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Volume 40 Issue 5
May  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(5): 875-879

Clinical controversies over antiviral therapy for patients in the immune-tolerant phase of hepatitis B virus infection

DOI: 10.12449/JCH240505

  • Department of Infectious Diseases，Peking University First Hospital，Beijing 100034，China

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  • Corresponding author: WANG Yan， wangyanwang@bjmu.edu.cn （ORCID： 0000-0002-8577-0527）
  • Received Date: 2024-03-03
  • Accepted Date: 2024-04-10
  • Published Date: 2024-05-25
    Abstract
  • To achieve the goal of “eliminating viral hepatitis as a public health hazard by 2030”， extensive screening， active prevention， and antiviral therapy are currently recommended for chronic hepatitis B virus （HBV） infection； however， no consensus has been reached on whether to initiate antiviral therapy for patients in the immune-tolerant phase of chronic HBV infection. Some experts believe that patients in the immune-tolerant phase tend to have a stable liver immune microenvironment， with a low risk of disease progression and poor response to treatment， and thus it is not recommended to initiate antiviral therapy. However， various other studies have shown that patients in the immune-tolerant phase still have inflammatory damage in the liver， with a risk of disease progression and a high level of cost effectiveness， and therefore， some experts suggest that antiviral therapy should be actively initiated for patients in the immune-tolerant phase. This article performs a literature review of the definition of patients in the immune-tolerant phase of chronic HBV infection and the advantages and disadvantages of antiviral therapy and conducts a preliminary analysis based on previous studies， in order to accumulate the evidence for whether to initiate antiviral therapy in the immune-tolerant phase of chronic HBV infection and lay a foundation for standardized clinical diagnosis and treatment of patients in the immune-tolerant phase.

     

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  • [1]
    ZHUANG H. Correction note on the estimated number of patients in the immune-tolerant phase of hepatitis B virus infection in China and globally[J]. J Clin Hepatol, 2021, 37( 4): 785- 786. DOI: 10.3969/j.issn.1001-5256.2021.04.012.

    庄辉. 全球和我国HBV感染免疫耐受期患者人数估计更正说明[J]. 临床肝胆病杂志, 2021, 37( 4): 785- 786. DOI: 10.3969/j.issn.1001-5256.2021.04.012.
    [2]
    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.
    [3]
    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.
    [4]
    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.
    [5]
    Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. Japan Society of Hepatology guidelines for the management of hepatitis C virus infection: 2019 update[J]. Hepatol Res, 2020, 50( 7): 791- 816. DOI: 10.1111/hepr.13503.
    [6]
    Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B(2022 version)[J]. Chin J Infect Dis, 2023, 41( 1): 3- 28. DOI: 10.3760/cma.j.cn311365-20230220-00050.

    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]. 中华传染病杂志, 2023, 41( 1): 3- 28. DOI: 10.3760/cma.j.cn311365-20230220-00050.
    [7]
    ZHENG PY, DOU YQ, WANG QY. Immune response and treatment targets of chronic hepatitis B virus infection: Innate and adaptive immunity[J]. Front Cell Infect Microbiol, 2023, 13: 1206720. DOI: 10.3389/fcimb.2023.1206720.
    [8]
    ZHENG JR, WANG ZL, FENG B. Hepatitis B functional cure and immune response[J]. Front Immunol, 2022, 13: 1075916. DOI: 10.3389/fimmu.2022.1075916.
    [9]
    TRAUM D, WANG YJ, SCHWARZ KB, et al. Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver[J]. JCI Insight, 2021, 6( 7): e146883. DOI: 10.1172/jci.insight.146883.
    [10]
    LIU Y, WANG GY, CHEN YX, et al. HBcAg-induced upregulated 4-1BB ligand on B cells contributes to B-cell hyperactivation during chronic hepatitis B infection[J]. J Med Virol, 2019, 91( 5): 781- 790. DOI: 10.1002/jmv.25377.
    [11]
    HU LH, CHENG H, YAO TT, et al. Role of perforin and granzyme B in different immune status of hepatitis B[J]. Infect Dis Inf, 2023, 36( 5): 458- 462, 468. DOI: 10.3969/j.issn.1007-8134.2023.05.014.

    胡林慧, 程浩, 姚甜甜, 等. 穿孔素与颗粒酶B在乙型肝炎不同免疫状态中的作用[J]. 传染病信息, 2023, 36( 5): 458- 462, 468. DOI: 10.3969/j.issn.1007-8134.2023.05.014.
    [12]
    Chinese Foundation for Hepatitis Prevention and Control; Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. Management algorithm for interrupting mother-to-child transmission of hepatitis B[J]. J Clin Hepatol, 2017, 33( 7): 1214- 1217. DOI: 10.3969/j.issn.1001-5256.2017.07.003.

    中国肝炎防治基金会, 中华医学会感染病学分会, 中华医学会肝病学分会. 乙型肝炎母婴阻断临床管理流程[J]. 临床肝胆病杂志, 2017, 33( 7): 1214- 1217. DOI: 10.3969/j.issn.1001-5256.2017.07.003.
    [13]
    ZHOU J, WANG FD, WANG ML, et al. Antiviral therapy for chronic HBV infection with persistently normal alanine aminotransferase: Controversy and consensus[J]. Front Med(Lausanne), 2021, 8: 717125. DOI: 10.3389/fmed.2021.717125.
    [14]
    BERTOLETTI A, KENNEDY PT. The immune tolerant phase of chronic HBV infection: New perspectives on an old concept[J]. Cell Mol Immunol, 2015, 12( 3): 258- 263. DOI: 10.1038/cmi.2014.79.
    [15]
    LIANG XS, ZHOU Y, LI CZ, et al. Natural course of chronic hepatitis B is characterized by changing patterns of programmed death type-1 of CD8-positive T cells[J]. World J Gastroenterol, 2010, 16( 5): 618- 624. DOI: 10.3748/wjg.v16.i5.618.
    [16]
    KENNEDY PTF, SANDALOVA E, JO J, et al. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B[J]. Gastroenterology, 2012, 143( 3): 637- 645. DOI: 10.1053/j.gastro.2012.06.009.
    [17]
    WEI JG, SHI TD, ZOU LY. The role of Th9 cells in different stages of chronic hepatitis B virus infection[J]. Immunol J, 2019, 35( 10): 879- 884. DOI: 10.13431/j.cnki.immunol.j.20190137.

    魏金刚, 石统东, 邹丽云. Th9细胞在慢性乙型肝炎病毒感染不同阶段中的作用[J]. 免疫学杂志, 2019, 35( 10): 879- 884. DOI: 10.13431/j.cnki.immunol.j.20190137.
    [18]
    DENG M, LI MH, LIU SN, et al. Studies about the level of CD4+ CD25+ regulatory T cells and relation between expression of Foxp3 and CD127 in peripheral blood of chronic HBV infection[J]. Chin J Exp Clin Virol, 2010, 24( 1): 21- 23. DOI: 10.3760/cma.j.issn.1003-9279.2010.01.008.

    邓敏, 李明慧, 刘顺爱, 等. 慢性HBV感染者调节性T细胞水平及Foxp3与CD127表达关系的研究[J]. 中华实验和临床病毒学杂志, 2010, 24( 1): 21- 23. DOI: 10.3760/cma.j.issn.1003-9279.2010.01.008.
    [19]
    BERTOLINI TB, BISWAS M, TERHORST C, et al. Role of orally induced regulatory T cells in immunotherapy and tolerance[J]. Cell Immunol, 2021, 359: 104251. DOI: 10.1016/j.cellimm.2020.104251.
    [20]
    XU QL, HUANG JS, FU JW, et al. Characteristics and clinical significance of T lymphocyte subsets in peripheral blood during immune tolerance period of chronic HBV infection[J/CD]. Electron J Emerg Infect Dis, 2022, 7( 4): 6- 11, 2. DOI: 10.19871/j.cnki.xfcrbzz.2022.04.002.

    徐清浪, 黄建生, 付吉伟, 等. 慢性HBV感染免疫耐受期外周血T淋巴细胞亚群变化特征及临床意义[J/CD]. 新发传染病电子杂志, 2022, 7( 4): 6- 11, 2. DOI: 10.19871/j.cnki.xfcrbzz.2022.04.002.
    [21]
    LOPES AR, KELLAM P, DAS A, et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection[J]. J Clin Invest, 2008, 118( 5): 1835- 1845. DOI: 10.1172/JCI33402.
    [22]
    CHAO DT, LIM JK, AYOUB WS, et al. Systematic review with meta-analysis: The proportion of chronic hepatitis B patients with normal alanine transaminase≤40 IU/L and significant hepatic fibrosis[J]. Aliment Pharmacol Ther, 2014, 39( 4): 349- 358. DOI: 10.1111/apt.12590.
    [23]
    PARK JY, PARK YN, KIM DY, et al. High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels[J]. J Viral Hepat, 2008, 15( 8): 615- 621. DOI: 10.1111/j.1365-2893.2008.00989.x.
    [24]
    LIN X. Correlation between HBsAg and Liver Fibrosis in Immune-tolerant Hepatitis B Patients[D]. Fuzhou: Fujian Medical University, 2020.

    林欣. HBsAg与乙肝免疫耐受期患者肝纤维化的关系研究[D]. 福州: 福建医科大学, 2020.
    [25]
    LI M, ZHOU ZH, SUN XH, et al. The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection[J]. Hepatol Int, 2016, 10( 4): 594- 601. DOI: 10.1007/s12072-015-9650-0.
    [26]
    KOFFAS A, MAK LY, GILL US, et al. Early treatment consideration in patients with hepatitis B‘e’ antigen-positive chronic infection: Is it time for a paradigm shift?[J]. Viruses, 2022, 14( 5): 900. DOI: 10.3390/v14050900.
    [27]
    LAI M, HYATT BJ, NASSER I, et al. The clinical significance of persistently normal ALT in chronic hepatitis B infection[J]. J Hepatol, 2007, 47( 6): 760- 767. DOI: 10.1016/j.jhep.2007.07.022.
    [28]
    KIM HL, KIM GA, PARK JA, et al. Cost-effectiveness of antiviral treatment in adult patients with immune-tolerant phase chronic hepatitis B[J]. Gut, 2021, 70( 11): 2172- 2182. DOI: 10.1136/gutjnl-2020-321309.
    [29]
    LI RQ, LIN X, WANG JY, et al. Cost-effectiveness of combination antiviral treatment with extended duration for hepatitis B e antigen(HBeAg)-negative chronic hepatitis B in China[J]. Ann Transl Med, 2021, 9( 17): 1365. DOI: 10.21037/atm-21-1666.
    [30]
    HUI CK, LEUNG N, YUEN ST, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase[J]. Hepatology, 2007, 46( 2): 395- 401. DOI: 10.1002/hep.21724.
    [31]
    CHEN CF, LEE WC, YANG HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma[J]. Gastroenterology, 2011, 141( 4): 1240- 1248, 1248. e1- 1248. e2. DOI: 10.1053/j.gastro.2011.06.036.
    [32]
    QUAN M, XING HC. Antiviral therapy is not recommended in immune-tolerant phase chronic hepatitis B patients without complications[J]. J Clin Hepatol, 2021, 37( 6): 1279- 1280. DOI: 10.3969/j.issn.1001-5256.2021.06.011.

    全敏, 邢卉春. 无合并症的真实慢性乙型肝炎免疫耐受期患者不建议抗病毒治疗[J]. 临床肝胆病杂志, 2021, 37( 6): 1279- 1280. DOI: 10.3969/j.issn.1001-5256.2021.06.011.
    [33]
    FELD JJ, TERRAULT NA, LIN HH S, et al. Entecavir and peginterferon alfa-2a in adults with hepatitis B e antigen-positive immune-tolerant chronic hepatitis B virus infection[J]. Hepatology, 2019, 69( 6): 2338- 2348. DOI: 10.1002/hep.30417.
    [34]
    WU ZX, CHEN FS, ZHOU XL, et al. Tenofovir and telbivudine combination therapy rapidly decreases viral loads in immune-tolerant chronic hepatitis B patients awaiting assisted reproduction: An open-label, randomized, controlled study[J]. Eur J Gastroenterol Hepatol, 2019, 31( 7): 832- 835. DOI: 10.1097/MEG.0000000000001345.
    [35]
    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.
    [36]
    LI YL, WANG Y, ZHOU YQ, et al. Antiviral therapy for patients with chronic hepatitis B in the immune-tolerant phase: A systematic review[J]. J Clin Hepatol, 2021, 37( 6): 1282- 1287. DOI: 10.3969/j.issn.1001-5256.2021.06.013.

    李彦霖, 王妍, 周颖琼, 等. 慢性乙型肝炎免疫耐受期的抗病毒治疗: 系统综述[J]. 临床肝胆病杂志, 2021, 37( 6): 1282- 1287. DOI: 10.3969/j.issn.1001-5256.2021.06.013.
    [37]
    JEON MY, KIM BK, LEE JS, et al. Negligible risks of hepatocellular carcinoma during biomarker-defined immune-tolerant phase for patients with chronic hepatitis B[J]. Clin Mol Hepatol, 2021, 27( 2): 295- 304. DOI: 10.3350/cmh.2020.0216.
    [38]
    LEE HA, LEE HW, KIM IH, et al. Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase[J]. Aliment Pharmacol Ther, 2020, 52( 1): 196- 204. DOI: 10.1111/apt.15741.
    [39]
    LEE HW, KIM SU, BAATARKHUU O, et al. Comparison between chronic hepatitis B patients with untreated immune-tolerant phase vs. those with virological response by antivirals[J]. Sci Rep, 2019, 9( 1): 2508. DOI: 10.1038/s41598-019-39043-2.
    [40]
    KIM GA, LIM YS, HAN S, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B[J]. Gut, 2018, 67( 5): 945- 952. DOI: 10.1136/gutjnl-2017-314904.
    [41]
    WANG FD, ZHOU J, ZHANG DM, et al. A study of the effectiveness of nucleos(t)ide analogues in the treatment of HBeAg-positive chronic hepatitis B with normal alanine aminotransferase and high level of HBV DNA[J]. Chin J Hepatol, 2022, 30( 4): 389- 394. DOI: 10.3760/cma.j.cn501113-20210705-00318.

    王发达, 周静, 张冬梅, 等. 核苷(酸)类似物治疗丙氨酸转氨酶正常HBeAg阳性且HBV DNA高水平慢性乙型肝炎的有效性研究[J]. 中华肝脏病杂志, 2022, 30( 4): 389- 394. DOI: 10.3760/cma.j.cn501113-20210705-00318.
    [42]
    ROSENTHAL P, LING SC, BELLE SH, et al. Combination of entecavir/peginterferon alfa-2a in children with hepatitis B e antigen-positive immune tolerant chronic hepatitis B virus infection[J]. Hepatology, 2019, 69( 6): 2326- 2337. DOI: 10.1002/hep.30312.
    [43]
    PERRILLO R, LIN HH S, SCHWARZ KB, et al. Changes in serum hepatitis B surface and e antigen, interferon-inducible protein 10, and aminotransferase levels during combination therapy of immune-tolerant chronic hepatitis B[J]. Hepatology, 2022, 76( 3): 775- 787. DOI: 10.1002/hep.32400.
    [44]
    ZHU SS, ZHANG HF, DONG Y, et al. Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open-label randomized study[J]. J Hepatol, 2018, 68( 6): 1123- 1128. DOI: 10.1016/j.jhep.2018.01.037.
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