Hepatitis B core-related antigen as a multifaceted biomarker in chronic hepatitis B: implications for immune activity and hepatocellular carcinoma prediction

Background/Aims: Hepatitis B core-related antigen (HBcrAg) reflects both serum hepatitis B virus (HBV) DNA and intrahepatic covalently closed circular DNA activity, offering potential advantages over conventional biomarkers in monitoring chronic hepatitis B (CHB). This study evaluated the clinical utility of HBcrAg across immune phases and its prognostic value for hepatocellular carcinoma (HCC).Methods: In this retrospective study, 281 CHB patients from Daejeon St. Mary’s Hospital (September 2022−July 2024) were classified into HBV phases. HBcrAg was quantified using the ultrasensitive iTACT−HBcrAg assay. HBcrAg level was compared across HBV phases, HCC presence, and patient characteristics.Results: HBcrAg levels varied significantly across immune phases, with an AUC of 0.97 for HBeAg(+) IA vs. IT, and 0.83 for HBeAg(-) IA vs. II. In HBeAg(-) IA, HBcrAg ≥ 3.8 LogU/mL was associated with higher HCC prevalence at AUC 0.69, while in HBeAg(+) IA, ≥ 4.9 LogU/mL was the optimal cut-off at AUC 0.71. In HBeAg(-) II, HBcrAg < 3.8 LogU/mL was linked to the absence of HCC. HBcrAg correlated inversely with age (r = -0.31, <i>p</i> < 0.0001), while the relationship with fibrosis severity differed according to HBeAg status. In multivariate analysis, HBcrAg remained independently associated with HCC (OR 1.64, <i>p</i> = 0.002). Residual HBcrAg positivity was observed in patients with HBsAg loss.Conclusions: HBcrAg is a robust biomarker capturing both virologic and immunologic activity in CHB, with additional prognostic value for HCC, particularly in IA phases. It may complement or surpass conventional markers in phase classification and risk stratification.