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: 8328014
• 负责人: DEBIKA BHATTACHARYA
• 金额: $ 40.69万
• 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/8328014
• 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. 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.

描述(由申请人提供)：在资源有限的环境中，艾滋病毒中的乙肝(乙肝)合并感染是常见的，也是死亡的主要原因。在艾滋病毒和乙肝流行的资源有限的情况下，包括在非洲，婴儿预防围产期乙肝病毒传播的免疫预防措施往往是不可用的。与艾滋病毒一样，抗病毒治疗可以有效地预防乙肝病毒母婴传播(PMTCT)。然而，对于预防母婴传播来说，单一抗病毒药物暴露可能会产生意想不到的后果。在HIV中，当单一药物奈韦拉平用于预防母婴传播时，通常会发生艾滋病毒耐药性，并与婴儿和母亲的艾滋病毒治疗失败有关。同样，拉米夫定是一种同时具有艾滋病毒和乙肝病毒活性的抗病毒药物，使用单一药物拉米夫定会导致高乙肝病毒耐药性和疫苗逃逸表型。尽管拉米夫定在世界卫生组织推荐的艾滋病毒预防母婴传播方案中在乙肝流行地区得到广泛使用，但尚不清楚拉米夫定将如何影响艾滋病毒合并感染中的乙肝病毒围产期传播和对乙肝病毒的耐药性。这项研究计划的长期目标是确定艾滋病毒/乙肝合并感染的孕妇预防母婴传播(PMTCT)的最佳方案。这里的目的是确定含有拉米夫定的PMTCT方案如何影响乙肝病毒的传播。中心假说是，拉米夫定会减少乙肝病毒的围产期传播，但会导致母婴对乙肝病毒的耐药性和乙肝疫苗逃逸突变。母系少数人群的耐药性也可能在耐药性的传播中起重要作用。其基本原理是，如果在含有拉米夫定的PMTCT治疗后，乙肝病毒耐药性普遍存在，那么将需要具有更高乙肝病毒效力的方案。这一中心假设将使用HPTN 046的血清库进行验证，HPTN 046是一项HIV PMTCT试验，对非洲1522对母婴进行了延长婴儿奈韦拉平预防试验。我们将追求三个具体目标：1)确定拉米夫定在预防艾滋病毒/乙肝合并感染孕妇中的围产期传播的影响；2)确定围产期乙肝传播的预测因素；3)确定拉米夫定对母婴乙肝病毒耐药性和疫苗逃逸表型的影响。根据前两个目标，将确定艾滋病毒合并感染中围产期乙肝病毒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，将审查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分析，也将检查作为传播预测因子的乙肝病毒少数变异的作用。这种方法是创新的，因为它将改变选择乙肝PMTCT方案的方式，因为它将利用一种新的少数变异检测方法，该方法比目前可用的技术具有几个优点。这项拟议的研究意义重大，因为它将是确定艾滋病毒/乙肝混合感染妇女最佳预防母婴传播方案的第一步。最终，这些知识将为全球乙肝公共卫生预防战略提供参考。 公共卫生相关性：拟议的研究与公共卫生相关，因为它将为预防乙肝病毒围产期传播的全球战略提供信息，该战略既适用于艾滋病毒合并感染，也适用于乙肝病毒单一感染。因此，拟议的研究与NIH的任务相关，特别是与艾滋病部门(DAIDS)相关，该部门已将病毒性肝炎确定为新出现的关键研究重点。