Three heads are better than two: Hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naïve HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatment-naïve cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naïve patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients.