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

Abstract Background & Aims Hepatitis B virus ( HBV ) covalently closed circular DNA (ccc DNA ) is a key to viral persistence in chronic hepatitis B infection. Serum hepatitis B core‐related antigen ( HB crAg) is a novel marker for HBV disease. We aimed to determine whether HB crAg could be a surrogate marker for intrahepatic ccc DNA . Methods Three hundred and five liver biopsies and the corresponding sera collected from 138 nucleos(t)ide analogues‐treated patients were analysed. 124 patients had paired liver biopsies at baseline and 1‐year post‐treatment, and 43 patients had a third biopsy after 6‐12 years of treatment. Serum HB crAg, HBV DNA and hepatitis B surface antigen ( HB sAg), and intrahepatic HBV DNA and ccc DNA were measured. Results HB crAg strongly correlated with ccc DNA ( r =.70), intrahepatic total HBV DNA ( r =.67) and serum HBV DNA ( r =.69; all P <.0001). In the 130 samples with undetectable serum HBV DNA , HB crAg was detectable in 101 (78%) samples, and HB crAg levels still correlated positively with ccc DNA ( r =.42, P <.0001). At ≥6 years of therapy, the median logarithmic reduction in HB crAg was 2.7 log kU/mL, which was comparable to the magnitude of reduction in ccc DNA . Twenty‐one patients had undetectable ccc DNA after ≥6 years of treatment, in whom 15 (71%) had detectable HB crAg (range: 1.2‐537 kU/mL). Conclusions Serum HB crAg is a reliable surrogate marker for intrahepatic ccc DNA . HB crAg could be a very sensitive marker to reflect the ccc DNA content and persistence of disease even with the ccc DNA levels below the detection limit of assays.