Antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand

描述(申请人提供)：该研究是一项在泰国进行的、多中心、对照、双盲、随机的III期临床试验，目的是比较两种药物的疗效、安全性和安全性。 替诺福韦和拉米夫定两种药物中的每一种与安慰剂相比的耐受性，这些药物用于HBeAg检测呈阳性且肝功能正常的慢性乙肝(HB)感染孕妇，从怀孕28周到产后两个月，以防止乙肝病毒(乙肝)的围产期传播。慢性乙肝，合并肝硬变和肝细胞癌，是全球第十大死亡原因。大约7%的泰国成年人是乙肝表面抗原携带者。普遍免疫方案无论在哪里实施，都极大地减少了感染的流行。婴儿在出生时接种乙肝疫苗和HB免疫球蛋白有效地防止了大多数感染乙肝病毒的母亲的传播，但尽管进行了主动和被动免疫，约有12%的高度病毒感染的母亲将病毒传播给她们的婴儿。HBe抗原(HBeAg)是高复制的标志。研究表明，在怀孕末期和产后进行抗病毒治疗可以降低传播给儿童的风险。这种方法的一个潜在限制是停用抗病毒药物后肝脏疾病恶化(Flare)的风险。 治疗，这没有得到适当的评估。没有一项随机临床试验充分证明了抗病毒治疗的有效性和安全性，肝病研究协会也不推荐使用这种方法。我们假设替诺福韦或拉米夫定可以降低乙肝病毒感染孕妇的病毒载量，从而降低婴儿在被动-主动免疫保护之前在宫内、产中和产后传播的风险。我们还假设，在停止短期的抗病毒疗程(5个月)后，只会观察到中度的耀斑。虽然这项研究的主要目标是评估替诺福韦或拉米夫定与安慰剂在预防高血压方面的疗效 在围产期传播方面，一个重要的次要目标是评估产后肝病恶化的风险。如果HBs Ag阳性的妇女HBeAg阳性，ALT为30U/L，她们将随机接受替诺福韦、拉米夫定或安慰剂治疗，从怀孕28周到产后2个月。在两年内，588名妇女及其婴儿将在泰国的PHPT网络的8个地点登记，这些小组在过去15年中在开展预防艾滋病毒母婴传播试验方面积累了相当多的经验。母亲和婴儿将被跟踪，直到产后一年。主要终点将是在出生6个月时检测乙肝表面抗原和HBVDNA。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，管理感染乙肝病毒的孕妇，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.