title: Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA.
abstract: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key to viral persistence in chronic hepatitis B infection. Serum hepatitis B core-related antigen (HBcrAg) is a novel marker for HBV disease. We aimed to determine whether HBcrAg could be a surrogate marker for intrahepatic cccDNA.
  
  
  
  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 HBcrAg, HBV DNA and hepatitis B surface antigen (HBsAg), and intrahepatic HBV DNA and cccDNA were measured.
  
  
  
  HBcrAg strongly correlated with cccDNA (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, HBcrAg was detectable in 101 (78%) samples, and HBcrAg levels still correlated positively with cccDNA (r=.42, P<.0001). At ≥6 years of therapy, the median logarithmic reduction in HBcrAg was 2.7 log kU/mL, which was comparable to the magnitude of reduction in cccDNA. Twenty-one patients had undetectable cccDNA after ≥6 years of treatment, in whom 15 (71%) had detectable HBcrAg (range: 1.2-537 kU/mL).
  
  
  
  Serum HBcrAg is a reliable surrogate marker for intrahepatic cccDNA. HBcrAg could be a very sensitive marker to reflect the cccDNA content and persistence of disease even with the cccDNA levels below the detection limit of assays.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Danny Ka-Ho
authors.initials: DK
authors.lastname: Wong
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Wai-Kay
authors.initials: WK
authors.lastname: Seto
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ka-Shing
authors.initials: KS
authors.lastname: Cheung
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Chun-Kong
authors.initials: CK
authors.lastname: Chong
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Fung-Yu
authors.initials: FY
authors.lastname: Huang
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: James
authors.initials: J
authors.lastname: Fung
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Man-Fung
authors.identifier: 0000-0001-7985-7725
authors.initials: MF
authors.lastname: Yuen
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D057205:Automation, Laboratory; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D004270:DNA, Circular / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D006512:Hepatitis B Core Antigens / Q000097:blood*; D006514:Hepatitis B Surface Antigens / Q000097:blood; D019694:Hepatitis B, Chronic / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006801:Humans; D008099:Liver / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D004270:DNA, Circular; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens
keywords: covalently closed circular DNA; hepatitis B; hepatitis B core-related antigen; hepatitis B serum markers; intrahepatic HBV DNA