Lamivudine and its Impact on Perinatal HBV Transmission in HIV/HBV Coinfection

描述（由申请人提供）：HIV合并B型肝炎（HBV）感染在资源有限的环境中很常见，是导致死亡的主要原因。在资源有限的艾滋病毒和乙型肝炎病毒流行地区，包括非洲，往往没有预防围产期乙型肝炎病毒传播的婴儿免疫预防措施。与HIV一样，抗病毒治疗可以有效预防HBV的母婴传播（PMTCT）。然而，对于PMTCT，单药抗病毒药物暴露可能会产生非预期的后果。在HIV中，当单药奈韦拉平用于PMTCT时，通常会发生HIV耐药，并与婴儿和母亲的HIV治疗失败有关。同样，使用拉米夫定（一种同时具有HIV和HBV活性的抗病毒药物）单药治疗会导致HBV耐药率高和疫苗逃逸表型。尽管拉米夫定在HBV流行地区的WHO推荐的HIV PMTCT方案中广泛使用，但拉米夫定如何影响HBV围产期传播和HIV合并感染中的HBV耐药性尚不清楚。本研究计划的长期目标是确定HIV/HBV合并感染孕妇的最佳预防母婴传播（PMTCT）方案。本研究的目的是确定含拉米夫定的预防母婴传播方案如何影响HBV传播。中心假设是拉米夫定将减少HBV的围产期传播，但会导致母婴HBV耐药和HBV疫苗逃逸突变。母亲的少数耐药人群也可能是重要的耐药传播。其基本原理是，如果HBV耐药是常见的拉米夫定后，含PMTCT治疗，那么方案与更高的HBV效力将需要。将使用HPTN 046的血清储存库对这一中心假设进行检验，这是一项在非洲1522对母婴中开展的延长婴儿奈韦拉平预防的HIV PMTCT试验。我们将追求三个具体目标：1）确定拉米夫定在预防HIV/HBV合并感染孕妇HBV围产期传播中的作用，2）确定围产期HBV传播的预测因子，3）确定拉米夫定对母婴HBV耐药性和疫苗逃逸表型的影响。根据前两个目标，将确定HIV合并感染中围产期HBV传播的发生率和预测因素，包括产前拉米夫定的作用。在第三个目标下，将检查拉米夫定暴露对母婴耐药性的影响。还将使用申请人开发的新型少数变异体检测方法，检查HBV少数变异体作为传播预测因子的作用。该方法是创新的，因为它将改变HBV PMTCT方案的选择方式，并且因为它将利用一种新的少数变异检测方法，该方法与现有技术相比具有几个优势。这项研究意义重大，因为它将是确定HIV/HBV合并感染妇女最佳PMTCT方案的第一步。最终，这些知识将为全球HBV公共卫生预防战略提供信息。 公共卫生相关性：拟议的研究与公共卫生有关，因为它将为预防HBV围产期传播的全球战略提供信息，适用于HIV合并感染和HBV单一感染。因此，拟议的研究与NIH的使命有关，特别是与艾滋病司（DAIDS）有关，该司已将病毒性肝炎确定为一个新兴的关键研究重点。

DESCRIPTION (provided by applicant): Hepatitis B (HBV) coinfection in HIV is common in resource-limited settings and is a leading cause of mortality. Infant immunoprophylaxis to prevent perinatal HBV transmission is often unavailable in resource- limited settings endemic for HIV and HBV, including those in Africa. As in HIV, antiviral therapy can be effective in the prevention of mother to child transmission (PMTCT) of HBV. However, there are potentially unintended consequences of single agent antiviral drug exposure for PMTCT. In HIV, when single agent nevirapine is used for PMTCT, HIV resistance commonly occurs and is associated with HIV treatment failure in infants and mothers. Similarly, the use of single agent lamivudine, an antiviral with both HIV and HBV activity, results in high rates of HBV resistance and a vaccine escape phenotype. Despite the widespread use of lamivudine in WHO-recommended HIV PMTCT regimens in areas endemic for HBV, it is unknown how lamivudine will impact HBV perinatal transmission and HBV drug resistance in HIV coinfection. The long-term goal of this research program is to identify the optimal prevention of mother to child transmission (PMTCT) regimen in HIV/HBV coinfected pregnant women. The objective here is to determine how lamivudine-containing PMTCT regimens impact HBV transmission. The central hypothesis is that lamivudine will reduce HBV perinatal transmission but result in maternal and infant HBV drug resistance and HBV vaccine escape mutations. Maternal minor populations of drug resistance may also be important in the transmission of resistance. The rationale is that if HBV drug resistance is common after lamivudine- containing PMTCT therapies, then regimens with higher HBV potency will be required. This central hypothesis will be tested using the serum repository of HPTN 046, an HIV PMTCT trial of extended infant nevirapine prophylaxis in 1522 mother-infant pairs in Africa. We will pursue three specific aims: 1) Determine the impact of lamivudine in the prevention of HBV perinatal transmission in HIV/HBV coinfected pregnant women, 2) Identify the predictors of perinatal HBV transmission and 3) Determine the impact of lamivudine on maternal and infant HBV drug resistance and vaccine escape phenotypes. Under the first two aims, the incidence and predictors of perinatal HBV transmission in HIV coinfection, including the role of antepartum lamivudine, will be determined. Under the third aim, the impact of lamivudine exposure on maternal and infant drug resistance will be examined. Using a novel minority variant assay developed by the applicant, the role of HBV minority variants as predictors of transmission will also be examined. The approach is innovative because it will change how HBV PMTCT regimens are selected and because it will utilize a novel minority variant detection assay that has several advantages over currently available techniques. The proposed research is significant because it will be the first step in defining the optimal PMTCT regimen in HIV/HBV coinfected women. Ultimately, such knowledge will inform global HBV public health prevention strategies. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health, as it will inform global strategies in the prevention of HBV perinatal transmission, applicable to both HIV coinfection and HBV monoinfection. Thus, the proposed research is relevant to NIH's mission, particularly to the Division of AIDS (DAIDS), which has identified viral hepatitis an emerging critical research priority.