Hepatitis B Clinical Research Network Clinical Center: Michigan-Hawaii consortium

描述(由申请人提供)：急性乙肝病毒(乙肝)感染发病率的下降并未转化为慢性感染流行率的相应下降。目前，来自流行国家的移民约占美国所有慢性乙肝病毒感染新病例的90%。美国人口的种族/民族多样性和许多乙肝病毒基因类型的存在为研究宿主-病毒关系及其与临床结果的关联提供了机会。目前，已批准的乙肝治疗方法有6种，但这些治疗方法并不能根除病毒。大多数患者需要长时间(或无限期)的治疗来维持病毒抑制，导致抗病毒耐药性和负担能力的问题。关于乙肝治疗的关键问题是：什么时候开始，应该使用哪种抗病毒药物(S)，什么时候停止，对抗病毒耐药的患者怎么办？该临床中心的申请包括两个地点：密歇根大学安娜堡和夏威夷医学中心东部/夏威夷大学火奴鲁鲁。陆博士是乙肝方面的国际权威，在乙肝研究方面有着长期的成功记录，她将担任首席执行官。蔡博士长期对乙肝的临床和研究感兴趣，并在社区外展项目中拥有丰富的经验，他将与L共同担任。这一临床中心应用程序的目标是加深我们对慢性乙肝病毒(HBV)感染的自然历史、病毒自发清除和治疗相关机制、抗病毒耐药突变对流行病学和临床的影响的了解，并确定针对慢性乙肝患者的最佳治疗方案。为了实现这一目标，我们将与其他临床中心、数据协调中心、免疫学中心、病毒学中心和NIDDK项目办公室密切合作；并将遵守乙肝临床研究网络(CRN)指导委员会的决定和所有HBVCRN委员会的政策。将建立一个数据库，以确定美国慢性乙肝病毒感染的谱、与疾病进展相关的因素，以及临床实践中抗病毒药物耐药性的发生率。提出了一项随机试验，比较恩替卡韦+替诺福韦、恩替卡韦与替诺福韦在以基因耐药为主要终点的代偿性肝病患者中的核苷NA、HBeAg+和HBeAg-的疗效。还讨论了其他重要主题的临床试验，如免疫耐受期患者的治疗和抗病毒耐药乙肝患者的最佳治疗。

DESCRIPTION (provided by applicant): Decrease in incidence of acute hepatitis B virus (HBV) infection has not been translated into a corresponding decrease in prevalence of chronic infection. Currently, immigration from endemic countries accounts for roughly 90% of all new cases of chronic HBV infection in the US. The diversity of race/ethnicity of the US population and the presence of many HBV genotypes presents an opportunity to study host-virus relationships and their association with clinical outcomes. Currently, there are 6 approved treatments for hepatitis B, but these treatments do not eradicate the virus. Most patients require long (or indefinite) durations of treatment to maintain virus suppression, leading to problems with antiviral resistance and affordability. The key questions regarding hepatitis B treatment are: when to start, which antiviral agent(s) should be used, when to stop, and what to do in patients with antiviral resistance? This Clinical Center application comprises 2 sites: University of Michigan in Ann Arbor and Hawaii Medical Center East/University of Hawaii in Honolulu. Dr. Lok is an international authority on hepatitis B and has a long record of success in hepatitis B research, she will be the PI. Dr. Tsai has a long standing clinical and research interest in hepatitis B and has extensive experience in community outreach programs, he will be the co-l. The goals of this Clinical Center application are to further our understanding of the natural history of chronic hepatitis B virus (HBV) infection, the mechanisms of spontaneous and treatment related virus clearance, the epidemiological and clinical impact of antiviral drug-resistant HBV mutations, and to determine the optimal treatment for patients with chronic hepatitis B. To achieve this goal, we will work in close collaboration with the other Clinical Centers, the Data Coordinating Center, the Immunology Center, the Virology Center, and the NIDDK Project Office; and will comply with the decisions of the HBV Clinical Research Network (CRN) Steering Committee and the policies of all HBV CRN committees. A database will be established to determine the spectrum of chronic HBV infection in the US, factors associated with disease progression, and incidence of antiviral drug resistance in clinical practice. A randomized trial comparing de novo combination of entecavir + tenofovir vs. entecavir vs. tenofovir in nucleoside na¿ve HBeAg+ and HBeAg- patients with compensated liver disease with genotypic resistance as the primary endpoint is proposed. Clinical trials on other important topics such as treatment of patients in the immune tolerance phase and optimal management of patients with antiviral-resistant HBV are also discussed.