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

计量
- 文章访问数: 930
- HTML全文浏览量: 311
- PDF下载量: 170
- 被引次数: 0
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

参考文献(50)

[1]	World Health Organization. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016-2021: actions for impact[EB/OL]. WHO, 2021. https://www.who.int/publications/i/item/9789240027077.
[2]	Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study[J]. Lancet Gastroenterol Hepatol, 2018, 3(6): 383-403. DOI: 10.1016/S2468-1253(18)30056-6.
[3]	LIU J, LIANG W, JING W, et al. Countdown to 2030: eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97(3): 230-238. DOI: 10.2471/BLT.18.219469.
[4]	World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Towards ending viral hepatitis[EB/OL]. WHO, 2016. https://www.who.int/publications/i/item/WHO-HIV-2016.06.
[5]	Polaris Observatory Collaborators. HBV progress towards coverage targets[EB/OL]. (2021-10-04)[2022-02-06]. https://cdafound.org/polaris-countries-dashboard/.
[6]	NING Q, WU D, WANG GQ, et al. Roadmap to functional cure of chronic hepatitis B: An expert consensus[J]. J Viral Hepat, 2019, 26(10): 1146-1155. DOI: 10.1111/jvh.13126.
[7]	MO Z, GAN W, ZHAO Q, et al. Functional cure of chronic hepatitis B: Efforts and prospects[J]. Liver Research, 2020, 4(1): 1-4. DOI: 10.1016/j.livres.2020.02.005.
[8]	KIM GA, LIM YS, AN J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability[J]. Gut, 2014, 63(8): 1325-1332. DOI: 10.1136/gutjnl-2013-305517.
[9]	LIU Y, LIU H, HU Z, et al. Hepatitis B virus virions produced under nucleos(t)ide analogue treatment are mainly not infectious because of irreversible DNA chain termination[J]. Hepatology, 2020, 71(2): 463-476. DOI: 10.1002/hep30844.
[10]	Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[11]	LI GX, LIU H, JIANG QQ, et al. The importance of selection of evaluation indicators for antiviral therapy of chronic hepatitis B based on the clinical trial results of a CpAM[J]. Chin J New Clin Med, 2021, 14(12): 1163-1168. DOI: 10.3969/j.issn.1674-3806.2021.12.02. 李桂馨, 刘慧, 姜倩倩, 等. 从某核衣壳抑制剂临床试验结果看慢性乙肝抗病毒治疗评价指标选择的重要性[J]. 中国临床新医学, 2021, 14(12): 1163-1168. DOI: 10.3969/j.issn.1674-3806.2021.12.02.
[12]	MEIER MA, CALABRESE D, SUSLOV A, et al. Ubiquitous expression of HBsAg from integrated HBV DNA in patients with low viral load[J]. J Hepatol, 2021, 75(4): 840-847. DOI: 10.1016/j.jhep.2021.04.051.
[13]	ALEXOPOULOU A, KARAYIANNIS P. HBeAg negative variants and their role in the natural history of chronic hepatitis B virus infection[J]. World J Gastroenterol, 2014, 20(24): 7644-7652. DOI: 10.3748/wjg.v20.i24.7644.
[14]	WEI L, PLOSS A. Hepatitis B virus cccDNA is formed through distinct repair processes of each strand[J]. Nat Commun, 2021, 12(1): 1591. DOI: 10.1038/s41467-021-21850-9.
[15]	WEI L, PLOSS A. Core components of DNA lagging strand synthesis machinery are essential for hepatitis B virus cccDNA formation[J]. Nat Microbiol, 2020, 5(5): 715-726. DOI: 10.1038/s41564-020-0678-0.
[16]	MARCHETTI AL, ZHANG H, KIM ES, et al. Proteomic analysis of nuclear hepatitis B virus relaxed circular DNA-associated proteins identifies UV-Damaged DNA binding protein as a host factor involved in covalently closed circular DNA formation[J]. J Virol, 2022, 96(2): e0136021. DOI: 10.1128/JVI.01360-21.
[17]	CAI D, YAN R, XU JZ, et al. Characterization of the termini of cytoplasmic hepatitis B virus deproteinated relaxed circular DNA[J]. J Virol, 2020, 95(1): e00922-2. DOI: 10.1128/JVI.00922-20.
[18]	PETERSEN J, THOMPSON AJ, LEVRERO M. Aiming for cure in HBV and HDV infection[J]. J Hepatol, 2016, 65(4): 835-848. DOI: 10.1016/j.jhep.2016.05.043.
[19]	WANG J, HUANG H, LIU Y, et al. HBV genome and life cycle[J]. Adv Exp Med Biol, 2020, 1179: 17-37. DOI: 10.1007/978-981-13-9151-4_2.
[20]	KO C, CHAKRABORTY A, CHOU WM, et al. Hepatitis B virus genome recycling and De novo secondary infection events maintain stable cccDNA levels[J]. J Hepatol, 2018, 69(6): 1231-1241. DOI: 10.1016/j.jhep.2018.08.012.
[21]	LUCIFORA J, ARZBERGER S, DURANTEL D, et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection[J]. J Hepatol, 2011, 55(5): 996-1003. DOI: 10.1016/j.jhep.2011.02.015.
[22]	SAEED U, KIM J, PIRACHA ZZ, et al. Parvulin 14 and parvulin 17 bind to HBx and cccDNA and upregulate hepatitis B virus replication from cccDNA to virion in an HBx-dependent manner[J]. J Virol, 2019, 93(6): e01840-18. DOI: 10.1128/JVI.01840-18.
[23]	HUANG Q, ZHOU B, CAI D, et al. Rapid turnover of hepatitis B virus covalently closed circular DNA indicated by monitoring emergence and reversion of signature-mutation in treated chronic hepatitis B patients[J]. Hepatology, 2021, 73(1): 41-52. DOI: 10.1002/hep.31240.
[24]	GAO L, MAO TH, PENG SW, et al. A short half-life of cccDNA offer or ignite hope for hepatitis B cure under nucleos(t)ide analogues treatment[J]. Chin J Hepatol, 2022, 30(1): 99-102. DOI: 10.3760/cma.j.cn501113-20200527-00277. 高林, 毛天皓, 彭思雯, 等. 核苷(酸)治疗下较短的cccDNA半衰期或给"乙肝治愈"点燃希望[J]. 中华肝脏病杂志, 2022, 30(1): 99-102. DOI: 10.3760/cma.j.cn501113-20200527-00277.
[25]	HSU Y, JUN D, PENG C, et al. Entecavir versus tenofovir disoproxil fumarate for seroclearance of hepatitis B surface antigen in an international real-world cohort[J]. Hepatology, 2021, 74(S1): 434A-436A. DOI: 10.1002/hep.32188.
[26]	LU F, FENG B, ZHENG SJ, et al. Current status of the research on low-level viremia in chronic hepatitis B patients receiving nucleos(t)ide analogues[J]. J Clin Hepatol, 2021, 37(6): 1268-1274. DOI: 10.3969/j.issn.1001-5256.2021.06.007. 鲁凤民, 封波, 郑素军, 等. 核苷(酸)类似物经治的慢性乙型肝炎患者低病毒血症的研究现状[J]. 临床肝胆病杂志, 2021, 37(6): 1268-1274. DOI: 10.3969/j.issn.1001-5256.2021.06.007.
[27]	PREVELIGE PE Jr. Inhibiting virus-capsid assembly by altering the polymerisation pathway[J]. Trends Biotechnol, 1998, 16(2): 61-65. DOI: 10.1016/s0167-7799(97)01154-2.
[28]	ZLOTNICK A, CERES P, SINGH S, et al. A small molecule inhibits and misdirects assembly of hepatitis B virus capsids[J]. J Virol, 2002, 76(10): 4848-4854. DOI: 10.1128/jvi.76.10.4848-4854.2002.
[29]	VENKATAKRISHNAN B, KATEN SP, FRANCIS S, et al. Hepatitis B virus capsids have diverse structural responses to small-molecule ligands bound to the heteroaryldihydropyrimidine pocket[J]. J Virol, 2016, 90(8): 3994-4004. DOI: 10.1128/JVI.03058-15.
[30]	TAN Z, PIONEK K, UNCHWANIWALA N, et al. The interface between hepatitis B virus capsid proteins affects self-assembly, pregenomic RNA packaging, and reverse transcription[J]. J Virol, 2015, 89(6): 3275-3284. DOI: 10.1128/JVI.03545-14.
[31]	WU G, LIU B, ZHANG Y, et al. Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly[J]. Antimicrob Agents Chemother, 2013, 57(11): 5344-5354. DOI: 10.1128/AAC.01091-13.
[32]	YAN Z, WU D, HU H, et al. Direct inhibition of hepatitis B e antigen by core protein allosteric modulator[J]. Hepatology, 2019, 70(1): 11-24. DOI: 10.1002/hep.30514.
[33]	LIU H, CHENG J, VISWANATHAN U, et al. Amino acid residues at core protein dimer-dimer interface modulate multiple steps of hepatitis B virus replication and HBeAg biogenesis[J]. PLoS Pathog, 2021, 17(11): e1010057. DOI: 10.1371/journal.ppat.1010057.
[34]	FUNG S, CHOI H, GEHRING A, et al. Getting to HBV cure: The promising paths forward[J]. Hepatology, 2022. DOI: 10.1002/hep.32314. [Online ahead of print]
[35]	FUNG S, SULKOWSKI M, LALEZARI J, et al. Antiviral activity and safety of the hepatitis B core inhibitor ABI-H0731 administered with a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg-negative chronic hepatitis B infection[J]. J Hepatol, 2020, 73(S1): S51-S52. DOI: 10.1016/S0168-8278(20)30649-8.
[36]	CORNBERG M, LOK AS, TERRAULT NA, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B-Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference[J]. J Hepatol, 2020, 72(3): 539-557. DOI: 10.1016/j.jhep.2019.11.003.
[37]	GAO TJ, HAN GY, LU FM. Mechanism relevant to hepatocellular carcinoma occurrence after negative conversion of viral DNA in treatment of chronic hepatitis B patients with nucleos(t)ide drugs[J]. Chin J Hepatol, 2019, 27(11): 905-909. DOI: 10.3760/cma.j.issn.1007-3418.2019.11.017. 高田敬, 韩耕愚, 鲁凤民. 核苷(酸)类药物治疗慢性乙型肝炎患者病毒DNA阴转后发生肝细胞癌的相关机制[J]. 中华肝脏病杂志, 2019, 27(11): 905-909. DOI: 10.3760/cma.j.issn.1007-3418.2019.11.017.
[38]	WANG J, SHEN T, HUANG X, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound[J]. J Hepatol, 2016, 65(4): 700-710. DOI: 10.1016/j.jhep.2016.05.029.
[39]	XIA M, CHI H, WU Y, et al. Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment[J]. Aliment Pharmacol Ther, 2021, 54(5): 709-714. DOI: 10.1111/apt.16538.
[40]	YUEN MF, GANE EJ, KIM DJ, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3-778 in patients with chronic HBV infection[J]. Gastroenterology, 2019, 156(5): 1392-1403. e7. DOI: 10.1053/j.gastro.2018.12.023.
[41]	ZOULIM F, LENZ O, VANDENBOSSCHE JJ, et al. JNJ-56136379, an HBV capsid assembly modulator, is well-tolerated and has antiviral activity in a phase 1 study of patients With chronic infection[J]. Gastroenterology, 2020, 159(2): 521-533. e9. DOI: 10.1053/j.gastro.2020.04.036.
[42]	PATEL N, WHITE SJ, THOMPSON RF, et al. HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly[J]. Nat Microbiol, 2017, 2: 17098. DOI: 10.1038/nmicrobiol.2017.98.
[43]	JUNKER-NIEPMANN M, BARTENSCHLAGER R, SCHALLER H. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA[J]. EMBO J, 1990, 9(10): 3389-3396. DOI: 10.1002/j.1460-2075.tb07540.x.
[44]	GANE E, SULKOWSKI M, MA X, et al. Viral response and safety following discontinuation of treatment with the core inhibitor vebicorvir and a nucleos(t)ide reverse transcriptase inhibitor in patients with HBeAg positive or negative chronic hepatitis B virus infection[J]. J Hepatol, 2021, 75(S2): S736. DOI: 10.1016/S0168-8278(21)01843-2.
[45]	FUKUTOMI K, HIKITA H, MURAI K, et al. Capsid Allosteric modulators enhance the innate immune response in hepatitis B virus-infected hepatocytes during interferon administration[J]. Hepatol Commun, 2022, 6(2): 281-296. DOI: 10.1002/hep4.1804.
[46]	YE J, CHEN J. Interferon and hepatitis B: Current and future perspectives[J]. Front Immunol, 2021, 12: 733364. DOI: 10.3389/fimmu.2021.733364.
[47]	FERNÁNDEZ G, L SANCHEZ A, JEREZ E, et al. Five-year follow-up of chronic hepatitis B patients immunized by nasal route with the therapeutic vaccine hebernasvac[J]. Euroasian J Hepatogastroenterol, 2018, 8(2): 133-139. DOI: 10.5005/jp-journals-10018-1279.
[48]	GANE E, VERDON DJ, BROOKS AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study[J]. J Hepatol, 2019, 71(5): 900-907. DOI: 10.1016/j.jhep.2019.06.028.
[49]	AGARWAL K, BRUNETTO M, SETO WK, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection[J]. J Hepatol, 2018, 68(4): 672-681. DOI: 10.1016/j.jhep.2017.11.039.
[50]	WU Z, XIE D, FU L, et al. Functional cure based on pegylated interferon α in long-term nucleoside analog suppressed HBeAg negative chronic hepatitis B: a multicenter real-world study (Everest Project in China), a sequential report - the predictors for HBsAg loss[J]. Hepatology, 2021, 74(S1): 483A. DOI: 10.1002/hep.32188.