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: 9983242
• 负责人: Janet Patricia Hapgood
• 金额: $ 34.99万
• 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/9983242
• 关键词: Address; Affect; Africa South of the Sahara; Androgens; Archives; 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; Female; 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; 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; 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.

拟议的研究试图了解合理的生物学机制，从而不同 避孕药可能会或可能不会影响对HIV-1等感染的敏感性。可注射量的高使用 避孕药具与撒哈拉以南非洲和南非的HIV-1感染的高流行有关。一个 HIV-1感染的强烈性别偏见发生在撒哈拉以南非洲的年轻妇女。 dep 乙酸甲羟丙烯（DMPA-IM），三个月的肌肉内（IM）注射150 mg MPa是 最常用的，而非甲酸酯（Net-en）（净EN），两个月的注射200 mg Net- EN在南非，尤其是在年轻女性中广泛使用。更高质量的观察性临床数据 与无激素避孕措施相比 DMPA-IM。有限的观察性研究发现，与 净EN没有激素避孕，而两个正面比较发现潜力为32-40％ DMPA-IM与净EN用户的HIV-1风险增加。随机回声试验的最新结果 与Net-EN相比，DMPA-IM感染HIV-1感染的风险，或dmpa-im的风险 激素避孕。但是，他们确实建议孕激素特异性效应，最佳估计为23-29％ 与仅18个月的含左旋肺癌的植入物相比，DMPA-IM的风险增加。这是 同时考虑到DMPA-IM和Net-EN之间的HIV-1风险差异为32-40％ 垂直和水平传播可能会在较长时间内对流行病产生重要影响 在高风险人群中，可能与想要明智选择的个体女性高度相关。鉴于 观察性研究中的混淆因素的潜力，这是关于相对HIV-1风险的确定答案 DMPA-IM和Net-EN仍然难以捉摸。洞悉DMPA-的相对风险的另一种方法 IM与Net-EN是要对反应的高质量临床生物学数据获得并评估反应的高质量临床生物学数据 与随机分配到DMPA-IM和NET-EN的妇女的HIV-1获取有关。我们将获得存档 来自这种随机试验的样品（该试验（第1部分）试验），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。我们还将执行一系列体内和Ex Vivo 调查MPA和NET的合理生物学机制的机理研究，用于HIV-1的获取和 确定这些结果与临床数据的相关性。结果将提供有关是否及是否及 DMPA-IM和Net-EN如何发挥不同的生物学作用，对女性HIV-1的获取产生影响。 结果将对避孕和HIV-1领域的科学知识产生重大贡献。他们是 可能会影响临床实践，卫生政策和国际准则，以确保 可互换的使用或建议优先使用这些可注射避孕药之一，而不是 HIV-1感染高风险的种群。