title: Mechanisms downstream of reverse transcription reduce serum levels of HBV DNA but not of HBsAg in chronic hepatitis B virus infection.
abstract: BACKGROUND
  Hepatitis B virus (HBV) DNA in serum of chronically infected patients declines by 3-4 log10 units at loss of HBe antigen (HBeAg) from serum. The mechanisms behind this decline, and the much smaller decline of surface antigen (HBsAg) levels, are still not well known. The aim of this study was to get a better understanding of this process by analysing both serum and intrahepatic markers of HBV replication.
  
  
  METHODS
  Levels of HBV DNA and HBsAg in serum, and covalently closed circular DNA (cccDNA), pregenomic RNA (pgRNA) and S-RNA and total intrahepatic HBV DNA (ihDNA) in liver biopsies from 84 chronically infected patients (16 positive and 68 negative for HBeAg) were analysed.
  
  
  RESULTS
  Lower HBV DNA levels within HBeAg-positive stage reflected lower levels of cccDNA and pgRNA with strong correlation. In HBeAg-negative patients, ihDNA levels were greater and HBV DNA levels in serum lower than expected from pgRNA levels. A lower HBV DNA/HBsAg ratio corresponded with lower pgRNA/cccDNA (p < 0.01) and higher S-RNA/cccDNA (p < 0.0001) ratios, suggesting that in HBeAg-negative patients transcription of pgRNA, but not of S-RNA, becomes suppressed.
  
  
  CONCLUSIONS
  The marked reduction of HBV DNA in serum after loss of HBeAg appears to be due to combined reduction of cccDNA, pgRNA and yet unidentified mechanisms downstream of reverse transcription. Such mechanisms include faster clearance of circulating virus or blocked secretion of virions, the latter supported by the observed relative increase of ihDNA in HBeAg-negative patients. The smaller reduction of S-RNA than of pgRNA partly explains why HBsAg remain high in the HBeAg-negative stage, supporting the possibility of HBsAg synthesis from integrated HBV DNA.
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. simon.b.larsson@gu.se.
authors.forename: Simon B
authors.initials: SB
authors.lastname: Larsson
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. sebastian.malmstrom@gmail.com.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Malmström
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. charles.hannoun@microbio.gu.se.
authors.forename: Charles
authors.initials: C
authors.lastname: Hannoun
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. gunnar.norkrans@vgregion.se.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norkrans
authors.affiliation: Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. magnus.lindh@microbio.gu.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Lindh
mesh_terms: D000293:Adolescent; D000328:Adult; D001769:Blood / Q000821:virology*; D004279:DNA, Viral / Q000097:blood*; D005260:Female; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000821:virology*; D006801:Humans; D008099:Liver / Q000821:virology; D008297:Male; D008875:Middle Aged; D048348:Reverse Transcription; D014779:Virus Replication; D055815:Young Adult
chemical_list: D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens