Lok Anna S, Zoulim Fabien, Dusheiko Geoffrey, Ghany Marc G
Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.
Cancer Research Center of Lyon-INSERM U1052, Hospices Civils de Lyon, Lyon University, Lyon, France.
Hepatology. 2017 Oct;66(4):1296-1313. doi: 10.1002/hep.29323. Epub 2017 Aug 1.
The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).
目前接受慢性乙型肝炎治疗的大多数患者需要长期或终身治疗。新型乙肝病毒进入、复制、组装或分泌抑制剂以及免疫调节疗法正在研发中。这些新型化合物用于慢性乙型肝炎治疗，需要对这些治疗方法的疗效和安全性进行标准化评估，并确定新的或额外的终点指标以指导临床试验。为推动该领域发展并加快从发现到监管批准的进程，2016年9月与主要利益相关者举办了一次研讨会，就治疗终点达成共识，以指导旨在治愈乙肝的临床试验设计。达成的共识是，完全消除性治愈，即从宿主中根除病毒，不太可能实现。相反，以乙肝表面抗原持续丧失伴或不伴乙肝表面抗体血清学转换为特征的功能性治愈是一个可行的目标，这种治愈与改善的临床结果相关，在更高比例的患者中实现的可能性高于现有治疗方法目前所能达到的水平。针对更好地定义乙肝病毒治愈的新型生物标志物的标准化检测方法的开发应与新型抗病毒和免疫调节疗法的开发同步进行，以便新治疗方法的批准能够与用于评估疗效或预测反应的新诊断检测方法的批准相联系。可能需要联合抗病毒和免疫调节疗法来实现乙肝病毒的功能性治愈。在进行联合治疗之前，应先进行有限的概念验证单药治疗研究，以评估安全性和抗病毒活性。鉴于目前批准的核苷（酸）类似物具有出色的安全性，任何新的治愈性疗法的安全性将至关重要。（《肝脏病学》2017年）
