Durability of HBV DNA Suppression in Cirrhotics After Stopping Therapy

描述（由申请人提供）：使用口服抗病毒药物治疗慢性乙型肝炎（CHB）已被证明可以抑制病毒复制。有关于何时开始抗病毒治疗的指导方针，但没有关于何时停止治疗一旦开始。本研究基于这样一种观点，即对于已经完全和长期病毒抑制的晚期肝纤维化乙型肝炎感染者，努力获得持久的治疗后反应（DOTR）是安全和可取的。初步数据表明，DOTR是可以实现的，即使在代偿性肝硬化患者中，如果密切监测，停止治疗后也很少出现不良临床结果。本研究是对结构化治疗中断（STI）安全性的正式检验。我们的计划是在一项多中心、双盲、安慰剂对照的随机试验中评估替诺福韦（TDF）和特鲁瓦达，该试验针对的是HBV DNA =10 × 4拷贝/mL的稳定、代偿良好的肝硬化患者。具体目标是：1)测试2年和4年持续完全病毒抑制（HBV DNA <70拷贝/mL）后STI的安全性和成本效益；2)检验4年持续抑制是否优于2年持续完全抑制；3)确定TDF与Truvada之间是否存在显著差异；4)确定定量HBsAg水平、免疫标记物或肝内cccDNA水平是否可以预测实现DOTR的可能性。此外，我们提出了一个临床数据库结构，它可以促进临床管理，同时提供有关慢性乙型肝炎的流行病学信息以及影响慢性乙型肝炎结局的潜在社会经济、文化和临床因素。电子健康记录将把一系列临床和实验室数据输入数据库。临床提示将促进采取治疗干预措施的紧急行动的需要，并向患者提供及时随访的提醒。该数据库将用于研究病毒和宿主因素如何影响晚期慢性乙型肝炎患者肝脏相关并发症的发展。这项研究的结果可以为管理指南提供停止规则，这将构成该领域的重大进展。

DESCRIPTION (provided by applicant): Therapy of chronic hepatitis B (CHB) using oral antiviral agents has been shown to suppress viral replication. There are guidelines on when to start antiviral therapy but none on when to stop therapy once initiated. This study hinges on the argument that it is safe and desirable to endeavor to attain a durable off-treatment response (DOTR) to therapy in hepatitis B infected individuals with advanced liver fibrosis who have had complete and long-term viral suppression. Preliminary data demonstrate that a DOTR can be achieved and that it is rare to have adverse clinical outcomes after stopping therapy even in compensated cirrhotics if patients are closely monitored. This study is a formal test of the safety of structured treatment interruption (STI). Our plan is to evaluate Tenofovir (TDF) and Truvada in a multi-centre, double-blinded, placebo-controlled randomized trial of treatment-na¿ve stable, well-compensated cirrhotics with HBV DNA =10 X 4 copies/mL. Specific aims are: 1) to test the safety and cost-effectiveness of an STI after 2 years vs 4 years duration of continuous and complete viral suppression (HBV DNA <70 copies/mL); 2) to test whether 4 years is superior to 2 years duration of continuous and complete suppression; 3) to identify if there are marked differences between TDF and Truvada; and 4) to determine if quantitative HBsAg levels, immune markers, or intrahepatic cccDNA levels can predict the likelihood of achieving a DOTR. In addition, we propose a clinical database structure which can facilitate clinical management while providing information on the epidemiology of CHB and the underlying socioeconomic, cultural, and clinical factors that contribute to outcomes in CHB. Electronic health records will feed serial clinical and laboratory data into the database. Clinical prompts will facilitate the need for urgent action with therapeutic interventions and deliver patient reminders for timely follow-up. The database will be used to examine how viral and host factors influence the development of liver-related complications in patients with advanced CHB. Results from this study could produce stopping rules for management guidelines, which would constitute a major advancement in the field.