行一系列的体内和离体实验 机制研究，调查 MPA 和 NET 对于 HIV-1 获得和传播的合理生物学机制 确定这些结果如何与临床数据相关。结果将提供关于是否和 DMPA-IM 和 NET-EN 如何发挥不同的生物效应，对女性感染 HIV-1 产生影响。 研究结果将对避孕和 HIV-1 领域的科学知识做出重大贡献。他们是 可能会影响临床实践、卫生政策和国际指南，以消除人们的疑虑 互换使用或建议优先使用其中一种注射避孕药而不是另一种 HIV-1 感染高危人群。