Relationship between hepatocellular carcinoma development and serum viral markers in chronic hepatitis B patients who achieved undetectable serum HBV DNA while on long-term nucleoside analogue therapy

Abstract

BACKGROUND: Hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) are risk factors for the development of hepatocellular carcinoma (HCC). Linearized HBsAg (HQ-HBsAg) is a more sensitive assay to measure HBsAg level. However, their roles in predicting HCC development are unknown when there is profound viral suppression by nucleos(t)ide analogues (NA). METHODS: Seventy-six chronic hepatitis B (CHB) patients who developed HCC in 2007-2014 despite undetectable serum HBV DNA level after at least one-year NA therapy were recruited. 152 CHB patients without HCC were recruited as controls. They were matched by age, gender, HBeAg status, cirrhosis status, undetectable serum HBV DNA and duration of NA therapy with the 76 HCC patients in a 2:1 ratio. Serum HBsAg, HQ-HBsAg and HBcrAg levels were analysed and compared between the two groups. RESULTS: A statistically significant difference in the HBcrAg level was noted between the HCC group and non-HCC groups (10.2 and 1.7 kU/mL respectively, p=0.005), but was not observed in HBsAg or HQ-HBsAg levels. The area under receiver operating characteristic curve (AUROC) was 0.61 (95% CI: 0.54-0.69) with a negative predictive value (NPV) of 77.0% when a cutoff value of HBcrAg level ≥7.8 kU/mL was used. The odds ratio of HCC development was 3.27 (95% CI: 1.84-5.80). In the subgroup analysis for non-cirrhotic patients, a statistically significant difference in the HBcrAg level was noted between the HCC group and non-HCC groups (10.2 and 1.0 kU/mL respectively, p=0.001). The AUROC was 0.70 (95% CI: 0.58-0.81) with a NPV of 80.6% when a cutoff value of HBcrAg level ≥7.9 kU/mL was used. The odds ratio of HCC development was 5.95 (95% CI: 2.35-15.07). CONCLUSION: HBcrAg (but not HBsAg or HQ-HBsAg) can predict HCC risk in CHB patients who achieve undetectable serum HBV DNA while receiving NA therapy. Future prospective studies are warranted to further define the role of HBcrAg level in this group of patients.