Impact of HIV PMTCT Interventions on HIV/HBV Co-infected Women and Their Infants

项目总结/摘要 HIV合并B型肝炎（HBV）感染在资源有限环境（RLS）中很常见。抗病毒治疗可以是 有效预防HBV母婴传播（PMTCT），WHO建议 抗逆转录病毒治疗（ART）与替诺福韦（TDF）/恩曲他滨（FTC）或拉米夫定（3 TC）的双重HBV活性 HIV/HBV合并感染。也可以考虑单独使用3 TC作为唯一的HBV活性剂的ART。3 TC单独给药 导致HBV耐药和疫苗逃逸表型，而TDF可能与母体和 婴儿发病率尽管在HBV流行的地区使用了这些HIV PMTCT方案， 这些药物将影响HBV结果。我们计划的长期目标是确定最佳的预防母婴传播 HIV/HBV合并感染治疗策略这里的目的是确定是否产前方案， TDF/FTC方案上级优于3 TC方案。我们的中心假设是TDF/FTC双重HBV治疗 在病毒学结局方面上级单一HBV治疗，但在孕产妇结局方面可能不上级单一HBV治疗。 和婴儿安全，HBV临床结果将更糟，没有ART，艾滋病毒/HBV妇女将有 与未感染HBV的女性相比，结果更糟。理由是，如果TDF与 婴儿的发病率更高，如果3 TC与HBV耐药性几乎无关，那么可能存在一种 单独使用短程3 TC对感染HIV/HBV的孕妇的作用。这些发现将有助于 世卫组织指南。如果ART停止与临床上重要的不良结局相关，那么HBV单克隆抗体 感染指南需要重新考虑。最后，如果HIV/HBV女性的结局更差， 那么我们需要确定干预措施来解决这些不良后果。这些 中心假设将使用促进母婴存活的血浆库进行检验 Everywhere（PROMISE）研究，一项针对3500对母婴的HIV PMTCT试验，其中预先计划的HBV 子研究将HIV/HBV合并感染的妇女随机分为三种产前策略：ART+单用（齐多夫定 (ZDV)/3 TC/洛匹那韦/利托那韦（LPV/r）、双联（TDF/FTC/LPV/r）和无HBV活性治疗（ZDV，产时 单剂量奈韦拉平和TDF/FTC尾）。我们将追求三个具体目标：1）比较HBV病毒学 随机化组中HIV/HBV妇女及其婴儿的结局，2）比较临床肝脏 随机分组中HIV/HBV女性的结局，以及3）比较孕产妇和婴儿的临床结局 HBV感染和未感染的妇女及其子女之间的差异。接下来用一本小说 第二代测序（NGS）检测，HBV少数变异体的演变和作用及其与 将检查HBV传播。这种方法是创新的，因为它将改变HBV PMTCT 方案的选择，因为它将利用一种新的NGS测定法， 技术.这项研究具有重要意义，因为它将确定HIV/HBV患者的最佳PMTCT方案 合并感染这些知识将为全球HBV公共卫生预防战略提供信息。

PROJECT SUMMARY/ABSTRACT Hepatitis B (HBV) coinfection in HIV is common in resource-limited settings (RLS). Antiviral therapy can be effective in the prevention of mother to child transmission (PMTCT) of HBV and the WHO recommends antiretroviral therapy (ART) with dual HBV activity with tenofovir (TDF)/emtricitabine (FTC) or lamivudine (3TC) in HIV/HBV coinfection. ART with 3TC alone as the sole HBV active agent may also be considered. 3TC alone results in HBV resistance and a vaccine escape phenotype while TDF may be associated with maternal and infant morbidity. Despite the use of these HIV PMTCT regimens in areas endemic for HBV, it is unknown how these agents will impact HBV outcomes. The long-term goal of our program is to identify the optimal PMTCT strategy in HIV/HBV coinfection. The objective here is to determine whether an antepartum regimen with TDF/FTC is superior to a regimen with 3TC. Our central hypotheses are that dual HBV therapy with TDF/FTC will be superior to single HBV therapy in virologic outcomes but may not be superior with regards to maternal and infant safety, that HBV clinical outcomes will be worse without ART, and that HIV/HBV women will have worse outcomes, compared to HBV uninfected women. The rationales are that, if TDF is associated with greater morbidity among infants and if 3TC is associated with little HBV drug resistance, then there may be a role for short-course 3TC alone in HIV/HBV infected pregnant women. These findings would help inform WHO guidelines. If ART cessation is associated with clinically important adverse outcomes, then HBV mono- infection guidelines would need re-consideration. Finally, if HIV/HBV women have worse outcomes compared to HIV mono-infection then we need to identify interventions to address these adverse outcomes. These central hypotheses will be tested using the plasma repository of the Promoting Maternal and Infant Survival Everywhere (PROMISE) study, an HIV PMTCT trial of 3500 mother-infant pairs in which a pre-planned HBV substudy randomized HIV/HBV coinfected women to three antepartum strategies; ART with single (zidovudine (ZDV)/3TC/Lopinavir/ritonavir (LPV/r), dual (TDF/FTC/LPV/r), and no HBV active therapy (ZDV, intrapartum single dose nevirapine, and TDF/FTC tail). We will pursue three specific aims: 1) Compare HBV virologic outcomes in HIV/HBV women and their infants among randomized arms, 2) Compare clinical hepatic outcomes in HIV/HBV women among randomized arms, and 3) Compare maternal and infant clinical outcomes between HBV infected and uninfected women and their children, among randomized arms. Using a novel next generation sequencing (NGS) assay, the evolution and role of HBV minority variants and their association with HBV transmission will be examined. The approach is innovative because it will change how HBV PMTCT regimens are selected and because it will utilize a novel NGS assay that has several advantages over current techniques. The proposed research is significant because it will define the optimal PMTCT regimen in HIV/HBV coinfection. Such knowledge will inform global HBV public health prevention strategies.