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

鲁凤民; 黄鸿鑫; 毛天皓; 陈香梅; 庄辉

doi:10.3969/j.issn.1001-5256.2022.08.001

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

DOI: 10.3969/j.issn.1001-5256.2022.08.001

鲁凤民^{1, 2, , ,},
黄鸿鑫²,
毛天皓²,
陈香梅²,
庄辉^2, , ,

1.
北京大学人民医院肝病研究所，北京 100044
2.
北京大学医学部基础医学院病原生物学系暨北京大学感染病研究中心，北京 100191

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：鲁凤民、庄辉拟定写作思路并最终定稿；陈香梅指导文章撰写并修改文章关键内容；黄鸿鑫和毛天皓负责文献检索并参与起草文稿。

详细信息

通信作者:
鲁凤民, lu.fengmin@hsc.pku.edu.cn

庄辉, zhuangbmu@126.com

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出版历程
- 收稿日期: 2022-04-20
- 录用日期: 2022-05-20
- 出版日期: 2022-08-20

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

Fengmin LU^{1, 2
, ,
,},
Hongxin HUANG²,
Tianhao MAO²,
Xiangmei CHEN²,
Hui ZHUANG^{2
, ,
,}

1.
Hepatology Institute, Peking University People's Hospital, Beijing 100044, China
2.
Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

More Information

Corresponding author: LU Fengmin, lu.fengmin@hsc.pku.edu.cn(ORCID: 0000-0002-1832-3209); ZHUANG Hui, zhuangbmu@126.com(ORCID: 0000-0001-9119-6325)

摘要

摘要: 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，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。
- 乙型肝炎, 慢性 /
- 核苷类 /
- 核苷酸类 /
- 衣壳组装调节剂
Abstract: Chronic hepatitis B virus (HBV) infection is the main cause of viral hepatitis, liver cirrhosis, and primary liver cancer. At present, nucleos(t)ide analogues (NUC) and pegylated interferon α used 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 antiviral 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 antiviral 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.
- Hepatitis B, Chronic /
- Nucleosides /
- Nucleotides /
- Capsid Assembly Modulators

HTML全文

图 1 影响CpAM联合NUC对抑制HBV DNA复制发挥叠加作用的可能机制及启示

Figure 1. Possible mechanisms that affect the combined use of CpAM and NUC to exert the superimposed antiviral effects on inhibition of HBV DNA replication and their implications

下载: 全尺寸图片幻灯片

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