Reducing Vertical Transmission of Hepatitis B in Africa (REVERT-B Trial)

项目摘要/摘要 乙肝病毒感染在非洲孕妇中很流行，但大多数妇女都没有症状。 并且没有意识到他们的婴儿处于危险之中。90%在出生时感染的婴儿会发展为慢性乙肝病毒 晚期症状的感染，包括肝硬变和肝细胞癌。世界 卫生组织制定了到2030年消除乙肝病毒的目标，但目前非洲的围产期预防措施是 不够充分。这是降低人口疾病流行率的关键障碍。从出生起就接种乙肝疫苗 75%-95%的有效率但设施递送率低和疫苗冷链要求阻碍了这一项目的成功 单管齐下。非洲大多数感染了乙肝病毒的婴儿在2-3个月大的时候接种了第一次乙肝疫苗 这错过了围产期预防的窗口。为了解决这个紧迫的问题，此R01应用程序描述了 考虑到围产期乙肝病毒预防的潜在疗效，在科学知识方面的差距 基于亚洲两项已发表的随机试验和一项潜在研究的替诺福韦治疗降低乙肝病毒载量 拉米夫定对新生儿的预防作用。这项提议的中心目标是确定一种新的干预措施， 在非洲预防乙肝病毒围产期传播是有效、安全和务实的。这是在 对PA-18-031中引用的《消除种族歧视国际公约》的优先事项作出回应。为了实现这一目标，一项名为 “逆转-B：减少乙肝在非洲的垂直传播”是由一个 阿拉巴马大学伯明翰分校(UAB)合作、富有成效和经验丰富的研究团队 在喀麦隆。它将检验母亲和新生儿抗病毒预防显著减少的假设 非洲高危妇女中乙肝病毒垂直传播与优化护理标准(4剂)的比较 从出生开始接种乙肝疫苗)。通过追求两个共同的主要目标，这一假设将得到有效的检验 采用析因试验设计。在目标1中，将在四个产前进行随机、安慰剂对照试验 喀麦隆诊所测试替诺福韦对480名携带乙肝病毒的孕妇减少围产期的疗效 变速箱。妇女将随机服用每日替诺福韦或安慰剂，背景为优化的标准 护理(婴儿疫苗接种)。在目标2中，新生儿随机服用拉米夫定或安慰剂，为期六周。 目的：检验新生儿预防措施的效果。这两个目标的主要终点都是定义的围产期传播 6个月时活动性乙肝病毒感染(乙肝表面抗原阳性)婴儿的比例。次级目标将评估 预防和用药依从性的安全性。第三阶段试验的数据将用于支持后续行动 对孕妇和/或新生儿联合进行抗病毒预防的有效性和可行性的研究 一项对资源有限环境中的孕妇进行的多国研究。预期的结果是扩大 为携带乙肝病毒的孕妇提供科学工具包(类似于围产期艾滋病毒预防)，并朝着 在全球范围内消除围产期乙肝病毒传播的长期目标。

Project Summary/Abstract Hepatitis B virus (HBV) infection is endemic among pregnant women in Africa yet most women are asymptomatic and unaware that their infants are at risk. Ninety percent of infants infected at birth will develop chronic HBV infection with late manifestations of disease that include cirrhosis and hepatocellular carcinoma. The World Health Organization set a goal of HBV elimination by 2030 but current perinatal prophylaxis in Africa is inadequate. This is a key barrier to reducing the population prevalence of disease. HBV vaccination from birth is 75-95% effective but low facility delivery rates and vaccine cold chain requirements hinder the success of this one-pronged approach. Most HBV-exposed infants in Africa receive their first HBV vaccine at 2-3 months of age which misses the perinatal prevention window. To address this pressing problem, this R01 application describes gaps in scientific knowledge needed to advance perinatal HBV prevention considering the potential efficacy of tenofovir therapy in reducing HBV viral load based on two published randomized trials in Asia and a potential role for neonatal lamivudine prophylaxis. The central goal of this proposal is to identify a novel intervention that is effective, safe and pragmatic in preventing perinatal transmission of HBV in Africa. This was developed in response to NICHD priorities cited in PA-18-031. To meet this goal, an innovative, multicenter clinical trial titled “REVERT-B: Reducing Vertical Transmission of Hepatitis B in Africa” was designed to be carried out by a collaborative, productive and experienced research team at the University of Alabama at Birmingham (UAB) and in Cameroon. It will test the hypothesis that maternal and neonatal antiviral prophylaxis significantly reduces HBV vertical transmission among high-risk women in Africa compared to optimized standard of care (4-dose HBV vaccination beginning at birth). The hypothesis will be efficiently tested by pursuing two co-primary aims with a factorial trial design. In Aim 1, a randomized, placebo-controlled trial will be conducted in four prenatal clinics in Cameroon to test the efficacy of tenofovir in 480 pregnant women with HBV in reducing perinatal transmission. Women will be randomized to daily tenofovir or placebo with a background of optimized standard of care (infant vaccination). In Aim 2, neonates will be randomized to oral lamivudine or placebo for six weeks to test the efficacy of neonatal prophylaxis. The primary endpoint for both aims is perinatal transmission defined as the proportion of infants with active HBV infection (HBsAg+) at 6 months of age. Sub-aims will assess the safety of prophylaxis and medication adherence. Data from this Phase III trial will be used to support follow up studies to test the effectiveness and feasibility of combination maternal and/or neonatal antiviral prophylaxis in a multi-country study of pregnant women in resource-limited settings. The expected outcome is to expand the scientific toolkit for pregnant women with HBV (analogous to perinatal HIV prevention) and advance toward the long-term goal of eliminating perinatal HBV transmission worldwide.