title: Clinical significance of hepatitis B virion and SVP productivity: relationships between intrahepatic and serum markers in chronic hepatitis B patients.
abstract: BACKGROUND
  Clinical use of hepatitis B viral (HBV) quantitative seromarker\s remains questionable since it is not precisely known whether they represent intrahepatic viral replication. Covalently closed circular DNA (cccDNA), relaxed circular DNA (rcDNA), and pregenomic RNA (pgRNA) are more likely to represent active HBV replication and their measurement can be used to derive virion productivity (VP; rcDNA/cccDNA), subviral particle (SVP) productivity (quantitative HBsAg/cccDNA), and replicative activity (RA; pgRNA/cccDNA). These can be used to compare relative HBV replication between HBeAg-negative and -positive patients.
  
  
  OBJECTIVE
  To study the clinical significance of intrahepatic HBV replication phenomenon between HBeAg-negative and -positive patients and its correlation with quantitative HBV seromarkers.
  
  
  METHODS
  This was a prospective study between January 2010 and December 2011. Study subjects were naive chronic hepatitis B patients from Cipto Mangunkusumo and Medistra Hospitals. All patient samples underwent liver biochemistry and HBV seromarkers testing (HBeAg, quantitative HBsAg and HBV DNA levels), and patients underwent liver biopsy. Stored liver specimens were analysed for intrahepatic rcDNA, cccDNA, and pgRNA with quantification performed by real-time PCR. Comparison of HBV markers between HBsAg-positive and -negative patients was carried out using the Mann-Whitney U-test. Pearson's correlation test was performed among HBV intrahepatic and seromarkers using their log-transformed values.
  
  
  RESULTS
  A total of 104 patients were enrolled in this study; 54 (51.9%) were male. Patients' mean age was 41.9 ± 11.63 years (range 19-70 years). Sixty-one patients (58.7%) were HBeAg-negative. All HBV markers were significantly higher in HBeAg-positive than HBeAg-negative patients, except for SVP productivity and RA. Serum HBV DNA was strongly correlated with intrahepatic total HBV DNA (r = 0.771), cccDNA (r = 0.774), and rcDNA (r = 0.780) while serum quantitative HBsAg showed only moderate correlation with intrahepatic total DNA (r = 0.671), cccDNA (r = 0.632), rcDNA (r = 0.675), and SVP productivity (r = 0.557).
  
  
  CONCLUSIONS
  Serum HBV DNA concentration and quantitative HBsAg might not accurately predict intrahepatic viral activity. Virion and SVP production do not occur in parallel with replicative activity.
authors.affiliation: Hepatology, Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia ; Digestive Disease and GI Oncology Center, Medistra Hospital, Jakarta, Indonesia.
authors.forename: Cosmas Rinaldi Adithya
authors.initials: CR
authors.lastname: Lesmana
authors.affiliation: Victorian Infectious Disease Reference Laboratory, Melbourne, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Jackson
authors.affiliation: Division of Gastroenterology, Medicine, National University Hospital, Singapore, Singapore.
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.affiliation: Hepatology, Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
authors.forename: Ali
authors.initials: A
authors.lastname: Sulaiman
authors.affiliation: Digestive Disease and GI Oncology Center, Medistra Hospital, Jakarta, Indonesia.
authors.forename: Levina S
authors.initials: LS
authors.lastname: Pakasi
authors.affiliation: Hepatology, Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
authors.forename: Rino A
authors.initials: RA
authors.lastname: Gani
authors.affiliation: Hepatology, Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
authors.forename: Irsan
authors.initials: I
authors.lastname: Hasan
authors.affiliation: Hepatology, Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
authors.forename: Andri Sanityoso
authors.initials: AS
authors.lastname: Sulaiman
authors.affiliation: Hepatology, Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia ; Digestive Disease and GI Oncology Center, Medistra Hospital, Jakarta, Indonesia.
authors.forename: Laurentius A
authors.initials: LA
authors.lastname: Lesmana
authors.affiliation: Victorian Infectious Disease Reference Laboratory, Melbourne, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hammond
authors.affiliation: Victorian Infectious Disease Reference Laboratory, Melbourne, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Revill
authors.affiliation: Victorian Infectious Disease Reference Laboratory, Melbourne, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
authors.affiliation: Victorian Infectious Disease Reference Laboratory, Melbourne, Australia.
authors.forename: Scott David
authors.initials: SD
authors.lastname: Bowden
keywords: Chronic hepatitis B; intrahepatic cccDNA; quantitative HBsAg; subviral particles productivity; total HBV DNA; virion productivity