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A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook

Nature Reviews Gastroenterology & Hepatology volume 19, pages 727–745 (2022)Cite this article

Subjects

Abstract

Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.

Key points

  • As new therapies for hepatitis B virus (HBV) infection become available, new biomarkers to monitor viral and host responses are urgently needed.

  • This Roadmap summarizes current knowledge on existing and emerging serum biomarkers in the context of chronic HBV infection.

  • This Roadmap discusses the strengths, weaknesses, opportunities and challenges of serum HBV biomarkers.

  • This Roadmap provides suggestions of the way forward to advance the biomarkers required to fast-track an HBV cure for all, irrespective of resources, HBV genotype or disease stage.

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Fig. 1: Course of serum markers in acute resolving hepatitis B virus infection.
Fig. 2: Schematic representation of HBcrAg biogenesis29.
Fig. 3: Adaptive immune responses against HBV.

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References

  1. Tong, S. & Revill, P. Overview of hepatitis B viral replication and genetic variability. J. Hepatol. 64, S4–S16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Faure-Dupuy, S., Lucifora, J. & Durantel, D. Interplay between the hepatitis B virus and innate immunity: from an understanding to the development of therapeutic concepts. Viruses https://doi.org/10.3390/v9050095 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bertoletti, A. & Ferrari, C. Adaptive immunity in HBV infection. J. Hepatol. 64, S71–S83 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Maini, M. K. & Gehring, A. J. The role of innate immunity in the immunopathology and treatment of HBV infection. J. Hepatol. 64, S60–S70 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Kuipery, A., Gehring, A. J. & Isogawa, M. Mechanisms of HBV immune evasion. Antivir. Res. 179, 104816 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Rehermann, B. & Thimme, R. Insights from antiviral therapy into immune responses to hepatitis B and C virus infection. Gastroenterology 156, 369–383 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Bengsch, B. & Chang, K. M. Evolution in our understanding of hepatitis B virus virology and immunology. Clin. Liver Dis. 20, 629–644 (2016).

    Article  PubMed  Google Scholar 

  8. Grossi, G., Vigano, M., Loglio, A. & Lampertico, P. Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs). Liver Int. 37 (Suppl. 1), 45–51 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Lucifora, J. et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221–1228 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lok, A. S., Zoulim, F., Dusheiko, G. & Ghany, M. G. Hepatitis B cure: from discovery to regulatory approval. J. Hepatol. 67, 847–861 (2017).

    Article  PubMed  Google Scholar 

  11. Revill, P. A. et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol. Hepatol. 4, 545–558 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  12. WHO. Interim Guidance for Country Validation of Viral Hepatitis Elimination https://www.who.int/publications/i/item/9789240028395 (2021).

  13. Thomas, D. L. Global elimination of chronic hepatitis. N. Engl. J. Med. 380, 2041–2050 (2019).

    Article  PubMed  Google Scholar 

  14. Revill, P. A., Penicaud, C., Brechot, C. & Zoulim, F. Meeting the challenge of eliminating chronic hepatitis B infection. Genes https://doi.org/10.3390/genes10040260 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hepatitis B Foundation. Hepatitis B Foundation Drugwatch, https://www.hepb.org/treatment-and-management/drug-watch/ (2022).

  16. Testoni, B., Levrero, M. & Zoulim, F. Challenges to a cure for HBV infection. Semin. Liver Dis. 37, 231–242 (2017).

    Article  PubMed  Google Scholar 

  17. Sommer, G. & Heise, T. Posttranscriptional control of HBV gene expression. Front. Biosci. 13, 5533–5547 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Yuen, M. F. et al. Hepatitis B virus infection. Nat. Rev. Dis. Prim. 4, 18035 (2018).

    Article  PubMed  Google Scholar 

  19. Wooddell, C. I. 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. https://doi.org/10.1126/scitranslmed.aan0241 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gish, R. G. et al. Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antivir. Res. 121, 47–58 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Liu, D. et al. Clinical relevance of the in situ assay for HBV DNA: a cross-sectional study in patients with chronic hepatitis B. J. Clin. Pathol. 73, 813–818 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, X. et al. In situ analysis of intrahepatic virological events in chronic hepatitis B virus infection. J. Clin. Investig. 126, 1079–1092 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bowden, S., Jackson, K., Littlejohn, M. & Locarnini, S. Quantification of HBV covalently closed circular DNA from liver tissue by real-time PCR. Methods Mol. Med. 95, 41–50 (2004).

    CAS  PubMed  Google Scholar 

  24. Werle-Lapostolle, B. et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126, 1750–1758 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Coffin, C. S., Zhou, K. & Terrault, N. A. New and old biomarkers for diagnosis and management of chronic hepatitis B virus infection. Gastroenterology 156, 355–368 e353 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Revill, P. A. et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol. Hepatol. 4, 545–558 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Xu, H. et al. Role of anti-HBs in functional cure of HBeAg+chronic hepatitis B patients infected with HBV genotype A. J. Hepatol. 76, 34–45 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).

    Article  Google Scholar 

  29. Hong, X. et al. Characterization of hepatitis B precore/core-related antigens. J. Virol. https://doi.org/10.1128/JVI.01695-20 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Candotti, D., Assennato, S. M., Laperche, S., Allain, J. P. & Levicnik-Stezinar, S. Multiple HBV transfusion transmissions from undetected occult infections: revising the minimal infectious dose. Gut 68, 313–321 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Piermatteo, L. et al. Droplet digital PCR assay as an innovative and promising highly sensitive assay to unveil residual and cryptic HBV replication in peripheral compartment. Methods 201, 74–81 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Carey, I. 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. Hepatology 72, 42–57 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Raimondo, G. et al. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J. Hepatol. 71, 397–408 (2019).

    Article  PubMed  Google Scholar 

  34. WHO. Prevention of Mother-to-Child Transmission of Hepatitis B Virus: Guidelines on Antiviral Prophylaxis in Pregnancy https://apps.who.int/iris/bitstream/handle/10665/333391/9789240002708-eng.pdf?sequence=1&isAllowed=y (2020).

  35. Cornberg, M. et al. The role of quantitative hepatitis B surface antigen revisited. J. Hepatol. 66, 398–411 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. WHO. WHO Guidelines on Hepatitis B and C Testing https://apps.who.int/iris/bitstream/handle/10665/254621/9789241549981-eng.pdf?sequence=1 (2017).

  37. Kramvis, A. Challenges for hepatitis B virus cure in resource-limited settings in sub-Saharan Africa. Curr. Opin. Hiv. AIDS 15, 185–192 (2020).

    Article  PubMed  Google Scholar 

  38. Kosack, C. S., Page, A. L. & Klatser, P. R. A guide to aid the selection of diagnostic tests. Bull. World Health Organ. 95, 639–645 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sonderup, M. W. & Spearman, C. W. Global disparities in hepatitis B elimination — a focus on Africa. Viruses https://doi.org/10.3390/v14010082 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Scheiblauer, H. et al. Performance evaluation of 70 hepatitis B virus (HBV) surface antigen (HBsAg) assays from around the world by a geographically diverse panel with an array of HBV genotypes and HBsAg subtypes. Vox Sang. 98, 403–414 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chevaliez, S. & Pawlotsky, J. M. New virological tools for screening, diagnosis and monitoring of hepatitis B and C in resource-limited settings. J. Hepatol. 69, 916–926 (2018).

    Article  PubMed  Google Scholar 

  42. Alavian, S. M., Carman, W. F. & Jazayeri, S. M. HBsAg variants: diagnostic-escape and diagnostic dilemma. J. Clin. Virol. 57, 201–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Thibault, V., Servant-Delmas, A., Ly, T. D., Roque-Afonso, A. M. & Laperche, S. Performance of HBsAg quantification assays for detection of Hepatitis B virus genotypes and diagnostic escape-variants in clinical samples. J. Clin. Virol. 89, 14–21 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Lange, B. et al. Diagnostic accuracy of detection and quantification of HBV-DNA and HCV-RNA using dried blood spot (DBS) samples - a systematic review and meta-analysis. BMC Infect. Dis. 17, 693 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shimakawa, Y. et al. Analytical validation of hepatitis B core-related antigen (HBcrAg) using dried blood spots (DBS). J. Viral Hepat. 28, 837–843 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jackson, K., Tekoaua, R., Li, X. & Locarnini, S. Real-world application of the Xpert(R) HBV viral load assay on serum and dried blood spots. J. Med. Virol. 93, 3707–3713 (2021).

    Article  CAS  PubMed  Google Scholar 

  47. Abravanel, F. et al. Performance of the Xpert HBV Viral Load assay versus the Aptima Quant assay for quantifying hepatitis B virus DNA. Diagn. Microbiol. Infect. Dis. 96, 114946 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Zhu, X. et al. Prospective evaluation of FibroScan for the diagnosis of hepatic fibrosis compared with liver biopsy/AST platelet ratio index and FIB-4 in patients with chronic HBV infection. Dig. Dis. Sci. 56, 2742–2749 (2011).

    Article  PubMed  Google Scholar 

  49. Gerlich, W. H., Glebe, D., Kramvis, A. & Magnius, L. O. Peculiarities in the designations of hepatitis B virus genes, their products, and their antigenic specificities: a potential source of misunderstandings. Virus Genes 56, 109–119 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Seeger, C. & Mason, W. S. Hepatitis B virus biology. Microbiol. Mol. Biol. Rev. 64, 51–68 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang, J. et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J. Hepatol. 65, 700–710 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Jansen, L. et al. Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon Alfa-2a and nucleos(t)ide analogues. J. Infect. Dis. 213, 224–232 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Prakash, K. et al. High serum levels of pregenomic RNA reflect frequently failing reverse transcription in hepatitis B virus particles. Virol. J. 15, 86 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lam, A. M. et al. Hepatitis B virus capsid assembly modulators, but not nucleoside analogs, inhibit the production of extracellular pregenomic RNA and spliced RNA variants. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.00680-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Stadelmayer, B. et al. Full-length 5’RACE identifies all major HBV transcripts in HBV-infected hepatocytes and patient serum. J. Hepatol. 73, 40–51 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Wang, J. et al. Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients. J. Hepatol. 68, 16–24 (2018).

    Article  CAS  Google Scholar 

  57. Hacker, H. J., Zhang, W., Tokus, M., Bock, T. & Schroder, C. H. Patterns of circulating hepatitis B virus serum nucleic acids during lamivudine therapy. Ann. N. Y. Acad. Sci. 1022, 271–281 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Niu, C. et al. The Smc5/6 complex restricts HBV when localized to ND10 without inducing an innate immune response and is counteracted by the HBV X protein shortly after infection. PLoS One 12, e0169648 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wang, J. et al. HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient. J. Hepatol. 68, 847–849 (2018).

    Article  PubMed  Google Scholar 

  60. Gunther, S., Sommer, G., Iwanska, A. & Will, H. Heterogeneity and common features of defective hepatitis B virus genomes derived from spliced pregenomic RNA. Virology 238, 363–371 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Lim, C. S. et al. Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes. Microb. Genom. https://doi.org/10.1099/mgen.0.000492 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bai, L. et al. Extracellular hepatitis B virus RNAs are heterogeneous in length and circulate as capsid-antibody complexes in addition to virions in chronic hepatitis B patients. J. Virol. https://doi.org/10.1128/JVI.00798-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Butler, E. K. et al. Hepatitis B virus serum DNA and RNA levels in nucleos(t)ide analog-treated or untreated patients during chronic and acute infection. Hepatology 68, 2106–2117 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. van Bommel, F. et al. Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology 61, 66–76 (2015).

    Article  PubMed  Google Scholar 

  65. Mak, L. Y. et al. HBV RNA profiles in patients with chronic hepatitis B under different disease phases and antiviral therapy. Hepatology 73, 2167–2179 (2021).

    Article  CAS  PubMed  Google Scholar 

  66. van Campenhout, M. J. H. et al. Host and viral factors associated with serum hepatitis B virus RNA levels among patients in need for treatment. Hepatology 68, 839–847 (2018).

    Article  PubMed  Google Scholar 

  67. Anderson, M. et al. Circulating pregenomic HBV RNA is primarily full-length in chronic hepatitis B patients undergoing nucleos(t)ide analogue therapy. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa1015 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Wang, J. et al. Natural history of serum HBV-RNA in chronic HBV infection. J. Viral Hepat. 25, 1038–1047 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Volz, T. et al. Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients. Gastroenterology 133, 843–852 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Cathcart, A. L. et al. Evaluation of serum HBV RNA and HBcrAg in chronic hepatitis B patients achieving different serological outcomes on tenofovir disoproxil fumarate (TDF). J. Hepatol. 66, S476 (2017).

    Article  Google Scholar 

  71. Seto, W. K. 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 70, 775–783 (2021).

    Article  PubMed  Google Scholar 

  72. van Bömmel, F. et al. HBV RNA can still be quantified in serum in HBeAg negative patients after suppression of HBV DNA by nuleos(t)ide analogues for up to 10 years. Hepatology 68 (Suppl.), 273A (2018).

    Google Scholar 

  73. Fan, R. et al. Association between negative results from tests for hBV DNA and RNA and durability of response after discontinuation of nucles(t)ide analogue therapy. Clin. Gastroenterol. Hepatol. 18, 719–727.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  74. Klumpp, K. et al. Efficacy of NVR 3-778, alone and in combination with pegylated interferon, vs entecavir in uPA/SCID mice with humanized livers and HBV infection. Gastroenterology 154, 652–662.e8 (2018).

    Article  CAS  PubMed  Google Scholar 

  75. Yuen, M. F. et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3-778 in patients with chronic HBV infection. Gastroenterology 156, 1392–1403.e7 (2019).

    Article  CAS  PubMed  Google Scholar 

  76. Giersch, K., Allweiss, L., Volz, T., Dandri, M. & Lutgehetmann, M. Serum HBV pgRNA as a clinical marker for cccDNA activity. J. Hepatol. 66, 460–462 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. van Bommel, F. et al. Serum HBV RNA as a predictor of peginterferon Alfa-2a response in patients with HBeAg-positive chronic hepatitis B. J. Infect. Dis. 218, 1066–1074 (2018).

    Article  PubMed  Google Scholar 

  78. Hu, J. & Liu, K. Complete and incomplete hepatitis B virus particles: formation, function, and application. Viruses https://doi.org/10.3390/v9030056 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Liu, Y. Y. & Liang, X. S. Progression and status of antiviral monitoring in patients with chronic hepatitis B: from HBsAg to HBV RNA. World J. Hepatol. 10, 603–611 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Suzuki, F., Miyakoshi, H., Kobayashi, M. & Kumada, H. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J. Med. Virol. 81, 27–33 (2009).

    Article  PubMed  Google Scholar 

  81. Hige, S. et al. Sensitive assay for quantification of hepatitis B virus mutants by use of a minor groove binder probe and peptide nucleic acids. J. Clin. Microbiol. 48, 4487–4494 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Testoni, B. et al. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J. Hepatol. 70, 615–625 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Mak, L. Y. & Yuen, M. F. Letter: serum HBcrAg is a useful marker for disease monitoring, predicting treatment response and disease outcome of chronic hepatitis B virus infection-authors’ reply. Aliment. Pharmacol. Ther. 47, 1720–1721 (2018).

    Article  PubMed  Google Scholar 

  84. Mak, L. Y. et al. Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection. Aliment. Pharmacol. Therapeut. 47, 43–54 (2018).

    Article  CAS  Google Scholar 

  85. Maasoumy, B. et al. Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D. Clin. Microbiol. Infect. 21, 606.e1-10 (2015).

    Article  CAS  Google Scholar 

  86. Wong, G. L., Wong, V. W. & Chan, H. L. Virus and host testing to manage chronic hepatitis B. Clin. Infect. Dis. 62 (Suppl. 4), S298–305 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen, E. Q. et al. Serum hepatitis B core-related antigen is a satisfactory surrogate marker of intrahepatic covalently closed circular DNA in chronic hepatitis B. Sci. Rep. 7, 173 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Suzuki, Y. et al. Hepatitis B virus (HBV)-infected patients with low hepatitis B surface antigen and high hepatitis B core-related antigen titers have a high risk of HBV-related hepatocellular carcinoma. Hepatol. Res. 49, 51–63 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Seto, W. K. et al. Linearized hepatitis B surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B. Clin. Microbiol. Infect. 20, 1173–1180 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Riveiro-Barciela, M. et al. Serum hepatitis B core-related antigen is more accurate than hepatitis B surface antigen to identify inactive carriers, regardless of hepatitis B virus genotype. Clin. Microbiol. Infect. 23, 860–867 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Brunetto, M. R. et al. Incremental value of HBcrAg to classify 1582 HBeAg-negative individuals in chronic infection without liver disease or hepatitis. Aliment. Pharmacol. Therapeut. 53, 733–744 (2021).

    CAS  Google Scholar 

  92. Chuaypen, N. et al. Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon-based therapy. Clin. Microbiol. Infect. 24, 306.e7–306.e13 (2018).

    Article  CAS  Google Scholar 

  93. Inoue, T. et al. Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management of chronic hepatitis B and HBV reactivation. J. Hepatol. https://doi.org/10.1016/j.jhep.2021.02.017 (2021).

    Article  PubMed  Google Scholar 

  94. Honda, M. 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. 213, 1096–1106 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Tseng, T. C. et al. Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load. Aliment. Pharmacol. Therapeut. 53, 908–918 (2021).

    CAS  Google Scholar 

  96. Tada, T. et al. Hepatitis B virus core-related antigen levels predict progression to liver cirrhosis in hepatitis B carriers. J. Gastroenterol. Hepatol. 33, 918–925 (2018).

    Article  CAS  PubMed  Google Scholar 

  97. Hosaka, T. et al. Impact of hepatitis B core-related antigen on the incidence of hepatocellular carcinoma in patients treated with nucleos(t)ide analogues. Aliment. Pharmacol. Therapeut. 49, 457–471 (2019).

    Article  CAS  Google Scholar 

  98. Tseng, T. C. et al. High level of hepatitis B core-related antigen associated with increased risk of hepatocellular carcinoma in patients with chronic HBV infection of intermediate viral load. Gastroenterology 157, 1518–1529.e3 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Hosaka, T. Letter: impact of hepatitis B core-related antigen on the incidence of hepatocellular carcinoma in patients treated with nucleos(t)ide analogues-further clarifications needed. Authors’ reply. Aliment. Pharmacol. Therapeut. 50, 233 (2019).

    Article  Google Scholar 

  100. Wong, D. K. et al. Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA. Liver Int. 37, 995–1001 (2017).

    Article  CAS  PubMed  Google Scholar 

  101. van Campenhout, M. J. et al. Hepatitis B core-related antigen levels are associated with response to entecavir and peginterferon add-on therapy in hepatitis B e antigen-positive chronic hepatitis B patients. Clin. Microbiol. Infect. 22, 571.e5-9 (2016).

    PubMed  Google Scholar 

  102. Matsuzaki, T. et al. Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation. J. Gastroenterol. Hepatol. 28, 1217–1222 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Kimura, T. et al. Hepatitis B virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal arginine-rich domain. J. Biol. Chem. 280, 21713–21719 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Kimura, T. et al. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J. Clin. Microbiol. 40, 439–445 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fanning, G. C., Zoulim, F., Hou, J. & Bertoletti, A. Therapeutic strategies for hepatitis B virus infection: towards a cure. Nat. Rev. Drug Discov. 18, 827–844 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Hong, X. et al. Characterization and application of precore/core-related antigens in animal models of hepatitis B virus infection. Hepatology https://doi.org/10.1002/hep.31720 (2021).

    Article  PubMed  Google Scholar 

  107. Pfefferkorn, M. 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 67, 2045–2053 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Pfefferkorn, M. et al. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B. J. Hepatol. 74, 283–292 (2021).

    Article  CAS  PubMed  Google Scholar 

  109. Hassemer, M. et al. Comparative characterization of hepatitis B virus surface antigen derived from different hepatitis B virus genotypes. Virology 502, 1–12 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Farag, M. S. et al. Hepatitis B virus RNA as early predictor for response to PEGylated interferon Alfa in HBeAg negative chronic hepatitis B. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa013 (2020).

    Article  Google Scholar 

  111. van Campenhout, M. J. H. et al. Hepatitis B core-related antigen monitoring during peginterferon alfa treatment for HBeAg-negative chronic hepatitis B. J. Viral Hepat. 26, 1156–1163 (2019).

    Article  PubMed  Google Scholar 

  112. Zhang, M. Efficacy and safety of GLS4/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: interim results from phase 2b, multi-center study. J. Hepatol. 73, s878 (2020).

    Article  Google Scholar 

  113. Taverniti, V. et al. Capsid assembly modulators as antiviral agents against HBV: molecular mechanisms and clinical perspectives. J. Clin. Med. https://doi.org/10.3390/jcm11051349 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Ghany, M. G. et al. Serum alanine aminotransferase flares in chronic hepatitis B infection: the good and the bad. Lancet Gastroenterol. Hepatol. 5, 406–417 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Maini, M. K. & Burton, A. R. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat. Rev. Gastroenterol. Hepatol. 16, 662–675 (2019).

    Article  PubMed  Google Scholar 

  116. Tighe, P. J., Ryder, R. R., Todd, I. & Fairclough, L. C. ELISA in the multiplex era: potentials and pitfalls. Proteom. Clin. Appl. 9, 406–422 (2015).

    Article  CAS  Google Scholar 

  117. Grifoni, A. et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489–1501.e15 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Le Bert, N. et al. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection. J. Exp. Med. https://doi.org/10.1084/jem.20202617 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Weiskopf, D. et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci. Immunol. https://doi.org/10.1126/sciimmunol.abd2071 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Mazurek, G. H. & Villarino, M. E.; CDC. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. Centers for Disease Control and Prevention. MMWR Recomm. Rep. 52, 15–18 (2003).

    PubMed  Google Scholar 

  121. Cornberg, M., Lok, A. S., Terrault, N. A. & Zoulim, F.; 2019 EASL-AASLD HBV Ttretment 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(double dagger). J. Hepatol. 72, 539–557 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Gill, U. S. et al. Fine needle aspirates comprehensively sample intrahepatic immunity. Gut 68, 1493–1503 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Gill, U. S., Pallett, L. J., Kennedy, P. T. F. & Maini, M. K. Liver sampling: a vital window into HBV pathogenesis on the path to functional cure. Gut 67, 767–775 (2018).

    CAS  PubMed  Google Scholar 

  124. Hartmann, F. J. & Bendall, S. C. Immune monitoring using mass cytometry and related high-dimensional imaging approaches. Nat. Rev. Rheumatol. 16, 87–99 (2020).

    Article  PubMed  Google Scholar 

  125. Traum, D. et al. Highly multiplexed 2-dimensional imaging mass cytometry analysis of HBV-infected liver. JCI Insight https://doi.org/10.1172/jci.insight.146883 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Rendeiro, A. F. et al. The spatial landscape of lung pathology during COVID-19 progression. Nature 593, 564–569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Raimondo, G. et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J. Hepatol. 49, 652–657 (2008).

    Article  PubMed  Google Scholar 

  128. Caviglia, G. P. 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. 69, 301–307 (2018).

    Article  CAS  PubMed  Google Scholar 

  129. Deguchi, M. et al. Evaluation of the highly sensitive chemiluminescent enzyme immunoassay “Lumipulse HBsAg-HQ” for hepatitis B virus screening. J. Clin. Lab. Anal. 32, e22334 (2018).

    Article  PubMed  Google Scholar 

  130. Ozeki, I. et al. Analysis of hepatitis B surface antigen (HBsAg) using high-sensitivity HBsAg assays in hepatitis B virus carriers in whom HBsAg seroclearance was confirmed by conventional assays. Hepatol. Res. 48, E263–E274 (2018).

    Article  CAS  PubMed  Google Scholar 

  131. Pepe, M. S. et al. Phases of biomarker development for early detection of cancer. J. Natl Cancer Inst. 93, 1054–1061 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Kuhns, M. C. et al. Improved detection of early acute, late acute, and occult Hepatitis B infections by an increased sensitivity HBsAg assay. J. Clin. Virol. 118, 41–45 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Liu, Y., Cathcart, A. L., Delaney, W. E. T. & Kitrinos, K. M. Development of a digital droplet PCR assay to measure HBV DNA in patients receiving long-term TDF treatment. J. Virol. Methods 249, 189–193 (2017).

    Article  CAS  PubMed  Google Scholar 

  134. Musolino, C. et al. Behaviour of occult HBV infection in HCV-infected patients under treatment with direct-acting antivirals. Antivir. Ther. 24, 187–192 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Kazemi-Shirazi, L., Petermann, D. & Muller, C. Hepatitis B virus DNA in sera and liver tissue of HBsAg negative patients with chronic hepatitis C. J. Hepatol. 33, 785–790 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Kannangai, R. et al. Liver enzyme flares and occult hepatitis B in persons with chronic hepatitis C infection. J. Clin. Virol. 39, 101–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Chemin, I., Guillaud, O., Queyron, P. C. & Trepo, C. Close monitoring of serum HBV DNA levels and liver enzymes levels is most useful in the management of patients with occult HBV infection. J. Hepatol. 51, 824–825 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Saitta, C. et al. Risk of occult hepatitis B virus infection reactivation in patients with solid tumours undergoing chemotherapy. Dig. Liver Dis. 45, 683–686 (2013).

    Article  PubMed  Google Scholar 

  139. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 6 (2021).

    Article  PubMed  Google Scholar 

  140. Yang, H. C. et al. Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection. J. Hepatol. 69, 286–292 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Kusumoto, S. et al. Ultra-high sensitivity HBsAg assay can diagnose HBV reactivation following rituximab-based therapy in patients with lymphoma. J. Hepatol. 73, 285–293 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Parikh, N. D. et al. Biomarkers for the early detection of hepatocellular carcinoma. Cancer Epidemiol. Biomark. Prev. 29, 2495–2503 (2020).

    Article  CAS  Google Scholar 

  143. Chaiteerakij, R., Addissie, B. D. & Roberts, L. R. Update on biomarkers of hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 13, 237–245 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Guidotti, L. G. et al. Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829 (1999).

    Article  CAS  PubMed  Google Scholar 

  145. Xu, D., Su, C., Sun, L., Gao, Y. & Li, Y. Performance of serum Glypican 3 in diagnosis of hepatocellular carcinoma: a meta-analysis. Ann. Hepatol. 18, 58–67 (2019).

    Article  CAS  PubMed  Google Scholar 

  146. Ge, T. et al. Diagnostic values of alpha-fetoprotein, dickkopf-1, and osteopontin for hepatocellular carcinoma. Med. Oncol. 32, 59 (2015).

    Article  PubMed  Google Scholar 

  147. Johnson, P. J. et al. The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers. Cancer Epidemiol. Biomark. Prev. 23, 144–153 (2014).

    Article  CAS  Google Scholar 

  148. von Felden, J., Garcia-Lezana, T., Schulze, K., Losic, B. & Villanueva, A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 69, 2025–2034 (2020).

    Article  Google Scholar 

  149. Wang, T. & Zhang, K. H. New blood biomarkers for the diagnosis of AFP-negative hepatocellular carcinoma. Front. Oncol. 10, 1316 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Wong, G. L. et al. On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir. Hepatology 59, 986–995 (2014).

    Article  CAS  PubMed  Google Scholar 

  151. Marrero, J. A. Screening tests for hepatocellular carcinoma. Clin. Liver Dis. 9, 235–251 (2005).

    Article  PubMed  Google Scholar 

  152. Tzartzeva, K. et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology 154, 1706–1718.e1 (2018).

    Article  CAS  PubMed  Google Scholar 

  153. Gopal, P. et al. Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 12, 870–877 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Simmons, O. et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment. Pharmacol. Therapeut. 45, 169–177 (2017).

    Article  CAS  Google Scholar 

  155. Del Poggio, P. et al. Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 12, 1927–1933.e2 (2014).

    Article  PubMed  Google Scholar 

  156. Singal, A. G., Lampertico, P. & Nahon, P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J. Hepatol. 72, 250–261 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Loglio, A. et al. The combination of PIVKA-II and AFP improves the detection accuracy for HCC in HBV caucasian cirrhotics on long-term oral therapy. Liver Int. 40, 1987–1996 (2020).

    Article  CAS  PubMed  Google Scholar 

  158. Park, S. J. et al. Usefulness of AFP, AFP-L3, and PIVKA-II, and their combinations in diagnosing hepatocellular carcinoma. Medicine 96, e5811 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lee, E., Edward, S., Singal, A. G., Lavieri, M. S. & Volk, M. Improving screening for hepatocellular carcinoma by incorporating data on levels of alpha-fetoprotein, over time. Clin. Gastroenterol. Hepatol. 11, 437–440 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Choi, J. et al. Longitudinal assessment of three serum biomarkers to detect very early-stage hepatocellular carcinoma. Hepatology 69, 1983–1994 (2019).

    Article  CAS  PubMed  Google Scholar 

  161. Kramvis, A. Genotypes and genetic variability of hepatitis B virus. Intervirology 57, 141–150 (2014).

    Article  PubMed  Google Scholar 

  162. Bayliss, J. et al. Deep sequencing shows that HBV basal core promoter and precore variants reduce the likelihood of HBsAg loss following tenofovir disoproxil fumarate therapy in HBeAg-positive chronic hepatitis B. Gut 66, 2013–2023 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Wong, D. et al. ALT flares during nucleotide analogue therapy are associated with HBsAg loss in genotype A HBeAg-positive chronic hepatitis B. Liver Int. 38, 1760–1769 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Cornberg, M. & Glebe, D. Editorial: which factors influence HBsAg levels in HBV-infected patients? Aliment. Pharmacol. Therapeut. 52, 547–548 (2020).

    Article  Google Scholar 

  165. Rokuhara, A. et al. Hepatitis B virus RNA is measurable in serum and can be a new marker for monitoring lamivudine therapy. J. Gastroenterol. 41, 785–790 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Wang, J. et al. Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients. J. Hepatol. https://doi.org/10.1016/j.jhep.2017.08.021 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Wang, J. et al. Reply to: “Serum HBV pgRNA as a clinical marker for cccDNA activity”: consistent loss of serum HBV RNA might predict the “para-functional cure” of chronic hepatitis B. J. Hepatol. 66, 462–463 (2017).

    Article  CAS  PubMed  Google Scholar 

  168. Limothai, U. et al. Reverse transcriptase droplet digital PCR vs reverse transcriptase quantitative real-time PCR for serum HBV RNA quantification. J. Med. Virol. https://doi.org/10.1002/jmv.25792 (2020).

    Article  PubMed  Google Scholar 

  169. van Bommel, F. et al. Serum HBV RNA as a predictor of peginterferon Alfa-2a (40KD) response in patients with HBeAg-positive chronic hepatitis B. J. Infect. Dis. 218, 1066–1074 (2018).

    Article  PubMed  Google Scholar 

  170. Tsuge, M. et al. Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients. J. Gastroenterol. 48, 1188–1204 (2013).

    Article  CAS  PubMed  Google Scholar 

  171. Huang, Y. W. et al. On-treatment low serum HBV RNA level predicts initial virological response in chronic hepatitis B patients receiving nucleoside analogue therapy. Antivir. Ther. 20, 369–375 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Laras, A., Koskinas, J., Dimou, E., Kostamena, A. & Hadziyannis, S. J. Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients. Hepatology 44, 694–702 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Scholtès, C. et al. Performance of a novel automated assay for the detection and quantification of HBV pregeomic RNA/ circulating RNAs in chronic HBV patients. Hepatology 72, 447A (2020).

    Google Scholar 

  174. Loggi, E. et al. Serum hepatitis B core-related antigen is an effective tool to categorize patients with HBeAg-negative chronic hepatitis B. J. Viral Hepat. 26, 568–575 (2019).

    Article  CAS  PubMed  Google Scholar 

  175. Lee, H. W. & Ahn, S. H. Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients. World J. Gastroenterol. 22, 8314–8321 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Weusten, J., Vermeulen, M., van Drimmelen, H. & Lelie, N. Refinement of a viral transmission risk model for blood donations in seroconversion window phase screened by nucleic acid testing in different pool sizes and repeat test algorithms. Transfusion 51, 203–215 (2011).

    Article  PubMed  Google Scholar 

  177. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J. Hepatol. 67, 370–398 (2017).

    Article  Google Scholar 

  178. Vermeulen, M. et al. Hepatitis B virus transmission by blood transfusion during 4 years of individual-donation nucleic acid testing in South Africa: estimated and observed window period risk. Transfusion 52, 880–892 (2012).

    Article  CAS  PubMed  Google Scholar 

  179. Ning, X. et al. Secretion of genome-free hepatitis B virus–single strand blocking model for virion morphogenesis of para-retrovirus. PLoS Pathog. 7, e1002255 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Garcia, P. D., Ou, J. H., Rutter, W. J. & Walter, P. Targeting of the hepatitis B virus precore protein to the endoplasmic reticulum membrane: after signal peptide cleavage translocation can be aborted and the product released into the cytoplasm. J. Cell Biol. 106, 1093–1104 (1988).

    Article  CAS  PubMed  Google Scholar 

  181. Ito, K., Kim, K. H., Lok, A. S. & Tong, S. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J. Virol. 83, 3507–3517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Wang, J., Lee, A. S. & Ou, J. H. Proteolytic conversion of hepatitis B virus e antigen precursor to end product occurs in a postendoplasmic reticulum compartment. J. Virol. 65, 5080–5083 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Thimme, R. et al. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77, 68–76 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Rehermann, B. Immune responses in hepatitis B virus infection. Semin. Liver Dis. 23, 21–38 (2003).

    Article  CAS  PubMed  Google Scholar 

  185. Seto, W. K. et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J. Clin. Oncol. 32, 3736–3743 (2014).

    Article  CAS  PubMed  Google Scholar 

  186. Hakim, M. S., Spaan, M., Janssen, H. L. & Boonstra, A. Inhibitory receptor molecules in chronic hepatitis B and C infections: novel targets for immunotherapy? Rev. Med. Virol. 24, 125–138 (2014).

    Article  CAS  PubMed  Google Scholar 

  187. Lopes, A. R. et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J. Clin. Invest. 118, 1835–1845 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Peppa, D. et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J. Exp. Med. 210, 99–114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Xu, D. et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J. Immunol. 177, 739–747 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Stoop, J. N. et al. Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41, 771–778 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Fisicaro, P. et al. Pathogenetic mechanisms of T cell dysfunction in chronic HBV infection and related therapeutic approaches. Front. Immunol. 11, 849 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Pallett, L. J. et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat. Med. 21, 591–600 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).

    Article  CAS  PubMed  Google Scholar 

  194. Salimzadeh, L. et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J. Clin. Invest. 128, 4573–4587 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Milich, D. & Liang, T. J. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38, 1075–1086 (2003).

    Article  CAS  PubMed  Google Scholar 

  196. Dunn, C. et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J. Exp. Med. 204, 667–680 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Das, A. et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111–2124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Sandalova, E. et al. Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. Gastroenterology 143, 78–87.e3 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Aiolfi, R. & Sitia, G. Chronic hepatitis B: role of anti-platelet therapy in inflammation control. Cell Mol. Immunol. 12, 264–268 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Tiegs, G. & Lohse, A. W. Immune tolerance: what is unique about the liver. J. Autoimmun. 34, 1–6 (2010).

    Article  CAS  PubMed  Google Scholar 

  201. Wohlleber, D. & Knolle, P. A. The role of liver sinusoidal cells in local hepatic immune surveillance. Clin. Transl. Immunol. 5, e117 (2016).

    Article  Google Scholar 

  202. Chang, K. M. et al. Distinct phenotype and function of circulating Vdelta1+and Vdelta2+gammadeltaT-cells in acute and chronic hepatitis B. PLoS Pathog. 15, e1007715 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Boeijen, L. L. 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. 216, 969–976 (2017).

    Article  CAS  PubMed  Google Scholar 

  204. Yoshio, S. et al. Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B. Hepatology 63, 83–94 (2016).

    Article  CAS  PubMed  Google Scholar 

  205. Hou, F. Q. et al. Rapid downregulation of programmed death-1 and interferon-gamma-inducible protein-10 expression is associated with favourable outcome during antiviral treatment of chronic hepatitis B. J. Viral Hepat. 20 (Suppl. 1), 18–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  206. Tan, A. T. et al. A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. J. Hepatol. 52, 330–339 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Wang, Y. et al. Predictive value of interferon-gamma inducible protein 10 kD for hepatitis B e antigen clearance and hepatitis B surface antigen decline during pegylated interferon alpha therapy in chronic hepatitis B patients. Antivir. Res. 103, 51–59 (2014).

    Article  CAS  PubMed  Google Scholar 

  208. Chen, Y. et al. Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines. Cytokine 56, 231–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  209. Cheng, H. Y. et al. Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma. PLoS One 9, e95870 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Zhou, L. et al. Soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B. J. Viral Hepat. 26, 795–802 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Jeng, W.-J. & Yang, H.-I. Discrepant range of sPD-1 in different studies of chronic hepatitis B. A letter in response to soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B. J. Viral Hepat. 26, 930–931 (2019).

    Article  PubMed  Google Scholar 

  212. Jaroszewicz, J. et al. Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues. Antivir. Ther. 16, 915–924 (2011).

    Article  CAS  PubMed  Google Scholar 

  213. Sonneveld, M. J., Arends, P., Boonstra, A., Hansen, B. E. & Janssen, H. L. Serum levels of interferon-gamma-inducible protein 10 and response to peginterferon therapy in HBeAg-positive chronic hepatitis B. J. Hepatol. 58, 898–903 (2013).

    Article  CAS  PubMed  Google Scholar 

  214. Yoshio, S. et al. Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients. JCI Insight https://doi.org/10.1172/jci.insight.122268 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Johnson Valiente, A. et al. The inflammatory cytokine profile associated with liver damage is broader and stronger in patients with chronic hepatitis B compared to patients with acute hepatitis B. J. Infect. Dis. 225, 470–475 (2022).

    Article  PubMed  Google Scholar 

  216. Xia, J. et al. Profiles of serum soluble programmed death-1 and programmed death-ligand 1 levels in chronic hepatitis B virus-infected patients with different disease phases and after anti-viral treatment. Aliment. Pharmacol. Therapeut. 51, 1180–1187 (2020).

    Article  CAS  Google Scholar 

  217. Dou, Y. et al. Elevated serum levels of soluble CD14 in HBeAg-positive chronic HBV patients upon Peginterferon treatment are associated with treatment response. J. Viral Hepat. 26, 1076–1085 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Sandler, N. G. et al. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 141, 1220–1230 (2011).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank the Workshop Participants: The ICE-HBV HBV Serum Biomarkers Workshop was held virtually in two sessions on 5th and 12th October 2020 (https://ice-hbv.org/hbv-serum-biomarkers-workshop/). The chairs of the workshop A.K. and P.R. organized the meeting with C.P. K.M.C., M.D., P.F., D.G., J.H., H.L.A.J., D.T.Y.L., T.P., B.T. and F.V.P. presented at the workshop. O.A., M.B.M., T.M.B., H.L.Y.C., G.A.C., W.D., A.M.G., A.G., O.L., M.M., V.M., U.P., J.Y., M.F.Y. and F.B. chaired the workshop sessions and/or participated in the panel discussions. The authors thank T. Candy (VIDRL, RMH, Doherty Institute, Melbourne, Victoria, Australia) for assistance with the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa

    Anna Kramvis

  2. The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Kyong-Mi Chang

  3. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Maura Dandri

  4. German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Hamburg, Germany

    Maura Dandri

  5. Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Patrizia Farci

  6. National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany

    Dieter Glebe

  7. German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany

    Dieter Glebe

  8. Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Philadelphia, PA, USA

    Jianming Hu

  9. Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada

    Harry L. A. Janssen

  10. Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Daryl T. Y. Lau

  11. Peter Doherty Institute for Infection and Immunity, Melbourne, Australia

    Capucine Penicaud

  12. Laboratory of Molecular Hepatology, Department of Human Pathology, University Hospital “G. Martino” of Messina, Messina, Italy

    Teresa Pollicino

  13. INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France

    Barbara Testoni

  14. University of Lyon, Université Claude-Bernard (UCBL), Lyon, France

    Barbara Testoni

  15. Department of Hepatology, Leipzig University Medical Center, Leipzig, Germany

    Florian Van Bömmel

  16. Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA

    Ourania Andrisani

  17. Janssen Infectious Diseases, Janssen, Titusville, USA

    Maria Beumont-Mauviel

  18. Baruch S. Blumberg Institute, Doylestown, Pennsylvania, USA

    Timothy M. Block

  19. Chinese University of Hong Kong, Shatin, Hong Kong

    Henry L. Y. Chan

  20. Union Hospital, Shatin, Hong Kong

    Henry L. Y. Chan

  21. ID Core Research, Abbott Laboratories, Abbott Park, IL, USA

    Gavin A. Cloherty

  22. Assembly Bio, South San Francisco, San Francisco, CA, USA

    William E. Delaney

  23. Roche Pharma Research & Early Development, Basel, Switzerland

    Anna Maria Geretti

  24. Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, University of Rome Tor Vergata, Rome, Italy

    Anna Maria Geretti

  25. Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London, UK

    Anna Maria Geretti

  26. Toronto Centre for Liver Disease, University Health Network, Toronto, Canada

    Adam Gehring

  27. Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia

    Kathy Jackson & Peter A. Revill

  28. Janssen Pharmaceutica, Beerse, Belgium

    Oliver Lenz

  29. Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK

    Mala K. Maini

  30. Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA

    Veronica Miller

  31. Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany

    Ulrike Protzer

  32. Gilead Sciences, Foster City, CA, USA

    Jenny C. Yang

  33. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China

    Man-Fung Yuen

  34. State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China

    Man-Fung Yuen

  35. INSERM Unit 1052 – Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France

    Fabien Zoulim

  36. Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia

    Peter A. Revill

Authors
  1. Anna Kramvis
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  2. Kyong-Mi Chang
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  3. Maura Dandri
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  4. Patrizia Farci
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  5. Dieter Glebe
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  6. Jianming Hu
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  7. Harry L. A. Janssen
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  8. Daryl T. Y. Lau
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  9. Capucine Penicaud
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  10. Teresa Pollicino
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  11. Barbara Testoni
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  12. Florian Van Bömmel
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  13. Ourania Andrisani
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  14. Maria Beumont-Mauviel
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  15. Timothy M. Block
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  16. Henry L. Y. Chan
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  17. Gavin A. Cloherty
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  18. William E. Delaney
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  19. Anna Maria Geretti
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  20. Adam Gehring
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  21. Kathy Jackson
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  22. Oliver Lenz
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  23. Mala K. Maini
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  24. Veronica Miller
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  25. Ulrike Protzer
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  26. Jenny C. Yang
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  27. Man-Fung Yuen
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  28. Fabien Zoulim
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  29. Peter A. Revill
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Contributions

P.R., A.K., K.M.C., M.D., P.F., D.G., J.H., H.L.J., D.L., M.C.P., T.P., B.T., F.B., O.M.A., M.B.M., T.B., H.L.Y.C., G.A.C., W.E.D., A.M.A.G., A.J.G., K.J., O.L., M.K.M., V.M., U.P., J.C.Y., M.F.Y. and F.Z. researched data for the article. P.R., A.K., K.M.C., M.D., P.F., D.G., J.H., H.L.J., D.L., M.C.P., T.P., B.T., F.B., O.M.A., M.B.M., T.B., H.L.Y.C., G.A.C., W.E.D., A.M.A.G., A.J.G., K.J., O.L., M.K.M., V.M., U.P., J.C.Y., M.F.Y. and F.Z. contributed substantially to discussion of the content. P.R., A.K., K.M.C., M.D., P.F., D.G., J.H., H.L.J., D.L., M.C.P., T.P., B.T., F.B., O.M.A., M.B.M., T.B., H.L.Y.C., G.A.C., W.E.D., A.M.A.G., A.J.G., O.L., M.K.M., V.M., U.P., J.C.Y., M.F.Y. and F.Z. wrote the article. P.R., A.K., K.M.C., M.D., P.F., D.G., J.H., H.L.J., D.L., M.C.P., T.P., B.T., F.B., O.M.A., M.B.M., T.B., H.L.Y.C., G.A.C., W.E.D., A.M.A.G., A.J.G., K.J., O.L., M.K.M., V.M., U.P., J.C.Y., M.F.Y. and F.Z. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Anna Kramvis or Peter A. Revill.

Ethics declarations

Competing interests

A.K. is a recipient of a grant from the Cancer Association of South Africa (CANSA). K.M.C. is supported by the Corporal Michael J. Crescenz VA Medical Center Research Program in Philadelphia, Pennsylvania 19104, USA and has served in the Scientific Advisory Committee for Arbutus Biopharma. M.D. is supported by the German Research Foundation (DFG; SFB841), the German Center for Infection Research (DZIF) and the Dandri lab has received collaborative funding from Gilead Sciences and MYR-GmbH. P.F. has nothing to declare and is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MA, USA. D.G. is supported by the German Research Foundation (DFG; SFB1021), the German Center for Infection Research (DZIF), the Robert Koch Institute, Berlin and the German Federal Ministry of Health. J.H. has been supported by funding from the National Institute of Allergy and Infectious Disease/NIH and Gilead for work relevant here and has consulted for Arbutus, Bristol-Myers-Squibb, Gilead, Janssen, Roche and Sanofi. H.L.A.J. received grants from AbbVie, Gilead Sciences, GlaxoSmithKline, Janssen, Roche, Vir Biotechnology Inc. and is a consultant for Aligos, Antios, Arbutus, Eiger, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, VBI Vaccines, Vir Biotechnology Inc. and Viroclinics. D.T.Y.L. received research grants from GlaxoSmithKline, Janssen and Abbott Laboratories. C.P. is a consultant for Janssen. T.P. has been a speaker for Gilead Science. B.T. has nothing to declare. F.V.B. has received research grants from Gilead Sciences, Roche Diagnostics, Ipsen and Janssen; has been part of speaker’s bureau for Gilead Sciences, Roche, Janssen, Ipsen, Eisai, MSD and GSK; and has received support for conference travels from Gilead, Janssen, Roche, Ibsen, MSD and Bayer. O.A. has nothing to disclose, supported by 5R01DK044533-23. M.B.M. is an employee of Janssen Pharmaceuticals. T.M.B. is on the Board of Hepion Pharma and has received support from Arbutus Biopharma and is a co-founder and equity holder in Glycotest. H.L.Y.C. has served as an adviser of AbbVie, Aligos, Arbutus, Gilead, GSK, Hepion, Janssen, Merck, Roche, Vaccitech, VenatoRx, Vir Biotechnology and Virion Therapeutics, and is a speaker for Gilead, Mylan and Roche. G.C. is an Abbott Employee and shareholder. W.E.D. is an employee of and owns stock in Assembly Bio and owns stock in Gilead Sciences. A.M.G. is an employee of Roche Pharma Research and Early Development and also holds stock units with the company. A.G. receives research funding from Janssen Pharmaceuticals, GSK, and Gilead Sciences and conducts consulting/scientific advising for Janssen Pharmaceuticals, Roche, GSK, Vir Biotech, Finch Therapeutics and SQZ Biotech. O.L. is an employee of Janssen Pharmaceutical NV and owns stock of Johnson and Johnson. K.J. performs contract research for Gilead Sciences and Arrowhead Pharmaceuticals. The M.K.M. lab has received collaborative funding from Gilead Sciences, VIR Biotechnology, Hoffmann-La-Roche and GSK (last 3 years), with no funds taken personally. M.K.M. is supported by Wellcome Investigator Award 21419/Z/18/Z. V.M. and the Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA: the Forum received unrestricted support from multiple companies, but did not receive funding specific to the writing of this manuscript. The companies are: Abbott Diagnostics, Aligos Therapeutics, Inc., Altimmune, Antios, Therapeutics, Assembly Biosciences, Eiger Biopharmaceuticals, ENYO Pharma, Gilead, GSK, Immunocore, Janssen Pharmaceuticals ID&V, Monogram Biosciences Quest Diagnostics, Roche Pharma R&D (pRED), Venatorx Pharmaceuticals, Inc., Vir Biotechnology, Virion Therapeutics, LLC, Viroclinics-DDL Diagnostic Laboratory. U.P. is co-founder and shareholder of SCG Cell Therapy, obtained research support from Abbott, ALIOS, Yhlo and VirBio, and received personal fees from Abbvie, Arbutus, Gilead, GSK, J&J, Roche, Sanofi, Sobi and Vaccitech. J.C.Y. was an employee of Gilead Sciences. M.F.Y. reports being an adviser/consultant for and/or having received grant/research support from AbbVie, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals, Silverback Therapeutics, Sysmex Corporation, Vir Biotechnology and Roche. F.Z. reports consulting for Aligos, Antios, Arbutus, Assembly, Enochian, Gilead, GSK, Roche Molecular Systems, and Zhimeng and research funding to INSERM from Assembly, Beam and Viravaxx. P.A.R. has previously received research funding from Gilead Sciences and is on the Scientific Advisory Board of Enochian Biosciences.

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Nature Reviews Gastroenterology & Hepatology thanks Jia-Horng Kao, Philippa Matthews and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

HBV Forum: https://forumresearch.org/hbv-forum/hbv-foruman-overview

Hepatitis B Foundation: https://www.hepb.org/

ICE-HBV: https://ice-hbv.org/

Workshop on HBV biomarkers: https://ice-hbv.org/hbv-serum-biomarkers-workshop/

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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 19, 727–745 (2022). https://doi.org/10.1038/s41575-022-00649-z

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