title: Hepatitis B Virus Pregenomic RNA Is Present in Virions in Plasma and Is Associated With a Response to Pegylated Interferon Alfa-2a and Nucleos(t)ide Analogues.
abstract: BACKGROUND
  Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA pregenome or HBV messenger RNA. Whether HBV RNA-containing particles continue to be secreted into the bloodstream remains controversial.
  
  
  METHODS
  We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir.
  
  
  RESULTS
  Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN-based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen-negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen-specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions.
  
  
  CONCLUSIONS
  HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CHB.
authors.affiliation: Department of Gastroenterology and Hepatology Department of Experimental Immunology.
authors.forename: L
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Experimental Immunology.
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.affiliation: Department of Experimental Immunology.
authors.forename: Karel A
authors.initials: KA
authors.lastname: van Dort
authors.affiliation: Department of Gastroenterology and Hepatology.
authors.forename: R Bart
authors.initials: RB
authors.lastname: Takkenberg
authors.affiliation: Department of Gastroenterology and Hepatology Department of Experimental Immunology.
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
authors.affiliation: Department of Clinical Virology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Zaaijer
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000547:Amantadine; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015415:Biomarkers; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D056945:Hep G2 Cells; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood* / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D015203:Reproducibility of Results; D000068698:Tenofovir / Q000627:therapeutic use; D014771:Virion / Q000187:drug effects / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D063065:Organophosphonates; D012367:RNA, Viral; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000068698:Tenofovir; D000547:Amantadine; D000225:Adenine; C100416:peginterferon alfa-2a
keywords: HBV life cycle; chronic hepatitis B; immunoprecipitation; nucleocapsids; response marker