Author information

¹Toronto Center for Liver Disease, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Canada.

²Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh, Pittsburgh, PA.

³Baylor Scott & White Medical Center, Dallas, TX.

⁴Masschusetts General Hospital, Harvard Medical School, Boston, MA.

⁵Johns Hopkins University School of Medicine, Baltimore, MD.

⁶Department of Gastroenterology & Hepatology, Erasmus MC University Hospital Rotterdam, The Netherlands.

⁷Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

Abstract

Background: Peginterferon-α (PegIFNα) is of limited utility during immunotolerant (IT) or immune active (IA) phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent levels of IFNα found in some treated patients are associated with limited/no virological responses.

Aim: To determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies.

Methods: Pre-, on- and post-treatment sera from 61 IT trial participants on PegIFNα/ entecavir therapy and 88 IA trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by pre-incubation of sera +/- recombinant-human IFNα (rhIFNα) added to Huh7 cells with measurement of interferon stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated.

Results: Pre-incubation of on-treatment serum from 26 IT (43%) and 13 IA (15%) participants with rhIFNα markedly blunted ISG-induction in Huh7 cells. Degree of ISG-inhibition correlated with IFNα antibody titer (p<0.0001; r=0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced qHBsAg and qHBeAg declines (p<0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults (p=0.004) but nAbs in children had less impact on virological responses.

Conclusions: The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.