综述 | 刘新/鲁凤民：慢性乙型肝炎患者长期核苷（酸）类似物治疗后仍然发生肝癌的原因探讨

[1] 中华人民共和国国家卫生健康委员会医政司 . 原发性肝癌诊疗指南 (2024 年版)[J]. 中华 肝 脏 病 杂 志 , 2024, 32(7):

581-630. DOI:10.3760/cma.j.cn501113-20240611-00290.

[2] Cao M, Ding C, Xia C, et al. Attributable deaths of liver

cancer in China[J]. Chin J Cancer Res, 2021, 33(4):480-489.

DOI: 10.21147/j.issn.1000-9604.2021.04.05.

[3] 中华医学会肝病学分会, 中华医学会感染病学分会 . 慢性乙型肝炎防治指南(2022年版)[J].中华肝脏病杂志, 2022, 30(12):

1309-1331. DOI: 10.3760/cma.j.cn501113-20221204-00607.

[4] Yip TC, Wong VW, Lai MS, et al. Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients

with hepatitis B surface antigen loss[J]. J Hepatol, 2023, 78(3):

524-533. DOI: 10.1016/j.jhep.2022.11.020.

[5] Kuang XJ, Jia RR, Huo RR, et al. Systematic review of risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance[J]. J Viral Hepat, 2018, 25(9):1026-1037. DOI:

10.1111/jvh.12905.

[6] Choi WM, Kim GA, Choi J, et al. Increasing on-treatment

hepatocellular carcinoma risk with decreasing baseline viral

load in HBeAg-positive chronic hepatitis B[J]. J Clin Invest,

2022, 132(10):e154833. DOI: 10.1172/JCI154833.

[7] 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.

[8] 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, 9:3389-3396. DOI: 10.1002/j.1460-2075.1990.

tb07540.x.

[9] Haines KM, Loeb DD. The sequence of the RNA primer and

the DNA template influence the initiation of plus-strand DNA

synthesis in hepatitis B virus[J]. J Mol Biol, 2007, 370:471-480.

DOI: 10.1016/j.jmb.2007.04.057.

[10] Lien JM, Aldrich CE, Mason WS. Evidence that a capped

oligoribonucleotide is the primer for duck hepatitis B virus

plus-strand DNA synthesis[J]. J Virol, 1986, 57:229-236. DOI:

10.1128/JVI.57.1.229-236.1986.

[11] Habig JW, Loeb DD. Sequence identity of the direct repeats,

DR1 and DR2, contributes to the discrimination between

primer translocation and in situ priming during replication of

the duck hepatitis B virus[J]. J Mol Biol, 2006, 364:32-43.

DOI: 10.1016/j.jmb.2006.08.095.

[12] Zhang D, Zhang K, Protzer U, et al. HBV integration induces

complex interactions between host and viral genomic functions

at the insertion site[J]. J Clin Transl Hepatol, 2021, 9(3):399-408.

DOI: 10.14218/JCTH.2021.00062.

[13] Tu T, Budzinska MA, Shackel NA, et al. HBV DNA

integration: molecular mechanisms and clinical Implications

[J]. Viruses, 2017, 9(4):75. DOI: 10.3390/v9040075.

[14] Sung WK, Zheng H, Li S, et al. Genome-wide survey of

recurrent HBV integration in hepatocellular carcinoma[J]. Nat

Genet, 2012, 44(7):765-769. DOI: 10.1038/ng.2295.

[15] Yeh SH, Li CL, Lin YY, et al. Hepatitis B virus DNA

integration drives carcinogenesis and provides a new biomarker

for HBV-related HCC[J]. Cell Mol Gastroenterol Hepatol,

2023, 15(4):921-929. DOI: 10.1016/j.jcmgh.2023.01.001.

[16] Li X, Zhang J, Yang Z, et al. The function of targeted host

genes determines the oncogenicity of HBV integration in

hepatocellular carcinoma[J]. J Hepatol, 2014, 60(5): 975-984.

DOI: 10.1016/j.jhep.2013.12.014.

[17] Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus

integrations in the pathogenesis of human hepatocellular

carcinoma[J]. J Hepatol, 2005, 42(5):760-777. DOI: 10.1016/j.

jhep.2005.02.005.

[18] Jiang S, Yang Z, Li W, et al. Re-evaluation of the carcinogenic

significance of hepatitis B virus integration in hepatocarcinogenesis

[J]. PLoS One, 2012, 7(9):e40363. DOI: 10.1371/journal.pone.

0040363.

[19] Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced

hepatocellular carcinoma[J]. J Hepatol, 2016, 64(1 Suppl):

S84-101. DOI: 10.1016/j.jhep.2016.02.021.

[20] Saigo K, Yoshida K, Ikeda R, et al. Integration of hepatitis B

virus DNA into the myeloid/lymphoid or mixed-lineage

leukemia (MLL4) gene and rearrangements of MLL4 in

human hepatocellular carcinoma[J]. Hum Mutat, 2008, 29:

703-708. DOI: 10.1002/humu.20701.

[21] Lau CC, Sun T, Ching AK, et al. Viral-human chimeric

transcript predisposes risk to liver cancer development and

progression[J]. Cancer Cell, 2014, 25:335-349. DOI: 10.1016/

j.ccr.2014.01.030.

[22] Larsson SB, Tripodi G, Raimondo G, et al. Integration of

hepatitis B virus DNA in chronically infected patients assessed

by Alu-PCR[J]. J Med Virol, 2018, 90(10):1568-1575. DOI: 10.

1002/jmv.25227.

[23] Tu T, Mason WS, Clouston AD, et al. Clonal expansion of

hepatocytes with a selective advantage occurs during all stages

of chronic hepatitis B virus infection[J]. J Viral Hepat, 2015,

22(9):737-753. DOI: 10.1111/jvh.12380.

[24] Liu Y, Qi X, Zeng Z, et al. CRISPR/Cas9-mediated p53 and

Pten dual mutation accelerates hepatocarcinogenesis in adult

hepatitis B virus transgenic mice[J]. Sci Rep, 2017, 7(1):2796.

DOI: 10.1038/s41598-017-03070-8.

[25] 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]. 中华肝脏病杂志, 2019, 27(12):

938-961. DOI: 10.3760/cma.j.issn.1007-3418.2019.12.007.

[26] European Association for the Study of the Liver. EASL 2017

clinical practice guidelines on the management of hepatitis B virus

infection[J]. J Hepatol, 2017, 67(2):370-398. DOI: 10.1016/j.

jhep.2017.03.021.

[27] Terrault NA, Lok ASF, Mcmahon BJ, et al. Update on prevention,

diagnosis, and treatment of chronic hepatitis B: AASLD 2018

hepatitis B guidance[J]. Hepatology, 2018, 67(4):1560-1599. DOI:

10.1002/hep.29800.

[28] Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical

practice guidelines on the management of hepatitis B: a 2015

update[J]. Hepatol Int, 2016, 10(1):1-98. DOI: 10.1007/s12072-

015-9675-4.

[29] Toy M, Hutton D, Jia J, et al. Costs and health impact of

delayed implementation of a national hepatitis B treatment

program in China[J]. J Glob Health, 2022, 12:04043. DOI: 10.

7189/jogh.12.04043.

[30] Sinn DH, Kim SE, Kim BK, et al. The risk of hepatocellular

carcinoma among chronic hepatitis B virus-infected patients

outside current treatment criteria[J]. J Viral Hepat, 2019, 26(12):

1465-1472. DOI: 10.1111/jvh.13185.

[31] Yuen MF, Wong DK, Fung J, et al. HBsAg seroclearance in

chronic hepatitis B in Asian patients: replicative level and risk

of hepatocellular carcinoma[J]. Gastroenterology, 2008, 135(4):

1192-1199. DOI: 10.1053/j.gastro.2008.07.008.

[32] 刘燕娜, 李明蔚, 王雷婕, 等 . 扩大慢性乙型肝炎抗病毒治疗

应重视 ALT 正常、年龄≤30 岁的 HBeAg 阴性慢性 HBV 感染

者[J]. 临床肝胆病杂志, 2022, 38(7):1477-1481. DOI: 10.3969/

j.issn.1001-5256.2022.07.006.

[33] Zhou J, Wang FD, Li LQ, et al. Antiviral therapy favors a

lower risk of liver cirrhosis in HBeAg-negative chronic

hepatitis B with normal alanine transaminase and HBV DNA

positivity[J]. J Clin Transl Hepatol, 2023, 11(7):1465-1475. DOI:

10.14218/JCTH.2023.00272.

[34] Fung J, Lai CL, Seto WK, et al. Nucleoside/nucleotide analogues

in the treatment of chronic hepatitis B[J]. J Antimicrob Chemother,

2011, 66(12):2715-2725. DOI:10.1093/jac/dkr388.

[35] 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.

[36] Kim JH, Sinn DH, Kang W, et al. Low-level viremia and the

increased risk of hepatocellular carcinoma in patients receiving

entecavir treatment[J]. Hepatology, 2017, 66(2):335-343. DOI:

10.1002/hep.28916.

[37] 王雷婕, 顾智强, 许梓萌, 等 . 核苷(酸)类药物经治慢性乙型肝

炎患者低病毒血症发生的可能机制[J]. 中华肝脏病杂志,

2021, 29(12):1151-1155. DOI: 10.3760/cma.j.cn501113-20211124-

00578.

[38] Mak LY, Huang Q, Wong DK, et al. Residual HBV DNA and

pgRNA viraemia is associated with hepatocellular carcinoma

in chronic hepatitis B patients on antiviral therapy[J]. J

Gastroenterol, 2021, 56(5):479-488. DOI: 10.1007/s00535-021-

01780-5.

[39] Carey I, Gersch J, Wang B, et al. Pregenomic HBV RNA and

hepatitis B core-related antigen predict outcomes in hepatitis

B e antigen-negative chronic hepatitis B patients suppressed

on nucleos(t)ide analogue therapy[J]. Hepatology, 2020, 72(1):

42-57. DOI: 10.1002/hep.31026.

[40] Hu B, Wang R, Fu J, et al. Integration of hepatitis B virus S

gene impacts on hepatitis B surface antigen levels in patients

with antiviral therapy[J]. J Gastroenterol Hepatol, 2018, 33(7):

1389-1396. DOI: 10.1111/jgh.14075.

[41] Chow N, Wong D, Lai CL, et al. Effect of antiviral treatment

on hepatitis B virus integration and hepatocyte clonal

expansion[J]. Clin Infect Dis, 2023, 76(3):e801-e809. DOI: 10.

1093/cid/ciac383.

[42] 步宏, 李一雷 . 病理学[M]. 第九版 . 北京:人民卫生出版社,

2018.

[43] Ning Q, Han M, Sun Y, et al. Switching from entecavir to

PegIFN alfa-2a in patients with HBeAg-positive chronic

hepatitis B: a randomised open-label trial (OSST trial)[J]. J

Hepatol, 2014, 61(4):777-784. DOI: 10.1016/j.jhep.2014.05.044.

[44] Han M, Jiang J, Hou J, et al. Sustained immune control in

HBeAg-positive patients who switched from entecavir therapy

to pegylated interferon- α2a: 1 year follow-up of the OSST

study[J]. Antiviral therapy, 2016, 21(4):337-344. DOI: 10.3851/

IMP3019.

[45] 梁晗, 王晨, 朱鹏飞, 等 . 核苷(酸)类似物经治慢性乙型肝炎

患者加用聚乙二醇干扰素-α 治疗的临床治愈效果研究[J].

中华肝脏病杂志, 2023, 31(12):1297-1305. DOI: 10.3760/cma.

j.cn501113-20230505-0000206.

[46] Gao N, Guan G, Xu G, et al. Integrated HBV DNA and

cccDNA maintain transcriptional activity in intrahepatic

HBsAg-positive patients with functional cure following

PEG-IFN-based therapy[J]. Aliment Pharmacol Ther, 2023,

58(10):1086-1098. DOI:10.1111/apt.17670.