Antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand

描述（由申请人提供）：拟定研究是一项在泰国进行的III期、多中心、对照、双盲、随机临床试验，旨在比较 从妊娠28周至产后2个月，对HBeAg检测阳性且肝功能检测正常的慢性B型肝炎（HB）孕妇给予替诺福韦和拉米夫定两种药物的耐受性与安慰剂相比，以预防B型肝炎病毒（HBV）的围产期传播。慢性HBV并发肝硬化和肝细胞癌（HCC）是全球第十大死亡原因。大约7%的泰国成年人是HBsAg携带者。普遍免疫计划在实施的任何地方都大大降低了感染率。婴儿HBV免疫接种和出生时给予的HB免疫球蛋白有效地防止了HBV感染母亲的大部分传播，但是，尽管有这种主动和被动免疫接种，约12%的HBV高病毒血症母亲将病毒传播给婴儿。抗原HBe（HBeAg）是高复制的标志物。研究表明，在怀孕结束时和产后进行抗病毒治疗可以降低传播给孩子的风险。这种方法的一个潜在局限性是在停用抗病毒药物后肝病加重（发作）的风险 治疗，尚未得到适当的评价。没有随机临床试验充分证明抗病毒治疗的有效性和安全性，这种方法不被肝病研究协会推荐。我们假设替诺福韦或拉米夫定可以降低HBV感染孕妇的HBV病毒载量，因此在婴儿受到被动-主动免疫保护之前，宫内、产时和产后传播的风险。我们还假设，在短期抗病毒治疗（5个月）中止后，仅观察到中度发作。虽然该研究的主要目的是评估替诺福韦或拉米夫定与安慰剂相比预防 为了预防围产期传播，一个重要的次要目标是评估产后肝病恶化的风险。如果HBsAg阳性女性的HBeAg检测结果为阳性且ALT 30 U/L，则将入组HBsAg阳性女性。她们将从怀孕28周到产后2个月随机接受替诺福韦或拉米夫定或安慰剂。在两年内，588名妇女和她们的婴儿将在泰国的PHPT网络的8个地点登记，在那里，小组在过去15年里在进行预防母婴传播艾滋病毒的试验方面取得了相当多的经验。母亲和婴儿将被随访至产后一年。主要终点将是出生后6个月时HBsAg和HBV DNA的检测。当一半的结果可用时，将进行中期分析。这项研究的结果将有助于制定政策，以管理HBV感染的孕妇，以防止围产期传播。

DESCRIPTION (provided by applicant): The proposed study is a phase III, multicenter, controlled, double blind, randomized clinical trial in Thailand to compare the efficacy, safety and tolerance of each of two drugs, tenofovir and lamivudine, versus placebo, given to hepatitis B (HB) chronically infected pregnant women with a positive HBeAg test and normal liver function tests, from 28 weeks' gestation until two months postpartum to prevent perinatal transmission of hepatitis B virus (HBV). Chronic HBV, complicated by cirrhosis and hepatocellular carcinoma (HCC), is the 10th leading cause of death worldwide. About 7% of Thai adults are HBsAg carriers. Universal immunization programs have dramatically reduced the prevalence of infection wherever they have been implemented. Infant HBV immunization and HB immunoglobulin administered at birth effectively prevent most transmission from HBV infected mothers but, despite this active and passive immunization, about 12% of HBV highly viremic mothers transmit the virus to their infants. The antigen HBe (HBeAg) is a marker of high replication. Studies have suggested that antiviral treatment at the end of pregnancy and in the postpartum can reduce the risk of transmission to the child. A potential limitation to this approach is the risk of hepatic disease exacerbation (flare) following discontinuation of antiviral treatment, which has not been properly evaluated. No randomized clinical trials have adequately demonstrated the efficacy and safety of antiviral treatment and this approach is not recommended by the Associations for the Study of Liver Diseases. We hypothesize that tenofovir or lamivudine can decrease HBV viral load in HBV infected pregnant women and therefore the risk of in utero, intrapartum and postpartum transmission before infants are protected by passive-active immunization. We also hypothesize that only moderate flares will be observed after discontinuation of a short antiviral course (5 months). While the primary objective of the study is to assess the efficacy of tenofovir or lamivudine versus placebo for the prevention of perinatal transmission, an important secondary objective is the assessment of the risk of postpartum hepatic disease exacerbation. HBsAg positive women will be enrolled if they have an HBeAg positive test and ALT 30 U/L. They will be randomized to receive tenofovir or lamivudine or placebo from 28 weeks of pregnancy until 2 months postpartum. Within 2 years, 588 women and their infants will be enrolled in 8 sites of the PHPT network in Thailand, where the teams have gained considerable experience in conducting trials for the prevention of mother to child transmission of HIV over the past 15 years. Mothers and infants will be followed until one year postpartum. The primary endpoint will be the detection of HBsAg and HBV DNA at six months of life. An interim analysis will be conducted when half of the outcomes are available. The results of the study will help define policy to manage HBV infected pregnant women to prevent perinatal transmission.