Harvard Hepatitis B Consortium

哈佛乙型肝炎联盟

基本信息

批准号：
8728820
负责人：
RAYMOND T CHUNG
金额：
$ 32.43万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728820
关键词：
Acute Hepatitis Address Adult Adverse effects Affect African Age Alcohol consumption Ancillary Study Antiviral Agents Antiviral Therapy Area Asians Awareness Biochemical Birth Birth Place Blood Platelets Boston Cessation of life Chronic Hepatitis B Cirrhosis Clinical Clinical Data Clinical Trials Collection Combined Modality Therapy Community Health Centers Complex Cross-Sectional Studies DNA Data Data Coordinating Center Data Set Databases Demographic Aging Development Disease Disease Progression Drug resistance Educational workshop Enrollment Ethnic Origin Event FDA approved Female Fibrosis Flare Freezing Gender Goals HBV Genotype HIV Hepatic Hepatitis Hepatitis B Hepatitis B Core Antigen Hepatitis B Surface Antigens Hepatitis B Therapy Hepatitis B Virus Hepatitis B e Antigens Hepatitis C virus Hepatocarcinogenesis Histologic Histology Human Resources Immune Immune Tolerance Immunology Infection Infiltration Inflammation Informed Consent Injection of therapeutic agent Injury to Liver Integration Host Factors Interferons Iron Lesion Life Liver Liver Failure Liver Fibrosis Liver diseases Lymphocyte Mediating Metabolic Monitor Multivariate Analysis Natural History Nonprofit Organizations Oral Patients Persons Pharmaceutical Preparations Phase Phase III Clinical Trials Polymerase Population Predictive Factor Primary carcinoma of the liver cells Principal Investigator Procedures Process Prospective Studies Public Health Qualifying Randomized Randomized Controlled Clinical Trials Recovery Recruitment Activity Regimen Research Research Design Resistance Resources Risk Roche brand of peginterferon alfa-2a Role Running Safety Sampling Serological Serum Spleen Staging Staining method Stains Strategic Planning Students Surrogate Markers Symptoms Tenofovir Time Tissue Sample Transaminases United States National Institutes of Health Viral Viremia Work Writing analog arm base cohort comparative efficacy design early childhood entecavir follow-up immune clearance indexing liver biopsy male mathematical model meetings mortality mutant novel diagnostics nucleoside analog open label peginterferon alfa-2a phrases prevent prognostic programs prospective research study response screening sound three-arm study tool treatment duration virology willingness

项目摘要

DESCRIPTION (provided by applicant): Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma (HCC) result in 1.2 million deaths per year, making CHB the 10th leading cause of mortality worldwide. The natural history of CHB is complex and variable. Many viral and host factors have been implicated in disease progression and hepatocarcinogenesis but most of these conclusions have been based on retrospective analyses with limited longitudinal data. Currently, six agents are FDA-approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical and histological benefits for both HBeAg positive and negative CHB. However, each are associated with limitations. The significant side-effect profile of interferon, for example, limits its long-term use. The approved oral agents are tolerable even with prolonged use but drug resistance has been identified with each of them. To date, the limited data on combination therapy with nucleoside analogue and pegylated interferon (PEGIFN) or two nucleos(t)ide analogues given for one year does not show their superiority in durability of response compared to monotherapy. However, there have been no studies to address the efficacy of prolonged combination therapy. In this proposal, by working collaboratively with the 10 clinical centers, the Data Coordinating Center (DCC), Virology Center, and Immunology Center within the NIH HBV network, we plan to (1)construct a prospective, comprehensive patient database that includes demographic and clinical features, viral factors, liver histology and radiological findings that will enable us to examine the natural history of hepatitis B and to identify predictors of disease progression and recovery using both cross-sectional and longitudinal clinical data; and (2) design a 3-year, phase III, prospective, multicenter, randomized, open-label study to compare the efficacy and safety of entecavir (ETV) versus ETV and tenofovir (TDF) versus ETV and PEGIFN-alpha-2a for treatment naive patients with HBeAg positive and negative CHB. Patients randomized to the third arm will receive a 2-year course of PEGIFN and a 3-year course of ETV. ETV and TDF are structurally distinct, potent antiviral agents that do not have cross-resistance. We hypothesize that(1) both combination therapy arms will have higher rates of HBV DNA suppression and lower rates of resistance compared to ETV monotherapy; and (2) the combination of PEGIFN with ETV will produce the highest rates of both HBeAg and HBsAg seroconversion and, hence, durability of response. Collectively, the database and trial will yield rich data regarding natural history and optimal therapy for CHB.

描述（由申请人提供）：慢性乙型肝炎（CHB）是一个主要的公共卫生问题，全球影响高达4亿人。 CHB的并发症包括肝衰竭和肝细胞癌（HCC）每年导致120万人死亡，这使CHB成为全球死亡率的第10个主要原因。 CHB的自然历史是复杂且可变的。许多病毒和宿主因素都与疾病进展和肝癌发生有关，但大多数结论都是基于纵向数据有限的回顾性分析。目前，六名代理被FDA批准用于治疗CHB。这些药物中的每一种都被证明可以为HBEAG阳性和阴性CHB产生病毒学，生化和组织学益处。但是，每个都与限制有关。例如，干扰素的显着副作用特征限制了其长期使用。即使长时间使用，经批准的口服剂也可以忍受，但是每个人都可以识别耐药性。迄今为止，与单一疗法相比，给予一年的核苷类似物和核苷类似物（PEGIFN）（PEGIFN）或两个核类似物（T）IDE类似物的组合数据有限的数据与单一疗法相比，其反应耐用性并不优势。但是，尚无研究来解决长期组合疗法的疗效。 In this proposal, by working collaboratively with the 10 clinical centers, the Data Coordinating Center (DCC), Virology Center, and Immunology Center within the NIH HBV network, we plan to (1)construct a prospective, comprehensive patient database that includes demographic and clinical features, viral factors, liver histology and radiological findings that will enable us to examine the natural history of hepatitis B and to identify predictors of disease progression and recovery using both横截面和纵向临床数据；（2）设计3年，第三阶段，前瞻性，多中心，随机，开放标签的研究，以比较Entecavir（ETV）与ETV和Tenofovir（TDF）与ETV和PEGIFN-Alpha-2a的疗效和安全性，用于治疗HBEAG正阳性和负CHB的天真患者。随机分配到第三臂的患者将接受2年的PEGIFN和3年的ETV课程。 ETV和TDF是没有交叉抗性的结构上不同的有效抗病毒剂。我们假设（1）与ETV单一疗法相比，（1）两种组合治疗臂的HBV DNA抑制率和耐药率较低；（2）PEGIFN与ETV的组合将产生HBEAG和HBSAG血清转化的最高速率，因此，响应的持久性。总体而言，数据库和试验将产生有关CHB自然病史和最佳治疗的丰富数据。