During HBV replication, pregenomic RNA can be transcribed from covalently closed circular DNA (cccDNA) to serve as the template of negative-strand DNA through reverse transcription, and then fully double-stranded DNA through DNA polymerase within the nucleocapsid, finally with the assembly of envelope protein to form mature HBV virions.2 Several mRNAs can also be transcribed from cccDNA and then translate to viral proteins. Therefore, several qualitative viral factors can be clinically useful, including HBV-DNA from the infectious particles and circulating viral proteins such as HBsAg and HBeAg.

Several host and viral factors predictive of HCC risk have been identified, and the REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) study has developed and validated a predictive score for the risk of development of HCC in patients with chronic hepatitis B.33 This study included risk score development cohort with 3,584 non-cirrhotic CHB Taiwanese and a validation cohort with 1,050 patients from three independent hospitals of Hong Kong and Republic of Korea. The 17-point risk score is composed of 5 predictors of HCC, including sex, age, serum ALT level, HBeAg status, and serum HBV-DNA level. The risk score could precisely estimate the risk of HCC development at 3, 5, and 10 years of follow-up. Nevertheless, this risk scoring system of HCC may underestimate risk for patients with very low viral load at baseline. In ERADICATE-B study, the risk of HCC for carriers with HBV-DNA <2,000 IU/mL and HBsAg ≧1,000 IU/mL was much higher than those with HBV-DNA <2,000 IU/mL and HBsAg <1,000 IU/mL.31 This finding indicated that high HBsAg level itself may reflect inadequate host immune control against HBV infection, leading to an increased HCC risk over time in patients with low viral load. Therefore, serum HBsAg level should be integrated into the HCC risk calculator for future management of patients with chronic HBV infection, particularly in those with low and intermediate viral loads. Furthermore, the relationships between HCC risk and dynamic changes of serum HBV-DNA, HBsAg, and ALT levels were determined in the ERADICATE-B study. Compared to patients with persistently low levels of HBV-DNA, HBsAg, or ALT, those with persistently high levels of these 3 factors were at a higher risk of HCC.32 Therefore, it is essential to incorporate qualitative and quantitative hepatitis B viral factors in risk calculation model to make it more comprehensive and to be clinically useful in various forms of chronic liver disease, including inactive carrier state, chronic hepatitis and cirrhosis (Fig.).

The severity of hepatic fibrosis is known to be associated with HCC risk,34 however, this parameter has not been incorporated in the risk model for HCC development because of the invasive nature of liver biopsy. Recently, liver stiffness measurement by using transient elastography has been introduced as a noninvasive method for assessing the severity of hepatic fibrosis.35 A previous study showed that the baseline liver stiffness values could be an independent predictor of HCC in patients with chronic HBV infection, where the 3-year cumulative incidence of HCC was significantly higher in patients with a higher liver stiffness value.34

A recent Korean study included 1,250 CHB patients with baseline liver stiffness values to construct a predictive model for HCC occurrence based on a Cox proportional hazards model.36 By using multivariate analysis, age, male gender, and liver stiffness values were independent predictors of HCC, whereas HBV-DNA level ≥20,000 IU/L showed borderline statistical significance. A predictive model for HCC was developed using these 4 variables, with a correlation coefficient of 0.905 between predicted risk and observed risk of HCC occurrence. The suggested formula for 3-year probability of HCC occurrence is 1 - PA (A=exp [0.05306×age+1.106×male gender+0.04858×liver stiffness value+0.50969×HBV DNA ≥20,000 IU/L]). Thus, this novel model may accurately estimate the risk of HCC occurrence in Asian patients with chronic HBV infection.