title: Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration.
abstract: OBJECTIVE
  Pegylated interferon-alpha (PegIFNα) remains an attractive treatment option for chronic hepatitis B virus (HBV) infection because it induces higher rates of antigen loss and seroconversion than treatment with polymerase inhibitors. Although early HBsAg decline is recognised as the best predictor of sustained response to IFN-based therapy, it is unclear whether immune cell functions are required to induce significant antigenemia reduction in the first weeks of treatment. Aim of the study was to investigate whether PegIFNα can induce sustained human hepatocyte responsiveness and substantial loss of circulating and intrahepatic viral antigen loads in a system lacking immune cell functions.
  
  
  METHODS
  HBV-infected humanized uPA/SCID mice received either PegIFNα, entecavir (ETV), or both agents in combination. Serological and intrahepatic changes were determined by qRT-PCR and immunohistochemistry and compared to untreated mice.
  
  
  RESULTS
  After 4 weeks of treatment, median viremia reduction was greater in mice treated with ETV (either with or without PegIFNα) than with PegIFNα. In contrast, levels of circulating HBeAg, HBsAg, and intrahepatic HBcAg were significantly reduced (p = 0.03) only in mice receiving PegIFNα alone or in combination, as compared to mice receiving ETV monotherapy. Progressive antigen reduction was also demonstrated in mice receiving PegIFNα for 12 weeks (HBeAg = Δ1log; HBsAg = Δ1.4log; p < 0.0001). Notably, repeated administrations of the longer-active PegIFNα could breach the impairment of HBV-infected hepatocyte responsiveness and induce sustained enhancement of human interferon stimulated genes (ISG).
  
  
  CONCLUSIONS
  The antiviral effects of PegIFNα exerted on the human hepatocytes can induce sustained responsiveness and trigger substantial HBV antigen decline without claiming the involvement of immune cell responses.
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Allweiss
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Lütgehetmann
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Giersch
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Bornscheuer
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Hoffmann-La Roche, Inc., Nutley, NJ, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Ma
authors.affiliation: Hoffmann-La Roche, Inc., Nutley, NJ, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.affiliation: Hoffmann-La Roche, Inc., Nutley, NJ, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fletcher
authors.affiliation: I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany. Electronic address: m.dandri@uke.de.
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004279:DNA, Viral / Q000097:blood; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006514:Hepatitis B Surface Antigens / Q000097:blood*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C413685:entecavir; D006147:Guanine; C417083:peginterferon alfa-2b
keywords: HBeAg; HBsAg; Hepatocyte responsiveness; Humanized mice; Interferon stimulated genes; cccDNA