title: Reduction of HBV replication prolongs the early immunological response to IFNα therapy.
abstract: OBJECTIVE
  The interaction between HBV replication and immune modulatory effects mediated by IFNα therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFNα-induced immunomodulatory mechanisms.
  
  
  METHODS
  We interrogated the transcriptional, serum cytokine/chemokine and cellular immune profiles of 28 patients with HBeAg+ chronic HBV infection (CHB) randomly assigned to one of 4 treatment cohorts (untreated n=5, weekly dosing of 360 μg Pegasys [PegIFNα] n=11, daily dose of 300 mg Viread [tenofovir disoproxil fumarate, TDF] n=6, or a combination of both n=6). Samples were characterized at multiple early time points through day 14 of therapy, after which all patients were given standard of care (180 μg Pegasys injected subcutaneously, weekly).
  
  
  RESULTS
  PegIFNα induced a distinct and rapid up-regulation of IFN signaling pathway that coincided with increase detection of distinct serum cytokines/chemokines (IL-15, IL-6, and CXCL-10) and the up-regulation of the frequency of proliferating NK and activated total CD8+ T cells. IFNα treatment alone did not result in rapid decay of HBV replication and was not able to restore the defective HBV-specific T cell response present in CHB patients. In addition, the IFNα immune-stimulatory effects diminished after the first dose, but this refractory effect was reduced in patients where HBV replication was simultaneously inhibited with TDF.
  
  
  CONCLUSIONS
  We present here the first comprehensive description of the early effects of IFNα treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFNα-induced innate immune activation directly benefits from the suppression of HBV replication.
authors.affiliation: Singapore Institute for Clinical Sciences, A(⁎)STAR, Singapore.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Tan
authors.affiliation: Genome Institute of Singapore, A(⁎)STAR, Singapore.
authors.forename: Long Truong
authors.initials: LT
authors.lastname: Hoang
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chin
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Erik
authors.initials: E
authors.lastname: Rasmussen
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Uri
authors.initials: U
authors.lastname: Lopatin
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Tom
authors.initials: T
authors.lastname: Chu
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Lore
authors.initials: L
authors.lastname: Gruenbaum
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Palani
authors.initials: P
authors.lastname: Ravindran
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Auckland City Hospital, Auckland, New Zealand.
authors.forename: Ed
authors.initials: E
authors.lastname: Gane
authors.affiliation: National University Hospital, Singapore.
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.affiliation: Singapore General Hospital, Singapore.
authors.forename: Wan Cheng
authors.initials: WC
authors.lastname: Chow
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Hoffmann-La Roche, Switzerland.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Petric
authors.affiliation: Singapore Institute for Clinical Sciences, A(⁎)STAR, Singapore; Program in Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore. Electronic address: antonio@sics.a-star.edu.sg.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.affiliation: Genome Institute of Singapore, A(⁎)STAR, Singapore.
authors.forename: Martin Lloyd
authors.initials: ML
authors.lastname: Hibberd
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a
keywords: Chronic HBV; PegIFNa; Tenofovir