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

 描述（由申请方提供）：慢性B型肝炎（CH B）影响≥ 150万美国人，其中亚裔美国人受影响不成比例，每年有≥ 5000人死于肝硬化和肝细胞癌。随着有效、耐受性良好的HBV治疗的可用性，肝脏相关死亡的减少是可以实现的。然而，尚未回答的问题包括目前的治疗目标群体是否应该扩大，如果药物组合是上级的单一药物，是否干扰素含有方案可以调节一个有利的免疫反应，增强早期（HBe）和表面（HBs）抗原血清转换，以及什么样的治疗持续时间和终点应最佳使用？旧金山弗朗西斯科HBV联盟与其他B肝炎研究网络（HBRN）研究者一起实施了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。迄今为止，有1，875名成人和375名儿童接受了纵向随访，生物储存库获得了191，000份血清/血浆、9，300份DNA、1，800份肝活检载玻片和120份肝组织标本，用于转化研究。我们的纵向队列研究的目的是确定疾病激活（肝炎发作，HBV临床表型转换，HBeAg/HBsAg丢失）和进展为肝硬化，肝衰竭和HCC的预测因子。正在研究的特殊人群包括孕妇、HDV合并感染者、急性B型肝炎患者和急性肝炎患者。此外，我们正在进行2项临床试验，主要目的是比较联合治疗与单药治疗作为一线治疗。免疫活性（IA）试验是一项随机（1：1）平行组设计试验，在200名HBeAg阳性和阴性活动性CHB患者中比较（i）替诺福韦（TDF）300 mg每日一次，持续192周（4年）和（ii）聚乙二醇干扰素α-2a 180µg每周一次，持续24周+TDF 300 mg每日一次，持续192周。主要终点是在有限的治疗期（4年）和停止治疗后48周内HBsAg的丢失。免疫耐受（IT）试验是一项单臂试验，旨在评估40名成人和60名HBeAg阳性CHB儿童（ALT水平正常或接近正常，血清HBV DNA水平较高）接受恩替卡韦（ETV）治疗8周，随后接受ETV和聚乙二醇干扰素α-2a治疗40周的情况。主要终点是停止治疗后48周HBeAg丢失和HBV DNA ≥ 1，000 IU/mL。旧金山弗朗西斯科HBV联盟进一步提议探索维生素D状态在形成慢性B型肝炎成人和儿童患者的临床表型、免疫学转变和治疗结果中的作用。

 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.