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

Background & Aims: The interaction between HBV replication and immune modulatory effects mediated by IFN alpha therapy is not well understood. We characterized the impact of HBV DNA replication on the early IFN alpha-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 mu g Pegasys (R) [PegIFN alpha] n = 11, daily dose of 300 mg Viread (R) [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 mu g Pegasys (R) injected subcutaneously, weekly). Results: PegIFN alpha 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. IFN alpha 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 IFN alpha 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 IFN alpha treatment on immune and viral biomarkers in HBeAg+ CHB patients. Our results show that PegIFN alpha-induced innate immune activation directly benefits from the suppression of HBV replication. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.