[Rational selection of virologic and immunological biomarkers and therapeutic endpoints in the clinical trials of new drugs treating chronic hepatitis B].

Hepatitis B virus (HBV) infection remains to be the major cause of chronic liver diseases in China. Since the nucleos(t)ide analogues and pegylated interferon-alpha do not directly target the covalently closed circular DNA (cccDNA) in the nuclei of HBV-infected hepatocytes, those standard-of-care medications cannot efficiently cure the infected hepatocytes and rarely achieve the functional cure of chronic hepatitis B (CHB). Therefore, new antiviral drugs targeting distinct steps of HBV replication and immunotherapeutics reinvigorating antiviral immune responses are urgently needed for the functional cure of CHB. Based on the extensive discussion of the biological and clinical significance of new virologic biomarkers and distinct mechanism of drug candidates currently in clinical development, we propose that the selection of virologic and immunological biomarkers for evaluation of therapeutic efficacy as well as setting the therapeutic endpoints in the clinical trials should be based on the mode of action of investigational drugs. In addition, due to the complexity of CHB pathogenesis, selection of specific subpopulation of CHB patients for the clinical trials of drugs with a specific mode of action should also be considered.乙型肝炎病毒（HBV）感染仍是我国慢性肝病的主要病因。现有的核苷（酸）类似物和聚乙二醇干扰素均不直接作用于肝细胞核内的HBV共价闭合环状DNA（cccDNA），难以实现HBV的彻底清除和慢性乙型肝炎（CHB）的临床治愈。因此，亟需研发靶向HBV生命周期各阶段及促进宿主抗HBV免疫的新型抗病毒药物。现汇总了目前处于临床试验不同阶段的抗HBV新药，并提出在临床试验中应根据在研药物的不同作用靶点与机制，确定最适的用于疗效评价和临床试验终点选择的病毒学和免疫学指标，从而有助于新药研发。此外，由于CHB疾病进程复杂，不同的在研药物可能有其最大获益的患者亚群，在临床试验中也应予以考虑。.