Hepatitis B core-related antigen levels after HBeAg seroconversion is associated with the development of hepatocellular carcinoma

J Viral Hepat. 2019 Dec;26(12):1473-1480. doi: 10.1111/jvh.13191. Epub 2019 Sep 2.


Hepatitis B core-related antigen (HBcrAg) is a novel serological marker for hepatitis B virus infection. Its clinical significance after HBeAg seroconversion has not been defined. We aimed to determine the relationship between HBcrAg levels after spontaneous HBeAg seroconversion and hepatocellular carcinoma (HCC). A total of 207 chronic hepatitis B patients with documented time of HBeAg seroconversion were enrolled. HBcrAg and HBsAg were checked within 3 years (as baseline), at 5 and 10 years after HBeAg seroconversion. HBV DNA was measured at the baseline. Multivariate Cox regression model was used to investigate the predictors for HCC development. The median follow-up time was 13.1 (11.8-15.5) years. Fourteen patients developed HCC (15-year cumulative incidence: 7%). The median level of HBcrAg at baseline was significantly higher in patients who developed HCC when compared with patients without HCC (5.68 vs 4.78 log U/ml, respectively; P = .003). Cox proportional hazards model indicated that age of HBeAg seroconversion older than 40 years (hazard ratio (HR): 4.60; P = .049), presence of baseline cirrhosis (HR: 6.23; P = .003) and a higher baseline HBcrAg (HR: 1.75; P = .032) were independently associated with HCC development. A cut-off value of baseline HBcrAg level ≥5.21 log U/mL yielded an AUROC of 0.74 with a negative predictive value of 97.7%. High HBcrAg levels within 3 years after HBeAg seroconversion were independently associated with the development of HCC in chronic hepatitis B patients.

Keywords: chronic hepatitis B; cirrhosis; hepatitis B core-related antigen; hepatocellular carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers
  • Carcinoma, Hepatocellular / blood*
  • Carcinoma, Hepatocellular / diagnosis
  • Carcinoma, Hepatocellular / etiology*
  • Disease Susceptibility
  • Female
  • Hepatitis B Core Antigens / blood*
  • Hepatitis B Core Antigens / immunology
  • Hepatitis B e Antigens / blood*
  • Hepatitis B e Antigens / immunology
  • Hepatitis B virus / immunology
  • Hepatitis B, Chronic / complications*
  • Hepatitis B, Chronic / immunology
  • Hepatitis B, Chronic / virology
  • Humans
  • Incidence
  • Liver Neoplasms / blood*
  • Liver Neoplasms / diagnosis
  • Liver Neoplasms / etiology*
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • ROC Curve
  • Risk Factors
  • Seroconversion


  • Biomarkers
  • Hepatitis B Core Antigens
  • Hepatitis B e Antigens