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Reduction of HBV replication prolongs the early immunological response to IFNα therapy
Anthony T. Tana, 1,
Long Truong Hoangb, 1,
Daniel Chin c,
Erik Rasmussen c,
Uri Lopatin c,
Stefan Hart c,
Hans Bitter c,
Tom Chu c,
Lore Gruenbaum c,
Palani Ravindran c,
Hua Zhong c,
Ed Gane d,
Seng Gee Lim e,
Wan Cheng Chow f,
Pei-Jer Chen g,
Rosemary Petric c,
Antonio Bertolettia, h, 1, Corresponding author contact information, E-mail the corresponding author, E-mail the corresponding author,
Martin Lloyd Hibberdb, 1
a Singapore Institute for Clinical Sciences, A∗STAR, Singapore
b Genome Institute of Singapore, A∗STAR, Singapore
c Hoffmann-La Roche
d Auckland City Hospital, Auckland, New Zealand
e National University Hospital, Singapore
f Singapore General Hospital, Singapore
g National Taiwan University Hospital, Taipei, Taiwan
h Program in Emerging Infectious Disease, Duke-NUS Graduate Medical School, Singapore
Abstract
Background and 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 360μg Pegasys® [Peg-IFNα] n=11, daily dose of 300mg 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 (180μg Pegasys® injected subcutaneously, weekly).
Results
Peg-IFNα 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 Peg-IFNα-induced innate immune activation directly benefits from the suppression of HBV replication |
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