Hosaka et al. observed 1268 chronic hepatitis B patients treated with nucleic acid analogues for more than 1 year for a median follow-up period of 8.9 years and reported that 113 cases developed HCC, that the HBcrAg level during treatment is a risk factor for the progression of HCC, and that HR was 6.15 with a cut-off level of 4.9 log U/L in HBe antigen-positive patients and 2.54 with cut-off level of 4.4 log U/mL in HBe antigen-negative patients [96]. Here, HBE1 is linked to chronic hepatitis B virus infection.