Download PDF
Semin Liver Dis 2024; 44(04): 474-491
DOI: 10.1055/a-2448-4157
Review Article

HBV Biomarkers and Their Role in Guiding Treatment Decisions

Lung-Yi Mak
1   Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
2   Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
,
Tobias Boettler
3   Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
,
Upkar S. Gill
1   Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
› Author Affiliations
› Further Information
    Permissions and Reprints


Abstract

Over 300 million individuals worldwide are chronically infected with hepatitis B virus and at risk for progressive liver disease. Due to the lack of a therapy that reliably achieves viral elimination and the variability of liver disease progression, treatment decisions are guided by the degree of liver disease and viral biomarkers as the viral life-cycle is well characterized and largely conserved between individuals. In contrast, the immunological landscape is much more heterogeneous and diverse and the measurement of its components is less well standardized. Due to the lack of a universal and easily measurable set of biomarkers, clinical practice guidelines remain controversial, aiming for a balance between simplifying treatment decisions by reducing biomarker requirements and using all available biomarkers to avoid overtreatment of patients with low risk for disease progression. While approved therapies such as nucleos(t)ide analogs improve patient outcomes, the inability to achieve a complete cure highlights the need for novel therapies. Since no treatment candidate has demonstrated universal efficacy, biomarkers will remain important for treatment stratification. Here, we summarize the current knowledge on virological and immunological biomarkers with a specific focus on how they might be beneficial in guiding treatment decisions in chronic hepatitis B.

Keywords

functional cure - finite treatment - risk stratification - treatment response - host–viral interaction


Publication History

Accepted Manuscript online:
23 October 2024

Article published online:
19 November 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 GBD 2019 Hepatitis B Collaborators. Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol 2022; 7 (09) 796-829
    CrossrefPubMedSearch in Google Scholar
  • 2 Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol 2018; 3 (06) 383-403
    CrossrefPubMedSearch in Google Scholar
  • 3 Global Hepatitis Report 2017. Geneva: World Health Organization; 2017
    Search in Google Scholar
  • 4 Razavi-Shearer D. The incidence of chronic HBV by age at the global and regional level, 2022. The Liver Meeting 2022. Washington, DC: Hepatology; 2022
    Search in Google Scholar
  • 5 McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009; 49 (5, Suppl): S45-S55
    CrossrefPubMedSearch in Google Scholar
  • 6 Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet 2014; 384 (9959): 2053-2063
    CrossrefPubMedSearch in Google Scholar
  • 7 Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003; 23 (01) 47-58
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Anderson RT, Choi HSJ, Lenz O. et al. Association between seroclearance of hepatitis B surface antigen and long-term clinical outcomes of patients with chronic hepatitis B virus infection: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021; 19 (03) 463-472
    CrossrefPubMedSearch in Google Scholar
  • 9 Yeo YH, Ho HJ, Yang HI. et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology 2019; 156 (03) 635-646.e9
    CrossrefPubMedSearch in Google Scholar
  • 10 Yuen MF, Wong DK, Fung J. et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008; 135 (04) 1192-1199
    CrossrefPubMedSearch in Google Scholar
  • 11 Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet 2023; 401 (10381): 1039-1052
    CrossrefPubMedSearch in Google Scholar
  • 12 Huang DQ, Li X, Le MH. et al. Natural history and hepatocellular carcinoma risk in untreated chronic hepatitis B patients with indeterminate phase. Clin Gastroenterol Hepatol 2022; 20 (08) 1803-1812.e5
    CrossrefPubMedSearch in Google Scholar
  • 13 Huang DQ, Tran A, Yeh ML. et al. Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase. Hepatology 2023; 78 (05) 1558-1568
    CrossrefPubMedSearch in Google Scholar
  • 14 Su TH, Kao JH. Improving clinical outcomes of chronic hepatitis B virus infection. Expert Rev Gastroenterol Hepatol 2015; 9 (02) 141-154
    CrossrefPubMedSearch in Google Scholar
  • 15 Zhu Y, Yamamoto T, Cullen J. et al. Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J Virol 2001; 75 (01) 311-322
    CrossrefPubMedSearch in Google Scholar
  • 16 Schmid J, Langhorst J, Gaß F. et al. Placebo analgesia in patients with functional and organic abdominal pain: a fMRI study in IBS, UC and healthy volunteers. Gut 2015; 64 (03) 418-427
    CrossrefPubMedSearch in Google Scholar
  • 17 Berg T, Simon KG, Mauss S. et al; FINITE CHB study investigators [First investigation in stopping TDF treatment after long-term virological suppression in HBeAg-negative chronic hepatitis B]. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol 2017; 67 (05) 918-924
    CrossrefPubMedSearch in Google Scholar
  • 18 Terrault NA, Lok ASF, McMahon BJ. et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67 (04) 1560-1599
    CrossrefPubMedSearch in Google Scholar
  • 19 European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67: 370-398
    CrossrefPubMedSearch in Google Scholar
  • 20 Sarin SK, Kumar M, Lau GK. et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016; 10 (01) 1-98
    CrossrefPubMedSearch in Google Scholar
  • 21 Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. Volume 2024. World Health Organization; Geneva, Switzerland: 2024
    Search in Google Scholar
  • 22 Ghany MG, Buti M, Lampertico P, Lee HM. 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference Faculty. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference. Hepatology 2023; 78 (05) 1654-1673
    CrossrefPubMedSearch in Google Scholar
  • 23 Cornberg M, Lok AS, Terrault NA, Zoulim F. 2019 EASL-AASLD HBV Treatment Endpoints Conference Faculty. Guidance for design and endpoints of clinical trials in chronic hepatitis B - report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology 2019
    PubMedSearch in Google Scholar
  • 24 Liaw YF. Hepatitis B flare: the good, the bad and the ugly. Expert Rev Gastroenterol Hepatol 2022; 16 (11-12): 1043-1051
    CrossrefPubMedSearch in Google Scholar
  • 25 Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology 2015; 479-480: 672-686
    CrossrefPubMedSearch in Google Scholar
  • 26 Rydell GE, Prakash K, Larsson SB. et al. Quantification of viral RNA in multiple pieces of explant liver tissue shows distinct focal differences in hepatitis B infection. J Infect Dis 2022; 226 (06) 1036-1040
    CrossrefPubMedSearch in Google Scholar
  • 27 Neuberger J, Patel J, Caldwell H. et al. Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology. Gut 2020; 69 (08) 1382-1403
    CrossrefPubMedSearch in Google Scholar
  • 28 Mani H, Kleiner DE. Liver biopsy findings in chronic hepatitis B. Hepatology 2009; 49 (5, Suppl): S61-S71
    CrossrefPubMedSearch in Google Scholar
  • 29 Gill US, Pallett LJ, Thomas N. et al. Fine needle aspirates comprehensively sample intrahepatic immunity. Gut 2019; 68 (08) 1493-1503
    CrossrefPubMedSearch in Google Scholar
  • 30 Testoni B, Roca Suarez AA, Battisti A. et al. Evaluation of the HBV liver reservoir with fine needle aspirates. JHEP Rep Innov Hepatol 2023; 5 (10) 100841
    CrossrefPubMedSearch in Google Scholar
  • 31 Rabe B, Vlachou A, Panté N, Helenius A, Kann M. Nuclear import of hepatitis B virus capsids and release of the viral genome. Proc Natl Acad Sci U S A 2003; 100 (17) 9849-9854
    CrossrefPubMedSearch in Google Scholar
  • 32 Yuen MF, Chen DS, Dusheiko GM. et al. Hepatitis B virus infection. Nat Rev Dis Primers 2018; 4: 18035
    CrossrefPubMedSearch in Google Scholar
  • 33 Zhao XL, Yang JR, Lin SZ. et al. Serum viral duplex-linear DNA proportion increases with the progression of liver disease in patients infected with HBV. Gut 2016; 65 (03) 502-511
    CrossrefPubMedSearch in Google Scholar
  • 34 Wong DK, Yuen MF, Yuan H. et al. Quantitation of covalently closed circular hepatitis B virus DNA in chronic hepatitis B patients. Hepatology 2004; 40 (03) 727-737
    CrossrefPubMedSearch in Google Scholar
  • 35 Lin LY, Wong VW, Zhou HJ. et al. Relationship between serum hepatitis B virus DNA and surface antigen with covalently closed circular DNA in HBeAg-negative patients. J Med Virol 2010; 82 (09) 1494-1500
    CrossrefPubMedSearch in Google Scholar
  • 36 Guner R, Karahocagil M, Buyukberber M. et al. Correlation between intrahepatic hepatitis B virus cccDNA levels and other activity markers in patients with HBeAg-negative chronic hepatitis B infection. Eur J Gastroenterol Hepatol 2011; 23 (12) 1185-1191
    CrossrefPubMedSearch in Google Scholar
  • 37 Gao Y, Li Y, Meng Q. et al. Serum hepatitis B virus DNA, RNA, and HBsAg: which correlated better with intrahepatic covalently closed circular DNA before and after Nucleos(t)ide analogue treatment?. J Clin Microbiol 2017; 55 (10) 2972-2982
    CrossrefPubMedSearch in Google Scholar
  • 38 Chen CJ, Yang HI, Iloeje UH. REVEAL-HBV Study Group. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology 2009; 49 (5, Suppl): S72-S84
    CrossrefPubMedSearch in Google Scholar
  • 39 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 Gastroenterol 2021; 56 (05) 479-488
    CrossrefPubMedSearch in Google Scholar
  • 40 Yuan HJ, Ka-Ho Wong D, Doutreloigne J, Sablon E, Lai CL, Yuen MF. Precore and core promoter mutations at the time of HBeAg seroclearance in Chinese patients with chronic hepatitis B. J Infect 2007; 54 (05) 497-503
    CrossrefPubMedSearch in Google Scholar
  • 41 Yuen MF, Tanaka Y, Fong DY. et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol 2009; 50 (01) 80-88
    CrossrefPubMedSearch in Google Scholar
  • 42 Mak LY, Cloherty G, Wong DK. et al. HBV RNA profiles in patients with chronic hepatitis B under different disease phases and antiviral therapy. Hepatology 2021; 73 (06) 2167-2179
    CrossrefPubMedSearch in Google Scholar
  • 43 Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50 (03) 661-662
    CrossrefPubMedSearch in Google Scholar
  • 44 Ma H, Yang RF, Wei L. Quantitative serum HBsAg and HBeAg are strong predictors of sustained HBeAg seroconversion to pegylated interferon alfa-2b in HBeAg-positive patients. J Gastroenterol Hepatol 2010; 25 (09) 1498-1506
    CrossrefPubMedSearch in Google Scholar
  • 45 Geng M, Li Y, Gao F. et al. A scoring model predicts hepatitis B e antigen seroconversion in chronic hepatitis B patients treated with nucleos(t)ide analogs: real-world clinical practice. Int J Infect Dis 2017; 62: 18-25
    CrossrefPubMedSearch in Google Scholar
  • 46 Wooddell CI, Yuen MF, Chan HL. et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med 2017; 9 (409) 9
    CrossrefPubMedSearch in Google Scholar
  • 47 Pfefferkorn M, Böhm S, Schott T. et al. Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers. Gut 2018; 67 (11) 2045-2053
    CrossrefPubMedSearch in Google Scholar
  • 48 Zacher BJ, Moriconi F, Bowden S. et al. Multicenter evaluation of the Elecsys hepatitis B surface antigen quantitative assay. Clin Vaccine Immunol 2011; Nov; 18 (11) 1943-1950
    CrossrefPubMedSearch in Google Scholar
  • 49 Maylin S, Boyd A, Delaugerre C. et al. Comparison between Elecsys HBsAg II and architect HBsAg QT assays for quantification of hepatitis B surface antigen among patients coinfected with HIV and hepatitis B virus. Clin Vaccine Immunol 2012; 19 (02) 242-248
    CrossrefPubMedSearch in Google Scholar
  • 50 Wursthorn K, Jaroszewicz J, Zacher BJ. et al. Correlation between the Elecsys HBsAg II assay and the Architect assay for the quantification of hepatitis B surface antigen (HBsAg) in the serum. J Clin Virol 2011; 50 (04) 292-296
    CrossrefPubMedSearch in Google Scholar
  • 51 Lou S, Taylor R, Pearce S, Kuhns M, Leary T. An ultra-sensitive Abbott ARCHITECT® assay for the detection of hepatitis B virus surface antigen (HBsAg). J Clin Virol 2018; 105: 18-25
    CrossrefPubMedSearch in Google Scholar
  • 52 Matsumoto A, Imaizumi M, Tanaka Y. et al. Novel and highly sensitive immunoassay for total hepatitis B surface antigen, including that complexed with hepatitis B surface antibody. J Gastroenterol 2017; 52 (03) 376-384
    CrossrefPubMedSearch in Google Scholar
  • 53 Shinkai N, Matsuura K, Sugauchi F. et al. Application of a newly developed high-sensitivity HBsAg chemiluminescent enzyme immunoassay for hepatitis B patients with HBsAg seroclearance. J Clin Microbiol 2013; 51 (11) 3484-3491
    CrossrefPubMedSearch in Google Scholar
  • 54 Wong DK, Chen C, Mak LY, Fung J, Seto WK, Yuen MF. Detection of the hepatitis B surface antigen in patients with occult hepatitis B by use of an assay with enhanced sensitivity. J Clin Microbiol 2022; 60 (02) e0220421
    CrossrefPubMedSearch in Google Scholar
  • 55 Thompson AJ, Nguyen T, Iser D. et al. Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers. Hepatology 2010; 51 (06) 1933-1944
    CrossrefPubMedSearch in Google Scholar
  • 56 Ungtrakul T, Sriprayoon T, Kusuman P. et al. Role of quantitative hepatitis B surface antigen in predicting inactive carriers and HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients. Medicine (Baltimore) 2017; 96 (13) e6554
    CrossrefPubMedSearch in Google Scholar
  • 57 Chan HL, Thompson A, Martinot-Peignoux M. et al. Hepatitis B surface antigen quantification: why and how to use it in 2011 - a core group report. J Hepatol 2011; 55 (05) 1121-1131
    CrossrefPubMedSearch in Google Scholar
  • 58 Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. The role of HBsAg quantification for monitoring natural history and treatment outcome. Liver Int 2013; 33 (Suppl. 01) 125-132
    CrossrefPubMedSearch in Google Scholar
  • 59 Tseng TC, Kao JH. Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog. J Gastroenterol 2013; 48 (01) 13-21
    CrossrefPubMedSearch in Google Scholar
  • 60 Chen YC, Jeng WJ, Chu CM, Liaw YF. Decreasing levels of HBsAg predict HBsAg seroclearance in patients with inactive chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2012; 10 (03) 297-302
    CrossrefPubMedSearch in Google Scholar
  • 61 Lin HC, Liu J, Pan MH. et al. Rapid decline rather than absolute level of HBsAg predicts its seroclearance in untreated chronic hepatitis B patients from Taiwanese communities. Clin Transl Gastroenterol 2023; 14 (08) e00586
    CrossrefPubMedSearch in Google Scholar
  • 62 Lam YF, Seto WK, Wong D. et al. Seven-year treatment outcome of entecavir in a real-world cohort: effects on clinical parameters, HBsAg and HBcrAg levels. Clin Transl Gastroenterol 2017; 8 (10) e125
    CrossrefPubMedSearch in Google Scholar
  • 63 Singh AK, Sharma MK, Hissar SS, Gupta E, Sarin SK. Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment. J Viral Hepat 2014; 21 (06) 439-446
    CrossrefPubMedSearch in Google Scholar
  • 64 Brunetto MR, Moriconi F, Bonino F. et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009; 49 (04) 1141-1150
    CrossrefPubMedSearch in Google Scholar
  • 65 Chan HL, Fung S, Seto WK. et al; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1 (03) 185-195
    CrossrefPubMedSearch in Google Scholar
  • 66 Hara T, Suzuki F, Kawamura Y. et al. Long-term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide-naïve chronic hepatitis B patients. J Viral Hepat 2014; 21 (11) 802-808
    CrossrefPubMedSearch in Google Scholar
  • 67 Ko KL, To WP, Mak LY. et al. A large real-world cohort study examining the effects of long-term entecavir on hepatocellular carcinoma and HBsAg seroclearance. J Viral Hepat 2020; 27 (04) 397-406
    CrossrefPubMedSearch in Google Scholar
  • 68 Buti M, Tsai N, Petersen J. et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci 2015; 60 (05) 1457-1464
    CrossrefPubMedSearch in Google Scholar
  • 69 Buti M, Gane E, Seto WK. et al; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol 2016; 1 (03) 196-206
    CrossrefPubMedSearch in Google Scholar
  • 70 Wong VW, Wong GL, Yan KK. et al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010; 51 (06) 1945-1953
    CrossrefPubMedSearch in Google Scholar
  • 71 Sonneveld MJ, Hansen BE, Piratvisuth T. et al. Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels. Hepatology 2013; 58 (03) 872-880
    CrossrefPubMedSearch in Google Scholar
  • 72 Zeng G, Koffas A, Mak LY, Gill US, Kennedy PTF. Utility of novel viral and immune markers in predicting HBV treatment endpoints: a systematic review of treatment discontinuation studies. JHEP Rep Innov Hepatol 2023; 5 (06) 100720
    CrossrefPubMedSearch in Google Scholar
  • 73 Chen CH, Hung CH, Hu TH. et al. Association between level of hepatitis B surface antigen and relapse after entecavir therapy for chronic hepatitis B virus infection. Clin Gastroenterol Hepatol 2015; 13 (11) 1984-92.e1
    CrossrefPubMedSearch in Google Scholar
  • 74 Chen CH, Hung CH, Wang JH, Lu SN, Hu TH, Lee CM. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect 2018; 24 (09) 997-1003
    CrossrefPubMedSearch in Google Scholar
  • 75 Jeng WJ, Chen YC, Sheen IS. et al. Clinical relapse after cessation of tenofovir therapy in hepatitis B e antigen-negative patients. Clin Gastroenterol Hepatol 2016; 14 (12) 1813-1820.e1
    CrossrefPubMedSearch in Google Scholar
  • 76 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 Hepatol 2021; 74 (02) 283-292
    CrossrefPubMedSearch in Google Scholar
  • 77 Mak LY, Wong DK, Cheung KS, Seto WK, Lai CL, Yuen MF. Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection. Aliment Pharmacol Ther 2018; 47 (01) 43-54
    CrossrefPubMedSearch in Google Scholar
  • 78 Kimura T, Rokuhara A, Sakamoto Y. et al. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol 2002; 40 (02) 439-445
    CrossrefPubMedSearch in Google Scholar
  • 79 Beudeker BJ, Groothuismink ZM, de Man RA. et al. Hepatitis B core-related antigen levels predict pegylated interferon-α therapy response in HBeAg-positive chronic hepatitis B. Antivir Ther 2020; 25 (04) 217-222
    CrossrefPubMedSearch in Google Scholar
  • 80 Chuaypen N, Posuwan N, Payungporn S. et al. Serum hepatitis B core-related antigen as a treatment predictor of pegylated interferon in patients with HBeAg-positive chronic hepatitis B. Liver Int 2016; 36 (06) 827-836
    CrossrefPubMedSearch in Google Scholar
  • 81 Adraneda C, Tan YC, Yeo EJ, Kew GS, Khakpoor A, Lim SG. A critique and systematic review of the clinical utility of hepatitis B core-related antigen. J Hepatol 2023; 78 (04) 731-741
    CrossrefPubMedSearch in Google Scholar
  • 82 Inoue T, Kusumoto S, Iio E. et al. Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management of chronic hepatitis B and HBV reactivation. J Hepatol 2021; 75 (02) 302-310
    CrossrefPubMedSearch in Google Scholar
  • 83 Shimakawa Y, Ndow G, Kaneko A. et al. Rapid point-of-care test for hepatitis B core-related antigen to diagnose high viral load in resource-limited settings. Clin Gastroenterol Hepatol 2023; 21 (07) 1943-1946.e2
    CrossrefPubMedSearch in Google Scholar
  • 84 Rokuhara A, Sun X, Tanaka E. et al. Hepatitis B virus core and core-related antigen quantitation in Chinese patients with chronic genotype B and C hepatitis B virus infection. J Gastroenterol Hepatol 2005; 20 (11) 1726-1730
    CrossrefPubMedSearch in Google Scholar
  • 85 Geissler R, Patel M, Anderson M, Vaillant A, Qiu X, Cloherty G. Novel fully automated prototype assays for specific detection of phosphorylated and non-phosphorylated hepatitis B core antigens. J Clin Virol 2023; 166: 105529
    CrossrefPubMedSearch in Google Scholar
  • 86 Lee HA, Lee HW, Park Y, Kim HS, Seo YS. Hepatitis B core-related antigen is useful for predicting phase and prognosis of hepatitis B e antigen-positive patients. J Clin Med 2022; 11 (06) 11
    CrossrefPubMedSearch in Google Scholar
  • 87 Ghany MG, King WC, Hinerman AS. et al. Use of HBV RNA and to predict change in serological status and disease activity in CHB. Hepatology 2023; 78 (05) 1542-1557
    PubMedSearch in Google Scholar
  • 88 Tseng TC, Hosaka T, Liu CJ. et al. Hepatitis B core-related antigen stratifies the risk of liver cancer in HBeAg-negative patients with indeterminate phase. Am J Gastroenterol 2022; 117 (05) 748-757
    CrossrefPubMedSearch in Google Scholar
  • 89 Wu JW, Kao JH, Tseng TC. Three heads are better than two: hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma. Clin Mol Hepatol 2021; 27 (04) 524-534
    CrossrefPubMedSearch in Google Scholar
  • 90 Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020; 26 (03) 261-279
    CrossrefPubMedSearch in Google Scholar
  • 91 Cheung KS, Seto WK, Wong DK, Lai CL, Yuen MF. Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy. J Viral Hepat 2017; 24 (08) 654-661
    CrossrefPubMedSearch in Google Scholar
  • 92 Honda M, Shirasaki T, Terashima T. et al. Hepatitis B virus (HBV) core-related antigen during nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis 2016; 213 (07) 1096-1106
    CrossrefPubMedSearch in Google Scholar
  • 93 Mak LY, Ko KL, To WP. et al. Entecavir reduced serum hepatitis B core-related antigen in chronic hepatitis B patients with hepatocellular carcinoma. Gut Liver 2020; 14 (05) 665-668
    CrossrefPubMedSearch in Google Scholar
  • 94 Sonneveld MJ, Park JY, Kaewdech A. et al; CREATE Study Group. Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels: a multicenter study (CREATE). Clin Gastroenterol Hepatol 2022; 20 (04) e784-e793
    CrossrefPubMedSearch in Google Scholar
  • 95 Kuo YH, Wang JH, Hung CH, Lu SN, Hu TH, Chen CH. Combining end-of-treatment HBsAg and baseline hepatitis B core-related antigen reduce HBV relapse rate after tenofovir cessation. Hepatol Int 2021; 15 (02) 301-309
    CrossrefPubMedSearch in Google Scholar
  • 96 Huang PY, Wang JH, Hung CH, Lu SN, Hu TH, Chen CH. The role of hepatitis B virus core-related antigen in predicting hepatitis B virus relapse after cessation of entecavir in hepatitis B e antigen-negative patients. J Viral Hepat 2021; 28 (08) 1141-1149
    CrossrefPubMedSearch in Google Scholar
  • 97 Hirode G, Choi HSJ, Chen CH. et al; RETRACT-B Study Group. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: an international, multicenter, multiethnic cohort (RETRACT-B Study). Gastroenterology 2022; 162 (03) 757-771.e4
    CrossrefPubMedSearch in Google Scholar
  • 98 Berg T, Lampertico P. The times they are a-changing - a refined proposal for finite HBV nucleos(t)ide analogue therapy. J Hepatol 2021; 75 (02) 474-480
    CrossrefPubMedSearch in Google Scholar
  • 99 Mak LY, Wong D, Kuchta A. et al. HBV pgRNA and HBcrAg reductions at week 4 predict favourable HBsAg response upon long-term nucleos(t)ide analogue in CHB. Clin Mol Hepatol 2022
    PubMedSearch in Google Scholar
  • 100 Deng R, Liu S, Shen S, Guo H, Sun J. Circulating HBV RNA: from biology to clinical applications. Hepatology 2022; 76 (05) 1520-1530
    CrossrefPubMedSearch in Google Scholar
  • 101 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 Hepatol 2016; 65 (04) 700-710
    CrossrefPubMedSearch in Google Scholar
  • 102 Anderson M, Gersch J, Luk KC. et al. Circulating pregenomic hepatitis B virus RNA is primarily full-length in chronic hepatitis B patients undergoing nucleos(t)ide analogue therapy. Clin Infect Dis 2021; 72 (11) 2029-2031
    CrossrefPubMedSearch in Google Scholar
  • 103 van Bömmel F, Bartens A, Mysickova A. et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology 2015; 61 (01) 66-76
    CrossrefPubMedSearch in Google Scholar
  • 104 Butler EK, Gersch J, McNamara A. et al. Hepatitis B virus serum DNA andRNA levels in nucleos(t)ide analog-treated or untreated patients during chronic and acute infection. Hepatology 2018; 68 (06) 2106-2117
    CrossrefPubMedSearch in Google Scholar
  • 105 Wang Y, Liu Y, Liao H. et al. Serum HBV DNA plus RNA reflecting cccDNA level before and during NAs treatment in HBeAg positive CHB patients. Int J Med Sci 2022; 19 (05) 858-866
    CrossrefPubMedSearch in Google Scholar
  • 106 Wang J, Yu Y, Li G. et al. Natural history of serum HBV-RNA in chronic HBV infection. J Viral Hepat 2018; 25 (09) 1038-1047
    CrossrefPubMedSearch in Google Scholar
  • 107 Testoni B, Scholtès C, Plissonnier ML. et al. Quantification of circulating HBV RNA expressed from intrahepatic cccDNA in untreated and NUC treated patients with chronic hepatitis B. Gut 2024; 73 (04) 659-667
    CrossrefPubMedSearch in Google Scholar
  • 108 Cortese MF, Riveiro-Barciela M, Tabernero D. et al. Standardized hepatitis B virus RNA quantification in untreated and treated chronic patients: a promising marker of infection follow-up. Microbiol Spectr 2022; 10 (02) e0214921
    CrossrefPubMedSearch in Google Scholar
  • 109 Scholtès C, Hamilton AT, Plissonnier ML. et al. Performance of the cobas® HBV RNA automated investigational assay for the detection and quantification of circulating HBV RNA in chronic HBV patients. J Clin Virol 2022; 150-151: 105150
    CrossrefPubMedSearch in Google Scholar
  • 110 Wang X, Chi X, Wu R. et al. Serum HBV RNA correlated with intrahepatic cccDNA more strongly than other HBV markers during peg-interferon treatment. Virol J 2021; 18 (01) 4
    CrossrefPubMedSearch in Google Scholar
  • 111 Farag MS, van Campenhout MJH, Pfefferkorn M. et al. Hepatitis B virus RNA as early predictor for response to pegylated interferon alpha in HBeAg-negative chronic hepatitis B. Clin Infect Dis 2021; 72 (02) 202-211
    CrossrefPubMedSearch in Google Scholar
  • 112 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. Gastroenterology 2019; 156 (05) 1392-1403.e7
    CrossrefPubMedSearch in Google Scholar
  • 113 Yuen MF, Asselah T, Jacobson IM. et al; REEF-1 Study Group. Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. Lancet Gastroenterol Hepatol 2023; 8 (09) 790-802
    CrossrefPubMedSearch in Google Scholar
  • 114 Seto WK, Liu KS, Mak LY. et al. Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation. Gut 2021; 70 (04) 775-783
    CrossrefPubMedSearch in Google Scholar
  • 115 Fan R, Peng J, Xie Q. et al; Chronic Hepatitis B Study Consortium. Combining hepatitis B virus RNA and hepatitis B core-related antigen: guidance for safely stopping nucleos(t)ide analogues in hepatitis B e antigen-positive patients with chronic hepatitis B. J Infect Dis 2020; 222 (04) 611-618
    CrossrefPubMedSearch in Google Scholar
  • 116 Papatheodoridi M, Papachristou E, Moschidis Z. et al. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy. J Viral Hepat 2022; 29 (11) 948-957
    CrossrefPubMedSearch in Google Scholar
  • 117 Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016; 64 (1, Suppl): S71-S83
    CrossrefPubMedSearch in Google Scholar
  • 118 Thimme R, Wieland S, Steiger C. et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003; 77 (01) 68-76
    CrossrefPubMedSearch in Google Scholar
  • 119 Roca Suarez AA, Zoulim F. Opportunities and challenges for hepatitis B cure. eGastroenterology 2023; 1: e100021
    CrossrefPubMedSearch in Google Scholar
  • 120 Kramvis A, Chang KM, Dandri M. et al. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022; 19 (11) 727-745
    CrossrefPubMedSearch in Google Scholar
  • 121 Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4+ T cells in immunity to viruses. Nat Rev Immunol 2012; 12 (02) 136-148
    CrossrefPubMedSearch in Google Scholar
  • 122 Jo J, Aichele U, Kersting N. et al. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 2009; 136 (04) 1391-1401
    CrossrefPubMedSearch in Google Scholar
  • 123 Gehring AJ, Mendez P, Richter K. et al. Immunological biomarker discovery in cure regimens for chronic hepatitis B virus infection. J Hepatol 2022; 77 (02) 525-538
    CrossrefPubMedSearch in Google Scholar
  • 124 Boni C, Fisicaro P, Valdatta C. et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007; 81 (08) 4215-4225
    CrossrefPubMedSearch in Google Scholar
  • 125 Boettler T, Gill US, Allweiss L, Pollicino T, Tavis JE, Zoulim F. Assessing immunological and virological responses in the liver: implications for the cure of chronic hepatitis B virus infection. JHEP Rep Innov Hepatol 2022; 4 (06) 100480
    CrossrefPubMedSearch in Google Scholar
  • 126 Boni C, Laccabue D, Lampertico P. et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143 (04) 963-73.e9
    CrossrefPubMedSearch in Google Scholar
  • 127 Rivino L, Le Bert N, Gill US. et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest 2018; 128 (02) 668-681
    CrossrefPubMedSearch in Google Scholar
  • 128 Rossi M, Vecchi A, Tiezzi C. et al. Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro. Gut 2023; 72 (11) 2123-2137
    CrossrefPubMedSearch in Google Scholar
  • 129 Jacobi FJ, Wild K, Smits M. et al. OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection. J Hepatol 2019; 70 (06) 1103-1113
    CrossrefPubMedSearch in Google Scholar
  • 130 Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol 2014; 61 (06) 1212-1219
    CrossrefPubMedSearch in Google Scholar
  • 131 Vanwolleghem T, Adomati T, Van Hees S, Janssen HLA. Humoral immunity in hepatitis B virus infection: rehabilitating the B in HBV. JHEP Rep Innov Hepatol 2021; 4 (02) 100398
    CrossrefPubMedSearch in Google Scholar
  • 132 Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology 2017; 152 (06) 1297-1309
    CrossrefPubMedSearch in Google Scholar
  • 133 Corti D, Lanzavecchia A. Broadly neutralizing antiviral antibodies. Annu Rev Immunol 2013; 31: 705-742
    CrossrefPubMedSearch in Google Scholar
  • 134 Gerlich WH. Medical virology of hepatitis B: how it began and where we are now. Virol J 2013; 10: 239
    CrossrefPubMedSearch in Google Scholar
  • 135 Dusheiko GM, Hoofnagle JH, Cooksley WG, James SP, Jones EA. Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers. J Clin Invest 1983; 71 (05) 1104-1113
    CrossrefPubMedSearch in Google Scholar
  • 136 Maini MK, Burton AR. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat Rev Gastroenterol Hepatol 2019; 16 (11) 662-675
    CrossrefPubMedSearch in Google Scholar
  • 137 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 Clin Invest 2018; 128 (10) 4573-4587
    CrossrefPubMedSearch in Google Scholar
  • 138 Burton AR, Pallett LJ, McCoy LE. et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest 2018; 128 (10) 4588-4603
    CrossrefPubMedSearch in Google Scholar
  • 139 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 Hepatol 2020; 72 (01) 34-44
    CrossrefPubMedSearch in Google Scholar
  • 140 Vanwolleghem T, Groothuismink ZMA, Kreefft K, Hung M, Novikov N, Boonstra A. Hepatitis B core-specific memory B cell responses associate with clinical parameters in patients with chronic HBV. J Hepatol 2020; 73 (01) 52-61
    CrossrefPubMedSearch in Google Scholar
  • 141 Sanz I, Wei C, Jenks SA. et al. Challenges and opportunities for consistent classification of human B cell and plasma cell populations. Front Immunol 2019; 10: 2458
    CrossrefPubMedSearch in Google Scholar
  • 142 Portugal S, Obeng-Adjei N, Moir S, Crompton PD, Pierce SK. Atypical memory B cells in human chronic infectious diseases: an interim report. Cell Immunol 2017; 321: 18-25
    CrossrefPubMedSearch in Google Scholar
  • 143 Poonia B, Ayithan N, Nandi M, Masur H, Kottilil S. HBV induces inhibitory FcRL receptor on B cells and dysregulates B cell-T follicular helper cell axis. Sci Rep 2018; 8 (01) 15296
    CrossrefPubMedSearch in Google Scholar
  • 144 Beasley RP, Hwang LY, Lin CC. et al. Hepatitis B immune globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state. Initial report of a randomised double-blind placebo-controlled trial. Lancet 1981; 2 (8243): 388-393
    CrossrefPubMedSearch in Google Scholar
  • 145 Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 2000; 32 (06) 1189-1195
    CrossrefPubMedSearch in Google Scholar
  • 146 Caviglia GP, Abate ML, Tandoi F. et al. Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: a new tool to detect occult infection. J Hepatol 2018; 69 (02) 301-307
    CrossrefPubMedSearch in Google Scholar
  • 147 Maruyama T, Schödel F, Iino S. et al. Distinguishing between acute and symptomatic chronic hepatitis B virus infection. Gastroenterology 1994; 106 (04) 1006-1015
    CrossrefPubMedSearch in Google Scholar
  • 148 Brakenhoff SM, de Knegt RJ, Oliveira J. et al. Levels of antibodies to hepatitis B core antigen are associated with liver inflammation and response to peginterferon in patients with chronic hepatitis B. J Infect Dis 2022; 227 (01) 113-122
    CrossrefPubMedSearch in Google Scholar
  • 149 Fan R, Sun J, Yuan Q. et al; Chronic Hepatitis B Study Consortium. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues. Gut 2016; 65 (02) 313-320
    CrossrefPubMedSearch in Google Scholar
  • 150 Cheng Y, Guindon S, Rodrigo A. et al. Cumulative viral evolutionary changes in chronic hepatitis B virus infection precedes hepatitis B e antigen seroconversion. Gut 2013; 62 (09) 1347-1355
    CrossrefPubMedSearch in Google Scholar
  • 151 Li D, He W, Liu X. et al. A potent human neutralizing antibody Fc-dependently reduces established HBV infections. eLife 2017; 6: 6
    CrossrefPubMedSearch in Google Scholar
  • 152 van der Kolk LE, Baars JW, Prins MH, van Oers MH. Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood 2002; 100 (06) 2257-2259
    CrossrefPubMedSearch in Google Scholar
  • 153 Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13 (03) 267-276
    CrossrefPubMedSearch in Google Scholar
  • 154 Chokshi S, Cooksley H, Riva A. et al. Identification of serum cytokine profiles associated with HBeAg seroconversion following antiviral treatment interruption. Viral Immunol 2014; 27 (05) 235-244
    CrossrefPubMedSearch in Google Scholar
  • 155 Schurich A, Pallett LJ, Lubowiecki M. et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog 2013; 9 (03) e1003208
    CrossrefPubMedSearch in Google Scholar
  • 156 Biron CA. Interferons alpha and beta as immune regulators – a new look. Immunity 2001; 14 (06) 661-664
    CrossrefPubMedSearch in Google Scholar
  • 157 Lei Q, Li T, Kong L. et al. HBV-Pol is crucial for HBV-mediated inhibition of inflammasome activation and IL-1β production. Liver Int 2019; 39 (12) 2273-2284
    CrossrefPubMedSearch in Google Scholar
  • 158 Bao S, Zheng J, Shi G. The role of T helper 17 cells in the pathogenesis of hepatitis B virus-related liver cirrhosis (Review). Mol Med Rep 2017; 16 (04) 3713-3719
    CrossrefPubMedSearch in Google Scholar
  • 159 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 Hepatol 2020; 72 (01) 45-56
    CrossrefPubMedSearch in Google Scholar
  • 160 Gill US, McCarthy NE. CD4 T cells in hepatitis B virus: “You don't have to be cytotoxic to work here and help”. J Hepatol 2020; 72 (01) 9-11
    CrossrefPubMedSearch in Google Scholar
  • 161 McAleer JP, Kolls JK. Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense. Immunol Rev 2014; 260 (01) 129-144
    CrossrefPubMedSearch in Google Scholar
  • 162 McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol 2006; 27 (01) 17-23
    CrossrefPubMedSearch in Google Scholar
  • 163 Zhou X, Yang F, Yang Y. et al. HBV facilitated hepatocellular carcinoma cells proliferation by up-regulating angiogenin expression through IL-6. Cell Physiol Biochem 2018; 46 (02) 461-470
    CrossrefPubMedSearch in Google Scholar
  • 164 Karimi-Googheri M, Daneshvar H, Nosratabadi R. et al. Important roles played by TGF-β in hepatitis B infection. J Med Virol 2014; 86 (01) 102-108
    CrossrefPubMedSearch in Google Scholar
  • 165 Yao Y, Li J, Lu Z. et al. Proteomic analysis of the interleukin-4 (IL-4) response in hepatitis B virus-positive human hepatocelluar carcinoma cell line HepG2.2.15. Electrophoresis 2011; 32 (15) 2004-2012
    CrossrefPubMedSearch in Google Scholar
  • 166 Das A, Ellis G, Pallant C. et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol 2012; 189 (08) 3925-3935
    CrossrefPubMedSearch in Google Scholar
  • 167 Peppa D, Micco L, Javaid A. et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 2010; 6 (12) e1001227
    CrossrefPubMedSearch in Google Scholar
  • 168 Yang K, Guan SH, Zhang H. et al. Enhanced levels of interleukin-8 are associated with hepatitis B virus infection and resistance to interferon-alpha therapy. Int J Mol Sci 2014; 15 (11) 21286-21298
    CrossrefPubMedSearch in Google Scholar
  • 169 Lee IC, Huang YH, Su CW. et al. CXCL9 associated with sustained virological response in chronic hepatitis B patients receiving peginterferon alfa-2a therapy: a pilot study. PLoS One 2013; 8 (10) e76798
    CrossrefPubMedSearch in Google Scholar
  • 170 Sonneveld MJ, Arends P, Boonstra A, Hansen BE, Janssen HL. Serum levels of interferon-gamma-inducible protein 10 and response to peginterferon therapy in HBeAg-positive chronic hepatitis B. J Hepatol 2013; 58 (05) 898-903
    CrossrefPubMedSearch in Google Scholar
  • 171 Wald O, Pappo O, Safadi R. et al. Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus. Eur J Immunol 2004; 34 (04) 1164-1174
    CrossrefPubMedSearch in Google Scholar
  • 172 Li Y, Tang L, Guo L. et al. CXCL13-mediated recruitment of intrahepatic CXCR5+CD8+ T cells favors viral control in chronic HBV infection. J Hepatol 2020; 72 (03) 420-430
    CrossrefPubMedSearch in Google Scholar
  • 173 Zhang Q, Huang H, Sun A. et al. Change of cytokines in chronic hepatitis B patients and HBeAg are positively correlated with HBV RNA, based on real-world study. J Clin Transl Hepatol 2022; 10 (03) 390-397
    CrossrefPubMedSearch in Google Scholar
  • 174 Zhong S, Zhang T, Tang L, Li Y. Cytokines and chemokines in HBV infection. Front Mol Biosci 2021; 8: 805625
    CrossrefPubMedSearch in Google Scholar
  • 175 Busca A, Kumar A. Innate immune responses in hepatitis B virus (HBV) infection. Virol J 2014; 11: 22
    CrossrefPubMedSearch in Google Scholar
  • 176 Ginhoux F, Jung S. Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 2014; 14 (06) 392-404
    CrossrefPubMedSearch in Google Scholar
  • 177 Boltjes A, Groothuismink ZM, van Oord GW, Janssen HL, Woltman AM, Boonstra A. Monocytes from chronic HBV patients react in vitro to HBsAg and TLR by producing cytokines irrespective of stage of disease. PLoS One 2014; 9 (05) e97006
    CrossrefPubMedSearch in Google Scholar
  • 178 Gehring AJ, Haniffa M, Kennedy PT. et al. Mobilizing monocytes to cross-present circulating viral antigen in chronic infection. J Clin Invest 2013; 123 (09) 3766-3776
    CrossrefPubMedSearch in Google Scholar
  • 179 Zhang JY, Zou ZS, Huang A. et al. Hyper-activated pro-inflammatory CD16 monocytes correlate with the severity of liver injury and fibrosis in patients with chronic hepatitis B. PLoS One 2011; 6 (03) e17484
    CrossrefPubMedSearch in Google Scholar
  • 180 Dunn C, Brunetto M, Reynolds G. et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 2007; 204 (03) 667-680
    CrossrefPubMedSearch in Google Scholar
  • 181 Wijaya RS, Read SA, Truong NR. et al. HBV vaccination and HBV infection induces HBV-specific natural killer cell memory. Gut 2021; 70 (02) 357-369
    PubMedSearch in Google Scholar
  • 182 Lunemann S, Malone DF, Hengst J. et al. Compromised function of natural killer cells in acute and chronic viral hepatitis. J Infect Dis 2014; 209 (09) 1362-1373
    CrossrefPubMedSearch in Google Scholar
  • 183 Tjwa ET, van Oord GW, Hegmans JP, Janssen HL, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 2011; 54 (02) 209-218
    CrossrefPubMedSearch in Google Scholar
  • 184 Du Y, Anastasiou OE, Strunz B. et al. The impact of hepatitis B surface antigen on natural killer cells in patients with chronic hepatitis B virus infection. Liver Int 2021; 41 (09) 2046-2058
    CrossrefPubMedSearch in Google Scholar
  • 185 Peppa D, Gill US, Reynolds G. et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210 (01) 99-114
    CrossrefPubMedSearch in Google Scholar
  • 186 Marotel M, Villard M, Drouillard A. et al. Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion. eLife 2021; 10: 10
    CrossrefPubMedSearch in Google Scholar
  • 187 Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 2000; 192 (07) 921-930
    CrossrefPubMedSearch in Google Scholar
  • 188 Baron JL, Gardiner L, Nishimura S, Shinkai K, Locksley R, Ganem D. Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 2002; 16 (04) 583-594
    CrossrefPubMedSearch in Google Scholar
  • 189 Tang XZ, Jo J, Tan AT. et al. IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. J Immunol 2013; 190 (07) 3142-3152
    CrossrefPubMedSearch in Google Scholar
  • 190 Jo J, Tan AT, Ussher JE. et al. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLoS Pathog 2014; 10 (06) e1004210
    CrossrefPubMedSearch in Google Scholar
  • 191 Boeijen LL, Montanari NR, de Groen RA. et al. Mucosal-associated invariant T cells are more activated in chronic hepatitis B, but not depleted in blood: reversal by antiviral therapy. J Infect Dis 2017; 216 (08) 969-976
    CrossrefPubMedSearch in Google Scholar
  • 192 Micco L, Peppa D, Loggi E. et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol 2013; 58 (02) 225-233
    CrossrefPubMedSearch in Google Scholar
  • 193 Gill US, Peppa D, Micco L. et al. Interferon alpha induces sustained changes in NK cell responsiveness to hepatitis B viral load suppression in vivo. PLoS Pathog 2016; 12 (08) e1005788
    CrossrefPubMedSearch in Google Scholar
  • 194 Boni C, Lampertico P, Talamona L. et al. Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B. Hepatology 2015; 62 (06) 1697-1709
    CrossrefPubMedSearch in Google Scholar