Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients



Hepatitis B core-related antigen (HBcrAg) is a novel serum viral marker. Recent studies showed that its level correlates with the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to evaluate the accuracy of serum HBsAg and HBcrAg levels at baseline to predict HCC.


1400 CHB patients who received nucleos(t)ide analogues (NA) treatment since December 2005 were included. Their stored serum samples at baseline were retrieved to measure HBsAg and HBcrAg levels. The primary endpoint was the cumulative incidence of HCC.


85 (6.1%) patients developed HCC during a mean (± SD) follow-up duration of 45 ± 20 months. Serum HBcrAg level above 2.9 log10 U/mL at baseline was an independent factor for HCC in hepatitis B e antigen (HBeAg)-negative patients by multivariable analysis (adjusted hazard ratio 2.13, 95% CI 1.10–4.14, P = 0.025). HBcrAg above 2.9 log10 U/mL stratified the risk of HCC in HBeAg-negative patients with high PAGE-B score (P = 0.024 by Kaplan–Meier analysis), and possibly in cirrhotic patients (P = 0.08). Serum HBsAg level did not show any correlation with the risk of HCC in all patients or any subgroups.


Serum HBcrAg level predicts the risk of HCC accurately in NA-treated HBeAg-negative CHB patients.

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  1. 1.

    Zhou Y-H. Global prevalence of hepatitis B virus infection and prevention of mother-to-child transmission. Lancet Gastroenterol Hepatol. 2018;3:598.

    Article  Google Scholar 

  2. 2.

    Chan SL, Wong VWS, Qin S, et al. Infection and Cancer: the Case of Hepatitis B. J Clin Oncol. 2015;34:83–90.

    Article  Google Scholar 

  3. 3.

    Wong GLH, Chan HLY, Mak CWH, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis. Hepatology. 2013;58:1537–47.

    CAS  Article  Google Scholar 

  4. 4.

    Hellan K, Anna SL. Hepatitis B therapy. Nat Rev Gastroenterol Hepatol. 2011;8:275.

    Article  Google Scholar 

  5. 5.

    Yip TC-F, Wong GL-H, Chan HL-Y, et al. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol. 2019;70:361–70.

    CAS  Article  Google Scholar 

  6. 6.

    Wong GL-H, Chan HL-Y, Chan H-Y, et al. Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment. Gastroenterology. 2013;144:933.

    Article  Google Scholar 

  7. 7.

    Lo AO-S, Wong GL-H. Current developments in nucleoside/nucleotide analogues for hepatitis B. New York: Taylor & Francis; 2014. p. 607–22.

    Google Scholar 

  8. 8.

    Chen C-J, Yang H-I, Su J, et al. Risk of Hepatocellular Carcinoma Across a Biological Gradient of Serum Hepatitis B Virus DNA Level. JAMA. 2006;295:65–73.

    CAS  Article  Google Scholar 

  9. 9.

    Wong G, Wong V. Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy. World J Gastroenterol. 2013;19:6515–22.

    Article  Google Scholar 

  10. 10.

    Wong GL-H, Chan HL-Y. Use of quantitative hepatitis B surface antigen with hepatitis B virus DNA in clinical practice. Clin Liver Dis. 2013;2:8.

    Article  Google Scholar 

  11. 11.

    Cornberg M, Wong VW-S, Locarnini S, et al. The role of quantitative hepatitis B surface antigen revisited. J Hepatol. 2017;66:398–411.

    CAS  Article  Google Scholar 

  12. 12.

    Tseng TC, Liu CJ, Yang HC, et al. High Levels of Hepatitis B Surface Antigen Increase Risk of Hepatocellular Carcinoma in Patients With Low HBV Load. Gastroenterology. 2012;142(1140–9):e3.

    Google Scholar 

  13. 13.

    Mak LY, Wong DKH, Cheung KS, et al. Review article: hepatitis B core‐related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection. 2018. p. 43–54.

  14. 14.

    Tada T, Kumada T, Toyoda H, et al. HBcrAg predicts hepatocellular carcinoma development: an analysis using time-dependent receiver operating characteristics. J Hepatol. 2016;65:48–56.

    CAS  Article  Google Scholar 

  15. 15.

    Hosaka T, Suzuki F, Kobayashi M, 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 Ther. 2019;49:457.

    CAS  Article  Google Scholar 

  16. 16.

    Wong GL-H, Chan HL-Y, Wong CKY, et al. Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis BDoctopic: CAN. J Hepatol. 2014;60:339–45.

    Article  Google Scholar 

  17. 17.

    Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hep Intl. 2016;10:1–98.

    CAS  Article  Google Scholar 

  18. 18.

    Lampertico P, Agarwal K, Berg T, et al. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370.

    Article  Google Scholar 

  19. 19.

    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;67:1560–99.

    Article  Google Scholar 

  20. 20.

    Chan HL-Y, Wong GL-H, Tse C-H, et al. Viral determinants of hepatitis B surface antigen seroclearance in hepatitis B e antigen-negative chronic hepatitis B patients. J Infect Dis. 2011;204:408.

    CAS  Article  Google Scholar 

  21. 21.

    Wong GLH, Wong VWS, Tan GM, et al. Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int. 2008;28:79–87.

    CAS  Article  Google Scholar 

  22. 22.

    Wong VW, Chan SL, Mo F, et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010;28:1660–5.

    CAS  Article  Google Scholar 

  23. 23.

    Wong G, Chan H, Lo A, et al. Serum hepatitis B surface antigen kinetics in severe reactivation of hepatitis B e antigen negative chronic hepatitis B patients receiving nucleoside/nucleotide analogues. Antivir Ther. 2013;18:979–86.

    CAS  Article  Google Scholar 

  24. 24.

    Kimura T, Rokuhara A, Matsumoto A, et al. New Enzyme Immunoassay for Detection of Hepatitis B Virus Core Antigen (HBcAg) and Relation between Levels of HBcAg and HBV DNA. J Clin Microbiol. 2003;41:1901.

    CAS  Article  Google Scholar 

  25. 25.

    Galle PR, Forner A, Llovet JM, et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  26. 26.

    Papatheodoridis G, Dalekos G, Sypsa V, et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol. 2016;64:800–6.

    CAS  Article  Google Scholar 

  27. 27.

    Riveiro-Barciela M, Tabernero D, Calleja JL, et al. Effectiveness and safety of entecavir or tenofovir in a Spanish Cohort of Chronic Hepatitis B Patients: validation of the Page-B Score to Predict Hepatocellular Carcinoma. Dig Dis Sci. 2017;62:784–93.

    CAS  Article  Google Scholar 

  28. 28.

    Wong VW-S, Chan SL, Mo F, et al. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol. 2010;28:1660.

    CAS  Article  Google Scholar 

  29. 29.

    Yuen M-F, Tanaka Y, Fong DY-T, et al. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol. 2009;50:80–8.

    Article  Google Scholar 

  30. 30.

    Yang H-I, Yuen M-F, Chan HL-Y, et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol. 2011;12:568–74.

    Article  Google Scholar 

  31. 31.

    Yu HJ, Suh JY, Jin WYJ, et al. Prediction model for hepatocellular carcinoma risk in treatment-naive chronic hepatitis B patients receiving entecavir/tenofovir. Eur J Gastroenterol Hepatol. 2019;31:865–72.

    CAS  Article  Google Scholar 

  32. 32.

    Chen C, Lee CM, Lai HC, et al. Prediction model of hepatocellular carcinoma risk in Asian patients with chronic hepatitis B treated with entecavir. Oncotarget. 2017;8:92431–41.

    Article  Google Scholar 

  33. 33.

    Zhu L, Li T, Ma X, et al. A Simple Noninvasive Index Can Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B. Sci Rep. 2017;7:8954.

    Article  Google Scholar 

  34. 34.

    Li Y-W, Yang F-C, Lu H-Q, et al. Hepatocellular carcinoma and hepatitis B surface protein. World J Gastroenterol. 2016;22:1943–52.

    CAS  Article  Google Scholar 

  35. 35.

    Lai CL, Yuen MF. Prevention of hepatitis B virus–related hepatocellular carcinoma with antiviral therapy. Hoboken. 2013. p. 399–408.

  36. 36.

    Lindh M, Rydell GE, Larsson SB. Impact of integrated viral DNA on the goal to clear hepatitis B surface antigen with different therapeutic strategies. Curr Opin Virol. 2018;30:24.

    CAS  Article  Google Scholar 

  37. 37.

    Suzuki F, Miyakoshi H, Kobayashi M, et al. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 2009;81:27–33.

    Article  Google Scholar 

  38. 38.

    Arends P, Sonneveld MJ, Zoutendijk R, et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut. 2015;64:1289.

    CAS  Article  Google Scholar 

  39. 39.

    Wong GLH, Chan HLY, Yiu KKL, et al. Meta-analysis: the association of hepatitis B virus genotypes and hepatocellular carcinoma. Aliment Pharmacol Ther. 2013;37:517–26.

    CAS  Article  Google Scholar 

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This work was supported by the Health and Medical Research Fund (HMRF) of the Food and Health Bureau (Reference no: 15160551) award to Grace Wong.

Author information




All authors were responsible for the study concept and design. Lilian Liang, Yee-Kit Tse, Terry Yip, Becky Yuen and Grace Wong were responsible for the acquisition and analysis of data, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors were responsible for the interpretation of data, the drafting, and critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Grace Lai-Hung Wong.

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Conflict of interest

Vincent Wong has served as an advisory committee member for 3 V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, TARGET-NASH and Terns; and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences and Merck. He has also received a research grant from Gilead Sciences. Hidenori Toyoda has served as a speaker for AbbVie and Merck. Terry Yip has served as a speaker for Gilead Sciences. Takashi Kumada has served as a speaker for Abbvie, Eisai and Gilead Sciences. Henry Chan is an advisor for AbbVie, Aptorum, Altimmune, Arbutus, Intellia, Janssen, Gilead, GRAIL, Medimmune, Roche, Vir Biotechnology; and a speaker for AbbVie, Gilead and Roche. Grace Lui has served as an advisory committee member for Gilead, speaker for Merck and Gilead, and received research grant from Gilead. Grace Wong has served as an advisory committee member for Gilead Sciences, as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche, and received research grant from Gilead Sciences. The other authors declare that they have no conflict of interest (potential personal and financial interests inclusive).

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Liang, L.Y., Wong, V.W., Toyoda, H. et al. Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients. J Gastroenterol (2020).

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  • Hepatitis B core-related antigen
  • Hepatitis B surface antigen
  • Hepatocellular carcinoma
  • Antiviral agents