Reduction of HBV replication prolongs the early immunological response to IFNα therapy
Journal
Journal of Hepatology
Journal Volume
60
Journal Issue
1
Pages
54-61
Date Issued
2014
Author(s)
Tan A.T.
Hoang L.T.
Chin D.
Rasmussen E.
Lopatin U.
Hart S.
Bitter H.
Chu T.
Gruenbaum L.
Ravindran P.
Zhong H.
Gane E.
Lim S.G.
Chow W.C.
Petric R.
Bertoletti A.
Hibberd M.L.
Abstract
Background & Aims 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. ? 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Subjects
Chronic HBV; PegIFNa; Tenofovir
SDGs
Other Subjects
CD4 antigen; CD8 antigen; gamma interferon; gamma interferon inducible protein 10; hepatitis B surface antigen; hepatitis B(e) antigen; interleukin 12p70; interleukin 15; interleukin 6; peginterferon alpha2a; tenofovir disoproxil; DNA; peginterferon alpha2a; tenofovir disoproxil; adaptive immunity; adult; article; CD4+ T lymphocyte; CD8+ T lymphocyte; clinical article; clinical feature; controlled study; follow up; gene expression; gene expression profiling; gene induction; health care quality; hepatitis B; Hepatitis B virus; human; immune response; innate immunity; lymphocyte proliferation; male; monotherapy; natural killer T cell; nonhuman; open study; peripheral blood mononuclear cell; priority journal; randomized controlled trial; signal transduction; T lymphocyte activation; upregulation; virus load; virus replication; antiviral therapy; Article; cell proliferation; cohort analysis; DNA replication; drug effect; drug inhibition; genetic transcription; hepatitis B; immunomodulation; immunostimulation; natural killer cell; parallel design; protein blood level; Chronic HBV; PegIFNa; Tenofovir; Adolescent; Adult; Antiviral Agents; Cohort Studies; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Polyethylene Glycols; Recombinant Proteins; T-Lymphocytes; Virus Replication
Type
journal article