High Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma in Patients with Low Hepatitis B Surface Antigen and High Hepatitis B Core-Related Antigen Titers

Abstract

Aim: Although the serum hepatitis B virus (HBV) DNA level is an important biomarker for the management of chronic HBV infection and a known independent predictor of hepatocellular carcinoma (HCC), HBV DNA is no longer useful as nucleos(t)ide analogue (NA) suppresses the serum HBV DNA titer. Because the viral markers HB surface antigen (HBsAg) and HB core-related antigen (HBcrAg) can reflect intrahepatic HBV replication activity and constitute important biomarkers for HCC, the value of using these two markers in combination to assess HCC risk was investigated in a patient cohort.
Methods: Included in this study were consecutive patients with chronic HBV infection in whom the association of HBsAg and HBcrAg with HCC risk was investigated cross-sectionally, and longitudinally.
Results: When the high-value cut-offs of HBsAg and HBcrAg were defined as 3.5 log IU/mL and 4.9 log U/mL among the HBe-negative patients, respectively, those with a history of HCC were found frequently in the low HBsAg group (p=0.017) and high HBcrAg group (p=0.040). When HBsAg and HBcrAg were combined, an HCC history was most frequent in the subset with low HBsAg and high HBcrAg (odds ratio [OR], 5.40; p<0.001), irrespective of NA therapy (OR, 5.71; p=0.012). These results were almost the same in the HBe-positive patients. In a longitudinal analysis of the subsequent development of HCC carried out on 374 patients without a history of HCC at enrollment, HCC developed significantly more frequently in the low HBsAg/high HBcrAg group (OR, 3.55; p=0.006).
Conclusions: This cross-sectional and longitudinal analysis showed that the patients with low HBsAg/high HBcrAg values were at high risk of developing HBV-related HCC, indicating that the combination of HBsAg and HBcrAg values may be an excellent biomarker for assessing HCC risk, especially in patients receiving NA treatment.