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ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 8
Aug.  2022
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Article Navigation >  Journal of Clinical Hepatology  > 2022  >  38(8): 1721-1725

Influencing factors for the functional cure of chronic hepatitis B and related mechanism

DOI: 10.3969/j.issn.1001-5256.2022.08.004
  • 1.

    National Medical Center for Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China

  • 2.

    Shanghai Institute of Major Infectious Diseases and Biosafety, Shanghai 200032, China

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  • Corresponding author: ZHANG Jiming, jmzhang@fudan.edu.cn(ORCID: 0000-0001-5820-950X)
  • Received Date: 2022-06-30
  • Accepted Date: 2022-07-31
  • Published Date: 2022-08-20
    Abstract
  • Functional cure of chronic hepatitis B (CHB), defined as negative hepatitis B surface antigen (HBsAg) with or without the presence of hepatitis B surface antibody (anti-HBs), is considered the optimal endpoint for CHB treatment at present. Studies have shown that HBsAg clearance can reduce the risk of HBV complications such as liver cirrhosis and hepatocellular carcinoma. However, HBsAg clearance rate remains at a relatively low level, which may be associated with the immune tolerance state caused by HBV infection. HBsAg clearance and/or the presence of anti-HBs indicate the partial recovery of HBV-specific immunity. This article discusses the influencing factors for the functional cure of CHB and the underlying mechanisms.

     

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  • [1]
    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.
    [2]
    YIP TC, WONG GL, CHAN HL, et al. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues[J]. J Hepatol, 2019, 70(3): 361-370. DOI: 10.1016/j.jhep.2018.10.014.
    [3]
    SIMONETTI J, BULKOW L, MCMAHON BJ, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus[J]. Hepatology, 2010, 51(5): 1531-1537. DOI: 10.1002/hep.23464.
    [4]
    ZHOU K, CONTAG C, WHITAKER E, et al. Spontaneous loss of surface antigen among adults living with chronic hepatitis B virus infection: a systematic review and pooled meta-analyses[J]. Lancet Gastroenterol Hepatol, 2019, 4(3): 227-238. DOI: 10.1016/S2468-1253(18)30308-X.
    [5]
    CAO Z, LIU Y, MA L, et al. A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha[J]. Hepatology, 2017, 66(4): 1058-1066. DOI: 10.1002/hep.29213.
    [6]
    SONNEVELD MJ, CHIU SM, PARK JY, et al. Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels[J]. J Hepatol, 2022, 76(5): 1042-1050. DOI: 10.1016/j.jhep.2022.01.007.
    [7]
    HIRODE G, CHOI H, CHEN CH, et al. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: An international, multicenter, multiethnic cohort (RETRACT-B Study)[J]. Gastroenterology, 2022, 162(3): 757-771. e4. DOI: 10.1053/j.gastro.2021.11.002.
    [8]
    PFEFFERKORN M, SCHOTT T, BÖHM S, et al. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B[J]. J Hepatol, 2021, 74(2): 283-292. DOI: 10.1016/j.jhep.2020.08.039.
    [9]
    TIAN Y, KUO CF, AKBARI O, et al. Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission[J]. Immunity, 2016, 44(5): 1204-1214. DOI: 10.1016/j.immuni.2016.04.008.
    [10]
    FUNG J, WONG DK, SETO WK, et al. Hepatitis B surface antigen seroclearance: Relationship to hepatitis B e-antigen seroclearance and hepatitis B e-antigen-negative hepatitis[J]. Am J Gastroenterol, 2014, 109(11): 1764-1770. DOI: 10.1038/ajg.2014.301.
    [11]
    WONG D, LITTLEJOHN M, YUEN L, et al. HBeAg levels at week 24 predict response to 8 years of tenofovir in HBeAg-positive chronic hepatitis B patients[J]. Aliment Pharmacol Ther, 2018, 47(1): 114-122. DOI: 10.1111/apt.14362.
    [12]
    HOU FQ, SONG LW, YUAN Q, et al. Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon[J]. Theranostics, 2015, 5(3): 218-226. DOI: 10.7150/thno.10636.
    [13]
    BRAKENHOFF SM, de KNEGT RJ, OLIVEIRA J, et al. Anti-HBc levels are associated with liver inflammation and response to peginterferon in chronic hepatitis B patients[J]. J Infect Dis, 2022. DOI: 10.1093/infdis/jiac210.[Online ahead of print]
    [14]
    TESTONI B, LEBOSSÉ F, SCHOLTES C, et al. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients[J]. J Hepatol, 2019, 70(4): 615-625. DOI: 10.1016/j.jhep.2018.11.030.
    [15]
    LIU J, YANG HI, LEE MH, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study[J]. Gastroenterology, 2010, 139(2): 474-482. DOI: 10.1053/j.gastro.2010.04.048.
    [16]
    VELKOV S, OTT JJ, PROTZER U, et al. The global hepatitis B virus genotype distribution approximated from available genotyping data[J]. Genes (Basel), 2018, 9(10): 495. DOI: 10.3390/genes9100495.
    [17]
    TSENG TC, LIU CJ, CHEN CL, et al. Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection[J]. Aliment Pharmacol Ther, 2015, 41(10): 949-960. DOI: 10.1111/apt.13170.
    [18]
    HEATHCOTE EJ, MARCELLIN P, BUTI M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B[J]. Gastroenterology, 2011, 140(1): 132-143. DOI: 10.1053/j.gastro.2010.10.011.
    [19]
    JANSSEN HL, VAN ZONNEVELD M, SENTURK H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial[J]. Lancet, 2005, 365(9454): 123-129. DOI: 10.1016/S0140-6736(05)17701-0.
    [20]
    TERRAULT NA, WAHED AS, FELD JJ, et al. Incidence and prediction of HBsAg seroclearance in a prospective multi-ethnic HBeAg-negative chronic hepatitis B cohort[J]. Hepatology, 2022, 75(3): 709-723. DOI: 10.1002/hep.32231.
    [21]
    WANG L, ZHAO J, LIU J, et al. Long-term benefits of interferon-α therapy in children with HBeAg-positive immune-active chronic hepatitis B[J]. J Viral Hepat, 2021, 28(11): 1554-1562. DOI: 10.1111/jvh.13598.
    [22]
    YAO N, WANG J, WU Y, et al. Frequent alanine aminotransferase flares and promising antiviral therapy efficacy during the preschool age: An opportunity to achieve HBsAg loss in children with mother-to-child transmitted hepatitis B[J]. J Viral Hepat, 2022. DOI: 10.1111/jvh.13720. [Online ahead of print]
    [23]
    HUANG J, ZHANG K, CHEN W, et al. Switching to PegIFNα-2b leads to HBsAg loss in patients with low HBsAg levels and HBV DNA suppressed by NAs[J]. Sci Rep, 2017, 7(1): 13383. DOI: 10.1038/s41598-017-13747-9.
    [24]
    BOURLIÈRE M, RABIEGA P, GANNE-CARRIE N, et al. Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial[J]. Lancet Gastroenterol Hepatol, 2017, 2(3): 177-188. DOI: 10.1016/S2468-1253(16)30189-3.
    [25]
    QIU K, LIU B, LI SY, et al. Systematic review with meta-analysis: combination treatment of regimens based on pegylated interferon for chronic hepatitis B focusing on hepatitis B surface antigen clearance[J]. Aliment Pharmacol Ther, 2018, 47(10): 1340-1348. DOI: 10.1111/apt.14629.
    [26]
    THIMME R, WIELAND S, STEIGER C, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection[J]. J Virol, 2003, 77(1): 68-76. DOI: 10.1128/jvi.77.1.68-76.2003.
    [27]
    PARK JJ, WONG DK, WAHED AS, et al. Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B[J]. Gastroenterology, 2016, 150(3): 684-695. e5. DOI: 10.1053/j.gastro.2015.11.050.
    [28]
    XIONG S, ZHU D, LIANG B, et al. Longitudinal characterization of phenotypic profile of T cells in chronic hepatitis B identifies immune markers associated with HBsAg loss[J]. EBioMedicine, 2021, 69: 103464. DOI: 10.1016/j.ebiom.2021.103464.
    [29]
    KIM JH, GHOSH A, AYITHAN N, et al. Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients[J]. Sci Rep, 2020, 10(1): 1835. DOI: 10.1038/s41598-020-58870-2.
    [30]
    ALIABADI E, URBANEK-QUAING M, MAASOUMY B, et al. Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection[J]. Gut, 2021. DOI: 10.1136/gutjnl-2021-324646. [Online ahead of print]
    [31]
    LE BERT N, GILL US, HONG M, et al. Effects of hepatitis B surface antigen on virus-specific and global T cells in patients with chronic hepatitis B virus infection[J]. Gastroenterology, 2020, 159(2): 652-664. DOI: 10.1053/j.gastro.2020.04.019.
    [32]
    HOOGEVEEN RC, DIJKSTRA S, BARTSCH LM, et al. Hepatitis B virus-specific CD4 T-cell responses differentiate functional cure from chronic surface antigen+ infection[J]. J Hepatol, 2022. DOI: 10.1016/j.jhep.2022.05.041. [Online ahead of print]
    [33]
    SETO WK, CHAN TS, HWANG YY, et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study[J]. J Clin Oncol, 2014, 32(33): 3736-3743. DOI: 10.1200/JCO.2014.56.7081.
    [34]
    LE BERT N, SALIMZADEH L, GILL US, et al. Comparative characterization of B cells specific for HBV nucleocapsid and envelope proteins in patients with chronic hepatitis B[J]. J Hepatol, 2020, 72(1): 34-44. DOI: 10.1016/j.jhep.2019.07.015.
    [35]
    BURTON AR, PALLETT LJ, MCCOY LE, et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B[J]. J Clin Invest, 2018, 128(10): 4588-4603. DOI: 10.1172/JCI121960.
    [36]
    SALIMZADEH L, LE BERT N, DUTERTRE CA, et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection[J]. J Clin Invest, 2018, 128(10): 4573-4587. DOI: 10.1172/JCI121957.
    [37]
    XU H, LOCARNINI S, WONG D, et al. Role of anti-HBs in functional cure of HBeAg+ chronic hepatitis B patients infected with HBV genotype A[J]. J Hepatol, 2022, 76(1): 34-45. DOI: 10.1016/j.jhep.2021.07.031.
    [38]
    DUNN C, PEPPA D, KHANNA P, et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection[J]. Gastroenterology, 2009, 137(4): 1289-1300. DOI: 10.1053/j.gastro.2009.06.054.
    [39]
    YANG F, YU X, ZHOU C, et al. Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection[J]. PLoS Pathog, 2019, 15(4): e1007690. DOI: 10.1371/journal.ppat.1007690.
    [40]
    VISVANATHAN K, SKINNER NA, THOMPSON AJ, et al. Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein[J]. Hepatology, 2007, 45(1): 102-110. DOI: 10.1002/hep.21482.
    [41]
    MITRA B, WANG J, KIM ES, et al. Hepatitis B virus precore protein p22 inhibits alpha interferon signaling by blocking STAT nuclear translocation[J]. J Virol, 2019, 93(13): e00196-19. DOI: 10.1128/JVI.00196-19.
    [42]
    OP DEN BROUW ML, BINDA RS, van ROOSMALEN MH, et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus[J]. Immunology, 2009, 126(2): 280-289. DOI: 10.1111/j.1365-2567.2008.02896.x.
    [43]
    BJÖRKSTRÖM NK, STRUNZ B, LJUNGGREN HG. Natural killer cells in antiviral immunity[J]. Nat Rev Immunol, 2022, 22(2): 112-123. DOI: 10.1038/s41577-021-00558-3.
    [44]
    NISHIO A, BOLTE FJ, TAKEDA K, et al. Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection[J]. Sci Transl Med, 2021, 13(587): eaba6322. DOI: 10.1126/scitranslmed.aba6322.
    [45]
    FANG Z, ZHANG Y, ZHU Z, et al. Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV[J]. J Exp Med, 2022, 219(4): e20211838. DOI: 10.1084/jem.20211838.
    [46]
    WANG H, LUO H, WAN X, et al. TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection[J]. J Hepatol, 2020, 72(1): 45-56. DOI: 10.1016/j.jhep.2019.08.024.
    [47]
    LUCIFORA J, XIA Y, REISINGER F, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA[J]. Science, 2014, 343(6176): 1221-1228. DOI: 10.1126/science.1243462.
    [48]
    TAN AT, HOANG LT, CHIN D, et al. Reduction of HBV replication prolongs the early immunological response to IFNα therapy[J]. J Hepatol, 2014, 60(1): 54-61. DOI: 10.1016/j.jhep.2013.08.020.
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