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J Hepatol. 2014 Jan;60(1):54-61. doi: 10.1016/j.jhep.2013.08.020. Epub 2013 Aug 29.

Reduction of HBV replication prolongs the early immunological response to IFNα therapy.

Author information

1
Singapore Institute for Clinical Sciences, A(⁎)STAR, Singapore.
2
Genome Institute of Singapore, A(⁎)STAR, Singapore.
3
Hoffmann-La Roche, Switzerland.
4
Auckland City Hospital, Auckland, New Zealand.
5
National University Hospital, Singapore.
6
Singapore General Hospital, Singapore.
7
National Taiwan University Hospital, Taipei, Taiwan.
8
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.

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.

KEYWORDS:

Chronic HBV; PegIFNa; Tenofovir

PMID:
23994382
DOI:
10.1016/j.jhep.2013.08.020
[Indexed for MEDLINE]
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