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

这项拟议的研究试图了解不同注射方式可能产生的生物学机制。 避孕药可能会也可能不会影响对艾滋病毒-1等感染的易感性。注射剂使用率高 避孕措施与撒哈拉以南非洲和南非艾滋病毒-1感染的高流行率有关。一个 在撒哈拉以南非洲，艾滋病毒-1感染的严重性别偏见发生在年轻妇女身上。Depo- 甲羟孕酮(DMPA-IM)，三个月一次，肌肉注射(IM)150毫克，是 最常用的是去甲炔诺酮(Net-en)，两个月一次，肌注200 mg Net-en。 EN在南非被广泛使用，特别是在年轻女性中。更高质量的观察性临床数据 显示与不使用激素避孕相比，感染HIV-1的风险显著增加40%-50% DMPA-IM。有限的观察性研究发现，与以下情况相比，感染HIV-1的风险没有显著增加 Net-en没有激素避孕，而两次面对面的比较发现潜在的32%-40% 与Net-EN用户相比，DMPA-IM用户的HIV-1风险增加。来自随机ECHO试验的最新结果 不告知DMPA-IM与Net-EN相比感染HIV-1的风险，或DMPA-IM与NO相比 荷尔蒙避孕。然而，他们确实提出了孕激素特有的影响，最佳估计为23%-29% 仅仅18个月，DMPA-IM的风险比含有左旋诺孕酮的植入物更高。它是 考虑到两者，DMPA-IM和Net-EN之间的HIV-1风险可能相差32%-40% 垂直和水平传播，可能在较长时间内对疫情产生重要影响 在高危人群中，并可能与希望做出知情选择的个别妇女高度相关。给定 观察性研究中混杂因素的可能性，关于以下情况下HIV-1相对风险的明确答案 DMPA-IM和Net-EN仍然难以捉摸。了解DMPA相对风险的另一种方法是- IM与Net-EN的对比是获取和评估高质量的临床生物学数据，并对反应进行强烈的评估 与随机接受DMPA-IM和Net-EN治疗的妇女感染HIV-1有关。我们将获得存档 来自这种随机试验(What(Part 1)试验)的样本，并测量免疫功能的生物标记物 以及其他艾滋病毒-1易感性的潜在标志物。我们还将进行一系列体内和体外的 机制研究，以调查可信的生物学机制的MPA和NET的艾滋病毒-1感染和 确定这些结果与临床数据的相关性。这一结果将为我们提供关于是否和 DMPA-IM和Net-EN如何发挥不同的生物学效应，以及对妇女感染HIV-1的影响。 这一结果将大大有助于避孕和艾滋病毒-1领域的科学知识。他们是 可能会对临床实践、卫生政策和国际指南产生影响，以保证 可互换使用或建议优先使用这些注射避孕药中的一种 艾滋病毒-1感染高危人群。

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.