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Hepatitis B core antibody and liver stiffness measurements predict HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with minimally elevated alanine aminotransferase (ALT) levels

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Alanine aminotransferase (ALT) levels between 1 and 2 times the upper limit of normal (ULN) are common in patients with chronic hepatitis B (CHB) infection. There are few clinical studies focused on this group of patients because of the poorer treatment outcomes compared to those with more than 2 × ULN ALT level. However, treatments are necessary to reduce liver damage for patients with minimally elevated ALT levels. And biomarkers are needed in predicting the treatment response. In this study, a total of 106 patients with CHB were enrolled and treated with entecavir, telbivudine or tenofovir disoproxil fumarate. Liver stiffness was measured by transient elastography, and quantitative levels of hepatitis B core antibody (HBcAb) were detected by ELISA. At week 96, 31 (29.25%) patients achieved hepatitis B e antigen (HBeAg) seroconversion. Notably, baseline HBcAb levels and liver stiffness measurements (LSM) were higher in patients who achieved HBeAg seroconversion. The multivariate analysis showed that the baseline HBcAb levels and LSM were independent predictors for HBeAg seroconversion. The area under receiver operating characteristic curve of baseline HBcAb, LSM and the combination of them for HBeAg seroconversion was 0.714, 0.720 and 0.717, respectively. In addition, we discovered that the patients with baseline HBcAb levels ≥ 4.15 log10 IU/mL and LSM ≥ 9.85 kPa had higher rates of HBeAg seroconversion. Therefore, the measurement of HBcAb and liver stiffness might be good approaches for the optimization of antiviral therapy for HBeAg-positive CHB patients with minimally elevated ALT levels.

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Alanine aminotransferase


Aspartate aminotransferase


Area under receiver operating characteristic curve


Chronic hepatitis B




Hepatitis B virus


Hepatitis B surface antigen


Hepatitis B e antigen


Hepatitis B e antibody


Hepatitis B core antibody








Liver stiffness measurement


Nucleos(t)ide analogues


Receiver operating characteristic


Standard deviation


Total bilirubin


Tenofovir disoproxil fumarate


Transient elastography


Upper limit of normal


  1. 1.

    Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.

  2. 2.

    Lampertico P, Agarwal K, Berg T, et al. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.

  3. 3.

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

  4. 4.

    Chen T, He Y, Liu X, et al. Nucleoside analogues improve the short-term and long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure. Clin Exp Med. 2012;12:159–64.

  5. 5.

    Chan HLY, Chan CK, Hui AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology. 2014;146:1240–8.

  6. 6.

    Wong VW, Hui AJ, Wong GL, et al. Four-year outcomes after cessation of tenofovir in immune-tolerant chronic hepatitis B patients. J Clin Gastroenterol. 2018;52:347–52.

  7. 7.

    Zeuzem S, Gane E, Liaw YF, et al. Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B. J Hepatol. 2009;51:11–20.

  8. 8.

    Wu IC, Lai CL, Han SH, et al. Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy-proven histological damage. Hepatology. 2010;51:1185–9.

  9. 9.

    de Ledinghen V, Wong VW, Vergniol J, et al. Diagnosis of liver fibrosis and cirrhosis using liver stiffness measurement: comparison between M and XL probe of FibroScan(R). J Hepatol. 2012;56:833–9.

  10. 10.

    Chen YP, Peng J, Hou JL. Non-invasive assessment of liver fibrosis in patients with chronic hepatitis B. Hepatol Int. 2013;7:356–68.

  11. 11.

    Li Y, Huang YS, Wang ZZ, et al. Systematic review with meta-analysis: the diagnostic accuracy of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B. Aliment Pharmacol Ther. 2016;43:458–69.

  12. 12.

    Bertoletti A. Ferrari C Adaptive immunity in HBV infection. J Hepatol. 2016;64:S71–83.

  13. 13.

    Gehring AJ. Protzer U targeting innate and adaptive immune responses to cure chronic HBV infection. Gastroenterology. 2019;156:325–37.

  14. 14.

    Shi TD, Zhang JM, Wang XF, et al. Effects of antiviral therapy with Telbivudine on peripheral iNKT cells in HBeAg(+) chronic hepatitis B patients. Clin Exp Med. 2012;12:105–13.

  15. 15.

    Song LW, Liu PG, Liu CJ, et al. Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection. Clin Microbiol Infect. 2015;21:197–203.

  16. 16.

    Zerbini A, Pilli M, Boni C, et al. The Characteristics of the cell-mediated immune response identify different profiles of occult hepatitis B virus infection. Gastroenterology. 2008;134:1470–81.

  17. 17.

    Fan R, Sun J, Yuan Q, et al. 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;65:313–20.

  18. 18.

    Hou F, Song L, Yuan Q, et al. Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon. Theranostics. 2015;5:218–26.

  19. 19.

    Yuan Q, Song LW, Liu CJ, et al. Quantitative hepatitis B core antibody level may help predict treatment response in chronic hepatitis B patients. Gut. 2013;62:182–4.

  20. 20.

    Li A, Yuan Q, Huang Z, et al. Novel double-antigen sandwich immunoassay for human hepatitis B core antibody. Clin Vaccine Immunol. 2010;17:464–9.

  21. 21.

    Liaw YF, Jia JD, Chan HL, et al. Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C. Hepatology. 2011;54:1591–9.

  22. 22.

    Fried MW, Piratvisuth T, Lau GK, et al. HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. Hepatology. 2008;47:428–34.

  23. 23.

    Rijckborst V, Hansen BE, Cakaloglu Y, et al. Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology. 2010;52:454–61.

  24. 24.

    Xu JH, Song LW, Li N, et al. Baseline hepatitis B core antibody predicts treatment response in chronic hepatitis B patients receiving long-term entecavir. J Viral Hepatitis. 2017;24:148–54.

  25. 25.

    Chi H, Li Z, Hansen BE, et al. Serum level of antibodies against hepatitis B core protein is associated with clinical relapse after discontinuation of nucleos(t)ide analogue therapy. Clin Gastroenterol Hepatol. 2019;17(182–191):e1.

  26. 26.

    Tseng C, Hsu Y, Chang C, et al. Quantification of serum hepatitis B core antibody to predict off-entecavir relapse in patients with chronic hepatitis B. J Formos Med Assoc. 2018;117:915–21.

  27. 27.

    Wang LY, Fan YC, Zhao J, et al. Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B. Clin Exp Med. 2018;18:263–72.

  28. 28.

    Han Q, Li N, Zhu Q, et al. Association of serum soluble human leukocyte antigen-G levels with chronic hepatitis B virus infection. Clin Exp Med. 2014;14:35–43.

  29. 29.

    Milich DR, McLachlan A, Thornton GB, et al. Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site. Nature. 1987;329:547–9.

  30. 30.

    Kefalakes H, Jochum C, Hilgard G, et al. Decades after recovery from hepatitis B and HBsAg clearance the CD8+ T cell response against HBV core is nearly undetectable. J Hepatol. 2015;63:13–9.

  31. 31.

    Zgair AK, Ghafil JA, Al-Sayidi RHE. Direct role of antibody-secreting B cells in the severity of chronic hepatitis B. J Med Virol. 2015;87:407–16.

  32. 32.

    Farci P, Diaz G, Chen Z, et al. B cell gene signature with massive intrahepatic production of antibodies to hepatitis B core antigen in hepatitis B virus-associated acute liver failure. Proc Natl Acad Sci. 2010;107:8766–71.

  33. 33.

    Wang Y, Li Y, Li N, et al. Transbody against hepatitis B virus core protein inhibits hepatitis B virus replication in vitro. Int Immunopharmacol. 2015;25:363–9.

  34. 34.

    Medrano LM, Garcia-Broncano P, Berenguer J, et al. Elevated liver stiffness is linked to increased biomarkers of inflammation and immune activation in HIV/hepatitis C virus-coinfected patients. AIDS. 2018;32:1095–105.

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This study was supported by Grant No. 201904010065 from the science and technology program of Guangzhou. We thank all patients, their families and nurses, for their kindly support.

Author information

Xihua Fu contributed to patient recruitment, acquisition and analysis of data, drafting of the manuscript and obtaining funding. Haibo Lou and Fang Chen contributed to patient recruitment and data collection. Xueping Gao and Zhanzhou Lin contributed to study concept and design, patient recruitment, interpretation of data, critical revision of the manuscript for important intellectual content. The article was approved to be published by all authors.

Correspondence to Xueping Gao or Zhanzhou Lin.

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All authors declare that they have no conflict of interest.

Ethical approval and Informed consent

All procedures followed were in accordance with the Helsinki Declaration, and the study protocol was permitted by the Ethics Committee of Panyu Central Hospital, Guangzhou, China and Huizhou Municipal Central Hospital, Huizhou, China. Informed consents were signed by all patients.

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Fu, X., Lou, H., Chen, F. et al. Hepatitis B core antibody and liver stiffness measurements predict HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with minimally elevated alanine aminotransferase (ALT) levels. Clin Exp Med (2020).

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  • Chronic hepatitis B
  • Minimally elevated ALT levels
  • Hepatitis B core antibody
  • Liver stiffness measurement