Kaneko S, Kurosaki M, Inada K, et al. - The virological characteristics of HBcrAg were examined in chronic hepatitis B (CHB) patients; the hepatocellular carcinoma (HCC) risk factors of hepatitis B e antigen (HBeAg)-negative patients were determined. Assessment of hepatitis B core-related antigen in 245 naive CHB patients before receiving nucleoside/nucleotide analog (NA) therapy revealed significantly higher median HBcrAg levels in HBeAg-positive vs HBeAg-negative patients. In HBeAg-negative patients, researchers observed correlation of higher HBcrAg levels with cirrhosis (119 chronic hepatitis/20 cirrhosis = 3.5/4.7 log U/mL) and higher serum hepatitis B virus DNA. During a median follow-up of 5.28 (1.03–12.0) years, the HBeAg-negative cohort showed the 5-year cumulative HCC incidence rate of 5.4%. Multivariate Cox regression analysis revealed higher HBcrAg levels at 1 year to be independently linked with HCC development in HBeAg-negative patients who received NA therapy and even in non-cirrhosis patients. These findings suggest hepatitis B core-related antigen as valuable for attaining insight into the disease progression in CHB patients and for stratifying the risk for carcinogenesis in HBeAg-negative patients receiving NA therapy.