A prospective cohort of HIV-infected Malawian women on Efavirenz initiating the Levonorgestrel Implant or the Depot Medroxyprogesterone Acetate Injectable

摘要 撒哈拉以南非洲(SSA)意外怀孕、孕产妇死亡率和围产期艾滋病毒的发生率很高。 增加有效避孕措施的使用可能会减少这三种情况。左炔诺孕酮(LNG)植入物是一种 一种高效且可逆的避孕药，特别适合像马拉维这样的环境，在那里我们的 将进行研究。LNG植入物有时被称为“可遗忘的避孕”，可提供多达 5年的保护，不依赖于外部因素，如定期就诊或在 医疗系统供应链。因此，LNG植入物的典型使用失败率非常低，第一次为0.1% 年。醋酸甲羟孕酮(DMPA)可注射剂是最常用的 SSA中的避孕药。然而，DMPA需要每3个月重复注射一次，导致更高的典型- 第一年使用失败率为6%。最近的观察性研究表明，联合管理 抗逆转录病毒Efavirenz(EFV)可能会降低LNG植入物的避孕效果，可能是由于 两种药物之间的药代动力学相互作用。引用这些小型研究，SSA中的一些国家是 考虑反对在EFV上为女性使用植入物的政策建议。南非和美国。 已经发布了这样的指导意见。在本应用程序中，我们认为数据不够强大，不足以支持 这一政策行动并提出了一项由两部分组成的研究，旨在向提供商和 政策制定者。目标1将比较LNG植入物和DMPA的典型使用妊娠率 可在1,420名使用EFV的HIV+妇女的预期队列中注射(710名开始LNG植入，710名 启动DMPA)。妇女在当地卫生机构接受她们选择的避孕药后将被登记 在研究中将在1个月后进行跟踪，然后每3个月进行一次，持续至少2年至4年。 泊松模型将被用来估计植入物和DMPA使用者的怀孕发生率。边缘地带 然后将使用结构泊松模型来估计植入物与DMPA相比的效果 妊娠率。Aim 2将对240名妇女进行2：1嵌套病例对照研究，研究对象为来自 确定头发中较高的EFV浓度(暴露于EFV的生物标志物)是否与 LNG植入避孕药失败。使用LNG植入物时怀孕的80例妇女(例) 将与使用相同时间的植入物后未怀孕的160名LNG植入者进行比较 (控制)。将使用条件Logistic回归来评估头发EFV与 浓度和LNG植入失败。我们还将评估“慢”EFV与 有LNG植入失败的代谢物，并评估是否存在LNG浓度阈值 EFV使用者中会出现植入失败的情况。这项研究将是美国国家航空航天局的研究人员之间的合作 位于教堂山的北卡罗来纳大学(UNC)、北卡罗来纳大学马拉维项目和灯塔信托基金。我们会工作的 与马拉维医学院和马拉维卫生部成员密切合作，指导研究 关于马拉维使用液化天然气植入物和EFV的执行和任何由此产生的政策决定。

ABSTRACT Sub-Saharan Africa (SSA) has high rates of unintended pregnancy, maternal mortality, and perinatal HIV. Increased use of effective contraception could reduce all three. The Levonorgestrel (LNG) implant is a highly-effective and reversible contraceptive that is particularly well-suited to settings like Malawi, where our research will take place. Sometimes referred to as “forgettable contraception,” the LNG implant provides up to 5 years of protection and is not dependent upon external factors such as regular clinic attendance or breaks in the health system supply chain. Thus, the LNG implant’s typical-use failure rate is very low at 0.1% in the first year. The Depot Medroxyprogesterone Acetate (DMPA) injectable is the most commonly-used contraceptive in SSA. However, DMPA requires repeat injections every 3 months, leading to a higher typical- use failure rate of 6% in the first year. Recent observational studies suggest that co-administration of the antiretroviral Efavirenz (EFV) may reduce the contraceptive efficacy of the LNG implant, possibly due to pharmacokinetic interaction between the two drugs. Citing these small studies, some countries in SSA are considering policy recommendations against use of implants for women on EFV. South Africa and the U.S. have already issued such guidance. We argue in this application that the data are not strong enough to support this policy action and propose a 2-part study designed to provide critical evidence to providers and policymakers. Aim 1 will compare the typical-use pregnancy rates of the LNG implant versus the DMPA injectable in a prospective cohort of 1,420 HIV+ women on EFV (710 initiating the LNG implant and 710 initiating DMPA). Women will be enrolled after receiving their chosen contraceptive at their local health facility and will be followed in the study after 1 month and then every 3 months for at least 2 years and up to 4 years. A Poisson model will be used to estimate pregnancy incidence among implant and DMPA users. A marginal structural Poisson model will then be used to estimate the effect of implant compared to DMPA upon pregnancy incidence. Aim 2 will study 240 women in a 2:1 nested case-control study of women from the cohort to determine if higher EFV concentrations in hair (a biomarker for EFV exposure) are associated LNG implant contraceptive failure. 80 women (cases) who become pregnant while using the LNG implant will be compared with 160 LNG implant users who were not pregnant after the same duration of implant use (controls). Conditional logistic regression will be used to assess the association between hair EFV concentrations and LNG implant failure. We will also evaluate the association between being a “slow” EFV metabolizer with LNG implant failure and assess if there is a LNG concentration threshold at which LNG implant failure occurs among EFV users. The study will be a collaboration between investigators at the University of North Carolina (UNC) in Chapel Hill, UNC Project-Malawi, and the Lighthouse Trust. We will work closely with members of the Malawi College of Medicine and the Malawi Ministry of Health to guide study implementation and any resulting policy decisions regarding the use of LNG implant and EFV in Malawi.