Hepatitis B Research Network (HBRN): Natural History and Treatment Studies

 描述(申请人提供)：慢性乙型肝炎(CHB)影响=150万美国人，其中亚裔美国人受到不成比例的影响，每年=5000人死于肝硬变和肝细胞癌。随着有效的、耐受性良好的乙肝治疗的出现，与肝脏相关的死亡的减少是可以实现的。然而，悬而未决的问题包括：是否应该扩大当前治疗的靶群；如果联合用药优于单一药物；含有干扰素的方案是否可以调节有利的免疫反应，从而增强早期(HBe)和表面(HBs)抗原血清转换；以及治疗持续时间和终点应该以什么为最佳？旧金山乙肝联盟与其他乙肝研究网络(HBRN)研究人员一起实施了5项临床方案(2项观察性研究和3项临床试验)和16项辅助研究，包括生活质量、流行病学、免疫学、病毒学和基因组学。到目前为止，1,875名成人和375名儿童正在进行纵向跟踪，该生物库获得了191,000份血清/血浆、9,300份DNA、1,800份肝活检切片和120份肝组织样本用于翻译研究。我们的研究旨在确定疾病活动性(肝炎发作、乙肝临床表型转换、HBeAg/HBs Ag丢失)和进展为肝硬变、肝功能衰竭和肝细胞癌的预测因子。研究中的特殊人群包括孕妇、合并感染HDV的人、急性乙肝和红斑症患者。此外，我们正在进行两项临床试验，主要目标是比较联合疗法和单一疗法作为一线疗法的疗效。免疫活性(IA)试验是一项随机(1：1)平行分组设计试验，比较(I)替诺福韦(TDF)300毫克每日服用192周(4年)和(Ii)聚乙二醇干扰素α-2a 180微克每周服用24周加TDF 300 mg每日服用192周，对200名HBeAg阳性和阴性活动性慢性乙肝患者进行比较。主要终点是在有限的治疗周期(4年)和停止治疗后48周后的乙肝表面抗原丢失。这项免疫耐受(IT)试验是一项单臂试验，用于评估恩替卡韦(ETV)治疗8周，然后对40名成人和60名儿童HBeAg阳性、ALT水平正常或接近正常、血清HBVDNA水平较高的CHB患者进行ETV治疗和聚乙二醇α-2a干扰素治疗。主要终点是停药48周后HBeAg阴转率和HBVDNA=1000IU/ml。旧金山乙肝联盟进一步建议探索维生素D状态在影响成人和儿童慢性乙肝患者的临床表型、免疫学转变和治疗结果方面的作用。

 DESCRIPTION (provided by applicant): Chronic hepatitis B (CHB) affects =1.5 million Americans, with Asian-Americans disproportionately affected, and =5000 deaths annually due to cirrhosis and hepatocellular carcinoma. With the availability of effective, well-tolerated HBV treatments, reductions in liver-related deaths are achievable. However, unanswered questions include whether the current target groups for treatment should be expanded, if combinations of drugs are superior to a single drug, whether interferon-containing regimens can modulate a favorable immune response that augments Early (HBe) and Surface (HBs) antigen seroconversion, and what treatment durations and endpoints should optimally be used? The San Francisco HBV Consortium together with other Hepatitis B Research Network (HBRN) investigators has implemented 5 clinical protocols (2 observational studies and 3 clinical trials) and 16 ancillary studies including quality of life, epidemiology, immunology, virology, and genomic. To date 1,875 adults and 375 children are in longitudinal follow-up and the biorepository acquired 191,000 aliquots of serum/plasma, 9,300 aliquots of DNA, 1,800 liver biopsy slides and 120 liver tissue specimens for translational studies. Our study aims for the longitudinal cohort are to identify predictors of disease activation (hepatitis flares, HBV clinica phenotype transitions, HBeAg/HBsAg loss) and progression to cirrhosis, liver failure, and HCC. Special populations under study include pregnant women, those with HDV coinfection, acute hepatitis B and patients with flares. Additionally, we are executing 2 clinical trials, with the primary goal of comparing combination versus monotherapy as first-line therapy The Immune Active (IA) trial is a randomized (1:1) parallel group design trial comparing (i) Tenofovir (TDF) 300 mg daily for 192 weeks (4 years) and (ii) peg-IFN alfa-2a 180µg weekly for 24 weeks plus TDF 300 mg daily for 192 weeks in 200 patients with HBeAg positive and negative active CHB. The primary endpoint is HBsAg loss after a finite period of treatment (4 years) and 48 weeks after stopping treatment. The Immune Tolerant (IT) trial is a single arm pilot to evaluate 8 weeks of entecavir (ETV) followed by 40 weeks of both ETV and peg-IFN alfa-2a in 40 adults and 60 children with HBeAg- positive CHB with normal or near normal ALT levels and high serum levels of HBV DNA. The primary endpoint is HBeAg loss and HBV DNA =1,000 IU/mL 48 weeks after stopping therapy. The San Francisco HBV Consortium further proposes to explore the role for vitamin D status in shaping the clinical phenotypes, immunologic transitions and treatment outcomes of adult and pediatric patients with chronic hepatitis B.