title: Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy.
abstract: OBJECTIVE
  Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a unique episomal replicative intermediate responsible for persistent infection of hepatocytes. Technical constraints have hampered the direct study of cccDNA maintenance and clearance mechanisms in patients. The aim of this study was to develop a sensitive and specific assay for quantifying cccDNA in biopsy samples from chronic hepatitis B patients during different natural history phases and in patients undergoing antiviral therapy.
  
  
  METHODS
  Intrahepatic cccDNA levels were quantified by a specific real-time PCR assay. Ninety-eight liver biopsy samples from patients in the major phases of the natural history of chronic hepatitis B and 32 pairs of samples from patients receiving adefovir dipivoxil (ADV) therapy were assessed.
  
  
  RESULTS
  cccDNA was detected, at levels ranging over 3 orders of magnitude, in patients in different phases of the natural history of chronic hepatitis B. cccDNA levels were strongly correlated with levels of total intracellular HBV DNA and serum HBV DNA. Forty-eight weeks of ADV therapy resulted in a significant 0.8 log decrease in cccDNA copies/cell. Changes in cccDNA were correlated with a similar reduction in serum HBsAg titer but not with a decrease in the number of HBV antigen-positive cells during ADV treatment.
  
  
  CONCLUSIONS
  cccDNA persists throughout the natural history of chronic hepatitis B, even in patients with serologic evidence of viral clearance. Long-term ADV therapy significantly decreased cccDNA levels by a primarily noncytolytic mechanism.
authors.affiliation: INSERM Unit 271, 151 Cours Albert Thomas, 69003 Lyon, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Werle-Lapostolle
authors.forename: Scott
authors.initials: S
authors.lastname: Bowden
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
authors.forename: Karsten
authors.initials: K
authors.lastname: Wursthorn
authors.forename: Jorg
authors.initials: J
authors.lastname: Petersen
authors.forename: George
authors.initials: G
authors.lastname: Lau
authors.forename: Christian
authors.initials: C
authors.lastname: Trepo
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Zachary
authors.initials: Z
authors.lastname: Goodman
authors.forename: William E
authors.initials: WE
authors.lastname: Delaney
authors.forename: Shelly
authors.initials: S
authors.lastname: Xiong
authors.forename: Carol L
authors.initials: CL
authors.lastname: Brosgart
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Chen
authors.forename: Craig S
authors.initials: CS
authors.lastname: Gibbs
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000225:Adenine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D000998:Antiviral Agents / Q000008:administration & dosage*; D001706:Biopsy; D004270:DNA, Circular / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis; D006512:Hepatitis B Core Antigens / Q000032:analysis; D006514:Hepatitis B Surface Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D063065:Organophosphonates; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: D000998:Antiviral Agents; D004270:DNA, Circular; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; D000225:Adenine; C106812:adefovir dipivoxil