Prediction of Hepatocellular Carcinoma by On-Therapy Response of Noninvasive Fibrosis Markers in Chronic Hepatitis B

Am J Gastroenterol. 2021 Aug 1;116(8):1657-1666. doi: 10.14309/ajg.0000000000001219.


Introduction: Antiviral therapy improves hepatic fibrosis and reduces hepatocellular carcinoma (HCC) incidence. This study aimed to evaluate whether on-therapy changes in scores for fibrosis index based on 4 factors and aspartate aminotransferase-to-platelet ratio index are associated with HCC development and establish an HCC risk score model incorporating noninvasive fibrosis marker (NFM) response.

Methods: This multicenter study recruited 5,147 patients with chronic hepatitis B (4,028 for derivation cohort and 1,119 for validation cohort) who were given entecavir/tenofovir for >12 months between 2007 and 2018. A risk prediction model for HCC was developed using predictors based on multivariable Cox models, and bootstrapping was performed for validation.

Results: The 10-year cumulative HCC incidence rates were 12.6% and 13.7% in the derivation and validation cohorts, respectively. The risk of HCC significantly differed with early NFM response, with a marked reduction in HCC risk in patients achieving a significant decrease in NFM by 12 months (P < 0.001). NFM response, sex, age, and cirrhosis were independently predictive of HCC. We developed the Fibrosis marker response, Sex, Age, and Cirrhosis (FSAC) score based on regression coefficients of each variable. For the 10-year prediction of HCC, FSAC showed higher C-index values than PAGE-B, modified PAGE-B, CU-HCC, and REACH-B (0.84 vs 0.77, 0.80, 0.77, and 0.67, respectively; all P < 0.005). The predictive performance of FSAC was corroborated in the validation cohort, with higher C-index than other models (all P < 0.050).

Discussion: On-therapy changes in NFM are an independent indicator of HCC risk. FSAC incorporating NFM response is a reliable risk score for risk estimation for HCC with better performance than other models.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use*
  • Biomarkers, Tumor / blood*
  • Carcinoma, Hepatocellular / blood*
  • Carcinoma, Hepatocellular / virology
  • Female
  • Hepatitis B, Chronic / drug therapy*
  • Humans
  • Incidence
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / virology
  • Liver Neoplasms / blood*
  • Liver Neoplasms / virology
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Risk Assessment


  • Antiviral Agents
  • Biomarkers, Tumor