Antiviral prophylaxis to prevent perinatal transmission of HBV in Thailand

泰国抗病毒预防措施预防围产期乙型肝炎病毒传播

• 批准号: 8916809
• 负责人: Gonzague Joseph Jourdain
• 金额: $ 29.44万
• 依托单位: INSTITUTE OF RESEARCH AND DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916809
• 关键词: Active Immunization; Acute; Adult; Alanine Transaminase; American; Antigens; Antiviral Agents; Antiviral Therapy; Asia; Asians; Birth; Cancer Etiology; Cause of Death; Cessation of life; Child; Childhood; Chronic; Chronic Hepatitis B; Cirrhosis; Country; Detection; Disease; Double-Blind Method; Effectiveness; Enrollment; Epidemic; European; Flare; Goals; Guidelines; HIV; Hepatitis; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Transmission; Hepatitis B Vaccination; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis B e Antigens; High Risk Woman; Immune; Immunization Programs; Immunoglobulins; Infant; Infection; Institute of Medicine (U.S.); Intervention; Lamivudine; Letters; Life; Liver; Liver Function Tests; Liver diseases; Malignant neoplasm of liver; Mothers; Neonatal; Outcome; Passive Immunization; Perinatal; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Policies; Postpartum Period; Practice Guidelines; Pregnancy; Pregnant Women; Prevalence; Prevention; Prevention trial; Primary carcinoma of the liver cells; Prophylactic treatment; Public Health; Randomized; Randomized Clinical Trials; Recommendation; Risk; Risk Assessment; Safety; Site; Societies; Surface Antigens; Tenofovir; Tenofovir disoproxil fumarate; Testing; Thailand; Third Pregnancy Trimester; United States National Institutes of Health; Vaccination; Vertical Disease Transmission; Viral Load result; Virus; Virus Diseases; Virus Replication; Woman; anti-hepatitis B; comparative efficacy; discontinuation study; experience; immunoprophylaxis; improved; in utero; intrapartum; liver injury; passive immunoprophylaxis; prevent; transmission process; viral DNA

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.

描述（由申请人提供）：拟议的研究是在泰国进行的一项 III 期、多中心、对照、双盲、随机临床试验，旨在比较疗效、安全性和 对比安慰剂，对 HBeAg 检测呈阳性且肝功能检测正常的乙型肝炎 (HB) 慢性感染孕妇从妊娠 28 周至产后两个月给予替诺福韦和拉米夫定两种药物的耐受性，以预防围产期传播乙型肝炎病毒（HBV）。慢性乙型肝炎并发肝硬化和肝细胞癌 (HCC)，是全球第十大死因。大约 7% 的泰国成年人是 HBsAg 携带者。全民免疫计划无论在何处实施，都大大降低了感染流行率。婴儿 HBV 免疫和出生时注射 HB 免疫球蛋白可有效防止大多数 HBV 感染母亲的传播，但尽管有这种主动和被动免疫，约 12% 的 HBV 高病毒血症母亲仍将病毒传播给婴儿。抗原 HBe (HBeAg) 是高复制的标记。研究表明，妊娠末期和产后的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限制是停止抗病毒药物后肝病恶化（耀斑）的风险 治疗，尚未得到适当的评估。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，肝病研究协会不推荐这种方法。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乙肝病毒载量，因此在婴儿受到被动主动免疫保护之前，可以降低子宫内、产时和产后传播的风险。我们还假设，在短期抗病毒疗程（5 个月）停止后，只会观察到中度的耀斑。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的预防效果 对于围产期传播，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 检测呈阳性且 ALT 30 U/L，则将被纳入。他们将在怀孕 28 周至产后 2 个月期间随机接受替诺福韦、拉米夫定或安慰剂治疗。两年内，588 名妇女及其婴儿将在泰国 PHPT 网络的 8 个地点注册，该网络的团队在过去 15 年中在预防艾滋病毒母婴传播试验方面积累了丰富的经验。母亲和婴儿将被跟踪直至产后一年。主要终点是出生后 6 个月时检测 HBsAg 和 HBV DNA。当一半结果可用时，将进行中期分析。该研究的结果将有助于制定管理乙型肝炎病毒感染孕妇的政策，以防止围产期传播。