Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA

Abstract

BACKGROUND: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key to viral persistence in chronic hepatitis B patients. We aimed to explore whether serum hepatitis B core-related antigen (HBcrAg) could be a surrogate marker for intrahepatic cccDNA in a large cohort of patients with liver biopsies. METHODS: 305 liver biopsies and the corresponding sera collected from 138 nucleoside/tide analogues-treated patients were analyzed. 124 patients had paired liver biopsies at baseline and 1 year posttreatment, and 43 patients had a third biopsy after [5 years of treatment. Serum HBcrAg, HBV DNA and hepatitis B surface antigen (HBsAg), and intrahepatic cccDNA were measured. RESULTS: HBcrAg strongly correlated with cccDNA (r = 0.695), serum HBV DNA (r = 0.691), and HBsAg (r = 0.449; all p\0.00001). Serum HBV DNA were undetectable (\20 IU/mL) in 120 samples. In these 120 samples, HBcrAg also correlated positively with cccDNA (r = 0.388, p = 0.00001). At baseline, all 124 patients had HBcrAg[1 kU/mL (median level: 3.6 log kU/mL). At year 1 and [5 years post-treatment, the median HBcrAg levels were 2.3 and 0.77 log kU/mL, with a median logarithmic reduction of 1.4 and 2.7 log kU/mL (compared with baseline), respectively. 21 patients had undetectable cccDNA (\0.005 copies/cell) after[5 years post-treatment, in which 15 (71 %) had HBcrAg levels [1 kU/mL (range 1.2–537 kU/mL). CONCLUSIONS: Serum HBcrAg might be a potentially reliable surrogate marker for intrahepatic cccDNA content even when serum HBV DNA became undetectable. Viral proteins were still synthesized in the majority of patients with undetectable cccDNA after long-term treatment.