Antiviral prophylaxis and infant vaccination to prevent perinatal hepatitis B infection

抗病毒预防和婴儿疫苗接种以预防围产期乙型肝炎感染

• 批准号: 9902195
• 负责人: Gonzague Joseph Jourdain
• 金额: $ 44.26万
• 依托单位: INSTITUTE OF RESEARCH AND DEVELOPMENT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902195
• 关键词: Active Immunization; Address; Adult; Adverse event; Age-Months; Antibodies; Antibody Response; Antigens; Antiviral Agents; Birth; Blood; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Chronic Hepatitis B; Cirrhosis; Clinical Research; Clinical Trials; Congenital Abnormality; Data; Detection; Dose; Double-Blind Method; Enrollment; Fetus; Fumarates; Guidelines; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B Transmission; Hepatitis B Vaccination; Hepatitis B Vaccines; Hepatitis B Virus; Immunoglobulins; Infant; Infection; Infection prevention; Laos; Life; Malignant neoplasm of liver; Maternal-Fetal Transmission; Mothers; National Institute of Child Health and Human Development; Newborn Infant; Perinatal; Perinatal transmission; Phase; Placebos; Policies; Population; Postpartum Period; Pregnancy; Pregnancy Outcome; Pregnant Women; Prevention; Program Efficiency; Prophylactic treatment; Protocols documentation; Public Health; Publishing; Randomized; Randomized Clinical Trials; Reporting; Resources; Risk; Risk Estimate; Safety; Site; Surface Antigens; Telbivudine; Tenofovir; Testing; Thailand; Third Pregnancy Trimester; Vaccinated; Vaccination; Vaccines; Vertical Disease Transmission; Viral; Viral Load result; Viremia; Virus; Virus Diseases; Virus Replication; Woman; anti-hepatitis B; arm; chronic infection; high risk; improved; in utero; infant outcome; infection risk; innovation; intrapartum; liver injury; neonatal infection; open label; particle; postnatal period; pre-exposure prophylaxis; prevent; primary endpoint; prospective; response; transmission process; viral DNA; viral transmission; virtual

PROJECT SUMMARY The vast majority of perinatal hepatitis B (HB) infections become chronic infections, causing cirrhosis and liver cancer in adulthood. More than 250 million people (about 6% of the world's population) are chronically infected with HB virus (HBV), causing nearly 780,000 deaths each year. Universal HB immunization, starting with a birth dose of vaccine, is not sufficient to prevent all mother-to-child transmission, especially when mothers have high viral loads. In such cases, administration of HB immune globulin (HBIg) is recommended in addition to vaccine. In three studies, including a randomized clinical trial (iTAP) conducted by our group in Thailand, no transmissions occurred when mothers received an anti-HBV antiviral treatment at the end of pregnancy and early postpartum period. Maternal antiviral treatment decreases viral loads to those levels seen in mothers who seldom transmit the virus. In these studies, the antiviral treatment was safe and well tolerated by the mothers and infants. We hypothesize that HBIg can be replaced by maternal antiviral treatment for infants vaccinated at birth. Our primary objective is to demonstrate that, when mothers with high viremia who receive antiviral prophylaxis and when the newborn does not receive HBIg, the risk of HBV transmission to infants is less than 2%, the lowest rate of transmission ever reported without antiviral. This is relevant to public health given that HBIg is not widely available and most infants born to HBV infected mothers do not receive it and that HBIg plus vaccine administered at birth cannot prevent all infections, especially those already established in utero. This innovative strategy has never been tested in a carefully controlled setting. We propose a multicenter, open-label, single arm, prospective clinical study in infants born to mothers with high viremia (HBe antigen positive) who receive the antiviral tenofovir disoproxil fumarate (TDF) from 28-30 weeks gestation until 2 months postpartum, while infants receive active immunization but no HBIg. The study will be conducted in Thailand and Laos PDR and will enroll 439 women and their infants in 32 sites of our clinical research network. HBsAg positive women will be enrolled if they have an HBeAg positive test (a widely available test of high virus replication). Mothers will be followed until one year postpartum and infants 18 months. The primary endpoint will be the detection of HBsAg confirmed by PCR detection of HBV DNA at six months of life. Demonstrating that antiviral treatment plus vaccine is sufficient to prevent virtually all perinatal HBV transmissions without the use of HBIg would revolutionize HBV PMTCT. The results of the study will help define policy to manage HBV infected pregnant women with an HBeAg positive test to prevent perinatal transmission.

项目概要 绝大多数围产期乙型肝炎 (HB) 感染会变成慢性感染，导致肝硬化和肝病 成年后患癌症。超过 2.5 亿人（约占世界人口的 6%）患有慢性感染 乙型肝炎病毒 (HBV) 每年导致近 78 万人死亡。全民乙肝疫苗接种，从出生开始 疫苗剂量不足以预防所有母婴传播，特别是当母亲感染高浓度疫苗时 病毒载量。在这种情况下，除了疫苗外，还建议注射 HB 免疫球蛋白 (HBIg)。 在三项研究中，包括我们小组在泰国进行的一项随机临床试验 (iTAP)，没有发现传播 当母亲在妊娠末期和产后早期接受抗乙肝病毒治疗时发生 时期。孕产妇抗病毒治疗可将病毒载量降低至很少传播的母亲的水平 病毒。在这些研究中，抗病毒治疗是安全的，并且母亲和婴儿的耐受性良好。 我们假设对于出生时接种疫苗的婴儿，HBIg 可以被母亲抗病毒治疗所取代。 我们的主要目标是证明，当接受抗病毒预防治疗的高病毒血症母亲 当新生儿不接受 HBIg 时，将 HBV 传播给婴儿的风险低于 2%，为最低 未使用抗病毒药物时报告的传播率。 鉴于 HBIg 尚未广泛获得且大多数婴儿出生时都感染了 HBV，因此这与公共卫生相关 母亲不会接种 HBIg 加疫苗，出生时接种并不能预防所有感染，尤其是 那些已经在子宫内建立的。这种创新策略从未在严格控制的环境中进行过测试。 我们提出了一项多中心、开放标签、单臂、前瞻性临床研究，对象是患有高血糖的母亲所生的婴儿。 28-30 周接受抗病毒药物富马酸替诺福韦二吡呋酯 (TDF) 的病毒血症（HBe 抗原阳性） 妊娠期至产后2个月，婴儿接受主动免疫但不接受HBIg。该研究将是 在泰国和老挝人民民主共和国进行，将在我们的 32 个临床中心招募 439 名妇女及其婴儿 研究网络。 HBsAg 阳性女性如果 HBeAg 检测呈阳性（广泛使用的 高病毒复制测试）。母亲将被跟踪至产后一年，婴儿将被跟踪至 18 个月。这 主要终点是在出生后 6 个月时通过 PCR 检测 HBV DNA 确认的 HBsAg 检测。 证明抗病毒治疗加疫苗足以预防几乎所有围产期乙型肝炎 不使用 HBIg 的传播将彻底改变 HBV PMTCT。研究结果将有助于定义 政策对 HBeAg 检测呈阳性的 HBV 感染孕妇进行管理，以预防围产期传播。