衣壳组装调节剂联合核苷(酸)类似物治疗慢性乙型肝炎临床试验中亟待解决的科学问题

Urgent scientific issues to be solved in clinical trials of capsid assembly modulator combined with nucleos(t)ide analogues for the treatment of chronic hepatitis B

慢性HBV感染是病毒性肝炎、肝硬化和原发性肝癌的主要病因。目前临床应用的核苷(酸)类似物(NUC)和聚乙二醇干扰素α(PEG-IFNα)均无法直接靶向共价闭合环状DNA,难以实现慢性乙型肝炎患者(CHB)的临床治愈。因此,33亟需研发靶向HBV复制周期各阶段的直接抗病毒药物。衣壳组装调节剂(CpAM)通过不同机制靶向病毒衣壳的组装,进而发挥直接抗病毒作用,其与NUC联用本应发挥良好的协同抗病毒作用,但现有临床试验结果均表明,接受有限疗程CpAM与NUC联合抗病毒治疗的慢性乙型肝炎患者均发生停药后病毒学反弹。本文根据两类药物的作用机制,对上述临床试验结果进行了合理解释,并提出在未来以安全停药为观察终点的临床试验中,可能需要更长时间的CpAM与NUC联合抗病毒治疗,以耗竭或沉默共价闭合环状DNA池,从而提高CHB患者安全停药的可能性。此外,多靶点的联合抗病毒治疗策略仍需进一步研究。

Chronic hepatitis B virus(HBV)infection is the main cause of viral hepatitis,liver cirrhosis,and primary liver cancer.At pres-ent,nucleos(t)ide analogues(NUC)and pegylated interferonαused in clinical practice cannot directly target covalently closed circular DNA,and it is difficult to achieve clinical cure of chronic hepatitis B patients;therefore,it is urgently needed to develop direct-acting an-tiviral agents targeting all stages of the HBV replication cycle.Capsid assembly modulator(CpAM)targets the assembly of viral capsids through various mechanisms,thereby exerting a direct-acting antiviral effect.Its combination with NUC should have a good synergistic anti-viral effect,but the results of existing clinical trials have shown that chronic hepatitis B patients who received a limited course of antiviral therapy with CpAM and NUC all experienced off-therapy viral rebound.Based on the mechanism of action of these two types of drugs,this article provides a reasonable explanation for the above clinical trial results and points out that a longer course of antiviral therapy with CpAM and NUC may be needed in the future clinical trials with safe drug withdrawal as the end point of observation,so as to deplete or silence the pool of covalently closed circular DNA and increase the possibility of safe drug withdrawal in CHB patients.In addition,further studies are needed to explore antiviral therapeutic strategies with a combination of multiple targets.