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.

项目总结 绝大多数围产期乙肝(HB)感染变成慢性感染，导致肝硬变和肝炎 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 HB病毒(乙肝)，每年造成近78万人死亡。普遍接种乙肝疫苗，从出生开始 疫苗的剂量不足以防止所有母婴传播，特别是当母亲有高 病毒载量。在这种情况下，建议在接种疫苗的同时注射乙肝免疫球蛋白(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 句号。母亲的抗病毒治疗将病毒载量降低到很少传播的母亲的水平 病毒。在这些研究中，母亲和婴儿对抗病毒治疗是安全的，耐受性很好。 我们假设，在婴儿出生时接种疫苗的母体抗病毒治疗可以取代HBIg。 我们的主要目标是证明，当接受抗病毒预防的高病毒血症母亲 而当新生儿没有接种HBIg时，乙肝病毒传播给婴儿的风险不到2%，是最低的 在没有抗病毒药物的情况下报告过的传播率。 这与公共卫生有关，因为HBIg没有广泛获得，而且大多数乙肝病毒出生的婴儿都感染了 母亲不会接种，而且在出生时接种HBIg加疫苗不能预防所有感染，特别是 那些已经在子宫中建立起来的。这一创新战略从未在精心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，研究对象为患有高血压病的母亲所生婴儿。 接受富马酸替诺福韦(TDF)治疗28-30周的病毒血症(HBe抗原阳性)患者 孕期到产后2个月，婴儿接受主动免疫，但不接种HBIg。这项研究将是 在泰国和老挝PDR进行，将在我们的临床32个地点招募439名妇女及其婴儿 研究网络。如果HBs Ag阳性妇女有HBeAg阳性检测(一种广泛使用的检测方法)，她们将被录取 高病毒复制测试)。母亲将被跟踪到产后一年，婴儿将被跟踪到18个月。这个 主要终点将是在出生6个月时通过聚合酶链式反应检测HBVDNA确认的乙肝表面抗原检测。 证明抗病毒治疗加疫苗足以预防几乎所有围产期的乙肝病毒 不使用HBIg的传播将使HBVPMTCT发生革命性变化。研究结果将有助于确定 对感染乙肝病毒的孕妇进行HBeAg阳性检测以防止围产期传播的政策。