HBV Research Network Database Protocol and Clinical Trial Study Proposals

HBV 研究网络数据库协议和临床试验研究提案

• 批准号: 7579185
• 负责人: Steven-Huy B Han
• 金额: $ 14.42万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579185
• 关键词: Affect; American; Antiviral Agents; Antiviral Therapy; Asian Americans; Caring; Chronic; Cirrhosis; Clinical Data; Clinical Trials; Clinical trial protocol document; Combined Modality Therapy; Data; Databases; Development; Disease Progression; Drug Combinations; End Point; Enrollment; Future; Hemodialysis; Hepatitis B Virus; High Prevalence; Histologic; Incidence; Individual; Infection; Injecting drug user; Liver; Liver Failure; Long-Term Effects; Measures; Mono-S; Natural History; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Predictive Factor; Primary carcinoma of the liver cells; Protocols documentation; Randomized; Rate; Relapse; Research; Research Design; Research Personnel; Resistance; Resistance development; Resistance profile; Resources; Risk Factors; Safety; Sampling; Serum; Simian B disease; Specimen; Standards of Weights and Measures; Tenofovir; Time; Tissue Sample; Tissues; Treatment Protocols; Upper arm; Viral; Week; analog; design; entecavir; intrahepatic; liver biopsy; men who have sex with men; new technology; prevent; prospective; repository; response; therapy duration; viral DNA

DESCRIPTION (provided by applicant): Chronic hepatitis B virus (HBV) infection affects 350 million persons worldwide and approximately 1.5 million Americans. Asian Americans have the highest prevalence of chronic HBV, approximately 10% to 15%, followed by other groups including men who have sex with men, injection drug users, and hemodialysis patients (3% to 5% each). Risk factors for liver failure or hepatocellular carcinoma (HCC) in HBV patients remain undefined, though recent data support virological markers (HBV DMA quantitation) as important. Many questions still remain regarding true factors predictive of disease progression (Significance of intrahepatic cccDNA?) and optimal antiviral treatment strategies defining duration of therapy while minimizing resistance. The objectives and aims of this 7-year study are: 1) to design a database to document HBV natural history, help identify risk factors for disease progression, and establish a well-characterized repository of serum samples and liver tissue for ongoing and future studies; 2) to design a long-term clinical trial to study the resistance profile, efficacy, durability of response, and tolerability of different combinations of nucleos(t)ide analog drugs; and 3) to measure intrahepatic cccDNA decline on the nucleos(t)ide drug combinations. For the database protocol, eAg (+) and eAg (-) chronic HBV patients will be prospectively enrolled into a long-term observational database. Patients will continue to be followed by the investigators per standard-of-care and have demographic data, clinical data, serum/tissue samples, and outcomes data collected at regular time points over the study duration. Antiviral treatment is at the discretion of the individual investigator. The resulting large repository of data and specimen samples will serve as an important resource for future studies. For the clinical trial study, eAg (+) and eAg (-) chronic HBV patients will be randomized 1:1:1 to receive either tenofovir monotherapy, entecavir monotherapy, or tenofovir + entecavir combination therapy for 240 weeks, then observed for relapse. Analyses of phenotypic/genotypic resistance development, rates of eAg seroconversion, HBV DNA undetectability, relapse after therapy, and tolerability will allow comparison of these endpoints between the three treatment strategies. End-of-treatment (Week 240) liver biopsies will allow determination of intrahepatic cccDNA decline for the three treatment strategies when compared to baseline liver biopsies. Information gained from this study will help determine the optimal treatment to prevent resistance + the optimal duration of therapy to achieve durable responses.

描述（由申请人提供）：慢性乙型肝炎病毒 (HBV) 感染影响着全世界 3.5 亿人以及大约 150 万美国人。亚裔美国人的慢性乙型肝炎患病率最高，约为 10% 至 15%，其次是其他群体，包括男男性行为者、注射吸毒者和血液透析患者（各为 3% 至 5%）。尽管最近的数据支持病毒学标志物（HBV DMA 定量）同样重要，但 HBV 患者发生肝衰竭或肝细胞癌 (HCC) 的危险因素仍未明确。关于预测疾病进展的真实因素（肝内 cccDNA 的意义？）以及定义治疗持续时间同时最大限度减少耐药性的最佳抗病毒治疗策略，仍然存在许多问题。这项为期 7 年的研究的目的和目标是：1) 设计一个数据库来记录 HBV 自然史，帮助识别疾病进展的危险因素，并为正在进行和未来的研究建立一个特征良好的血清样本和肝组织存储库; 2）设计长期临床试验，研究核苷（酸）类似物药物不同组合的耐药情况、疗效、反应持久性和耐受性； 3) 测量核苷（酸）药物组合的肝内 cccDNA 下降。对于数据库方案，eAg（+）和eAg（-）慢性乙型肝炎患者将被前瞻性地纳入长期观察数据库。研究人员将继续按照护理标准对患者进行随访，并在研究期间定期收集人口统计数据、临床数据、血清/组织样本和结果数据。抗病毒治疗由个体研究者自行决定。由此产生的大型数据和样本存储库将作为未来研究的重要资源。在临床试验研究中，eAg（+）和eAg（-）慢性乙型肝炎患者将按1:1:1的比例随机接受替诺福韦单药治疗、恩替卡韦单药治疗或替诺福韦+恩替卡韦联合治疗，为期240周，然后观察复发情况。对表型/基因型耐药发展、eAg 血清转化率、HBV DNA 不可检测、治疗后复发和耐受性的分析将允许对三种治疗策略之间的这些终点进行比较。 治疗结束（第 240 周）肝活检将能够确定与基线肝活检相比，三种治疗策略的肝内 cccDNA 下降情况。从这项研究中获得的信息将有助于确定预防耐药性的最佳治疗方法以及实现持久反应的最佳治疗持续时间。