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

拉米夫定及其对 HIV/HBV 合并感染围产期 HBV 传播的影响

• 批准号: 8623096
• 负责人: DEBIKA BHATTACHARYA
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623096
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Affect; Africa; African; Antiviral Agents; Antiviral Therapy; Area; Biological Assay; Breast Feeding; Clinical Trials; Data; Data Set; Detection; Drug Exposure; Drug resistance; Goals; HIV; HIV Infections; Health; Hepatitis B; Hepatitis B Incidence; Hepatitis B Prevalence; Hepatitis B Transmission; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis B e Antigens; Incidence; Individual; Infant; Knowledge; Lamivudine; Minor; Minority; Mission; Mothers; Mutation; National Institute of Child Health and Human Development; Nevirapine; Outcome; Perinatal; Phenotype; Population; Pregnant Women; Prevention; Prevention strategy; Prophylactic treatment; Public Health; Regimen; Research; Research Priority; Resistance; Resources; Risk Factors; Role; Sampling; Serum; Techniques; Tenofovir; Testing; Treatment Failure; Vaccines; Variant; Vertical Disease Transmission; Viral Load result; Viral hepatitis; Woman; antiretroviral therapy; base; design; immunoprophylaxis; innovation; mortality; novel; prevent; programs; repository; transmission process

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.

描述（由申请人提供）：乙型肝炎（HBV）合并感染艾滋病毒在资源有限的环境中很常见，是导致死亡的主要原因。在包括非洲在内的艾滋病毒和乙型肝炎流行的资源有限的环境中，往往无法获得预防围产期乙型肝炎病毒传播的婴儿免疫预防。与艾滋病毒一样，抗病毒治疗可有效预防乙型肝炎病毒母婴传播。然而，接触单一抗病毒药物对预防母婴传播有潜在的意想不到的后果。在艾滋病毒方面，当单药奈韦拉平用于预防母婴传播时，通常会出现艾滋病毒耐药性，并与婴儿和母亲的艾滋病毒治疗失败有关。同样，使用单药拉米夫定（一种同时具有艾滋病毒和乙型肝炎病毒活性的抗病毒药物）会导致乙型肝炎病毒的高耐药率和疫苗逃逸表型。尽管在HBV流行地区，拉米夫定在世卫组织推荐的艾滋病毒预防母婴传播方案中广泛使用，但尚不清楚拉米夫定将如何影响艾滋病毒合并感染中的HBV围产期传播和HBV耐药性。本研究项目的长期目标是确定HIV/HBV合并感染孕妇的最佳预防母婴传播（PMTCT）方案。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会减少HBV围产期传播，但会导致母婴HBV耐药性和HBV疫苗逃逸突变。母系少数耐药人群在耐药传播中也可能起重要作用。其基本原理是，如果在含拉米夫定的PMTCT治疗后HBV耐药是常见的，那么将需要更高HBV效力的方案。这一中心假设将使用HPTN 046血清库进行检验，HPTN 046是一项在非洲1522对母婴中进行的延长婴儿奈韦拉平预防的艾滋病毒预防母婴传播试验。我们将追求三个具体目标：1)确定拉米夫定在预防HIV/HBV共感染孕妇HBV围产期传播中的作用；2)确定围产期HBV传播的预测因素；3)确定拉米夫定对母婴HBV耐药和疫苗逃逸表型的影响。在前两个目标下，将确定围产期HBV传播在HIV合并感染中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，将研究拉米夫定暴露对母婴耐药性的影响。使用申请人开发的一种新的少数变异测定法，还将检查HBV少数变异作为传播预测因子的作用。这种方法是创新的，因为它将改变HBV PMTCT治疗方案的选择方式，并且因为它将利用一种新的少数变异检测方法，这种方法比目前可用的技术有几个优势。这项拟议的研究意义重大，因为它将是确定HIV/HBV合并感染妇女最佳预防母婴传播方案的第一步。最终，这些知识将为全球HBV公共卫生预防战略提供信息。