Lena Allweiss1, Tassilo Volz1, Marc Lütgehetmann2, Katja Giersch1, Till Bornscheuer1, Ansgar W Lohse3, Joerg Petersen4, Han Ma5, Klaus Klumpp5, Simon P Fletcher5, Maura Dandri6. 1. I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany. 2. I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany; Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany. 4. IFI Institute for Interdisciplinary Medicine at Asklepios Clinic St. Georg, Hamburg, Germany. 5. Hoffmann-La Roche, Inc., Nutley, NJ, USA. 6. I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Germany; German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Germany. Electronic address: m.dandri@uke.de.
Abstract
BACKGROUND & AIMS: Pegylated interferon-alpha (PegIFNα) remains an attractive treatment option for chronic hepatitis B virus (HBV) infection because it induces higher rates of antigen loss and seroconversion than treatment with polymerase inhibitors. Although early HBsAg decline is recognised as the best predictor of sustained response to IFN-based therapy, it is unclear whether immune cell functions are required to induce significant antigenemia reduction in the first weeks of treatment. Aim of the study was to investigate whether PegIFNα can induce sustained human hepatocyte responsiveness and substantial loss of circulating and intrahepatic viral antigen loads in a system lacking immune cell functions. METHODS: HBV-infected humanized uPA/SCID mice received either PegIFNα, entecavir (ETV), or both agents in combination. Serological and intrahepatic changes were determined by qRT-PCR and immunohistochemistry and compared to untreated mice. RESULTS: After 4 weeks of treatment, median viremia reduction was greater in mice treated with ETV (either with or without PegIFNα) than with PegIFNα. In contrast, levels of circulating HBeAg, HBsAg, and intrahepatic HBcAg were significantly reduced (p = 0.03) only in mice receiving PegIFNα alone or in combination, as compared to mice receiving ETV monotherapy. Progressive antigen reduction was also demonstrated in mice receiving PegIFNα for 12 weeks (HBeAg = Δ1log; HBsAg = Δ1.4log; p < 0.0001). Notably, repeated administrations of the longer-active PegIFNα could breach the impairment of HBV-infected hepatocyte responsiveness and induce sustained enhancement of human interferon stimulated genes (ISG). CONCLUSIONS: The antiviral effects of PegIFNα exerted on the human hepatocytes can induce sustained responsiveness and trigger substantial HBV antigen decline without claiming the involvement of immune cell responses.
BACKGROUND & AIMS: Pegylated interferon-alpha (PegIFNα) remains an attractive treatment option for chronic hepatitis B virus (HBV) infection because it induces higher rates of antigen loss and seroconversion than treatment with polymerase inhibitors. Although early HBsAg decline is recognised as the best predictor of sustained response to IFN-based therapy, it is unclear whether immune cell functions are required to induce significant antigenemia reduction in the first weeks of treatment. Aim of the study was to investigate whether PegIFNα can induce sustained human hepatocyte responsiveness and substantial loss of circulating and intrahepatic viral antigen loads in a system lacking immune cell functions. METHODS:HBV-infected humanized uPA/SCIDmice received either PegIFNα, entecavir (ETV), or both agents in combination. Serological and intrahepatic changes were determined by qRT-PCR and immunohistochemistry and compared to untreated mice. RESULTS: After 4 weeks of treatment, median viremia reduction was greater in mice treated with ETV (either with or without PegIFNα) than with PegIFNα. In contrast, levels of circulating HBeAg, HBsAg, and intrahepatic HBcAg were significantly reduced (p = 0.03) only in mice receiving PegIFNα alone or in combination, as compared to mice receiving ETV monotherapy. Progressive antigen reduction was also demonstrated in mice receiving PegIFNα for 12 weeks (HBeAg = Δ1log; HBsAg = Δ1.4log; p < 0.0001). Notably, repeated administrations of the longer-active PegIFNα could breach the impairment of HBV-infected hepatocyte responsiveness and induce sustained enhancement of human interferon stimulated genes (ISG). CONCLUSIONS: The antiviral effects of PegIFNα exerted on the human hepatocytes can induce sustained responsiveness and trigger substantial HBV antigen decline without claiming the involvement of immune cell responses.
Authors: Eva Billerbeck; Michiel C Mommersteeg; Amir Shlomai; Jing W Xiao; Linda Andrus; Ankit Bhatta; Koen Vercauteren; Eleftherios Michailidis; Marcus Dorner; Anuradha Krishnan; Michael R Charlton; Luis Chiriboga; Charles M Rice; Ype P de Jong Journal: J Hepatol Date: 2016-05-02 Impact factor: 25.083
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Authors: Philipp Tropberger; Alexandre Mercier; Margaret Robinson; Weidong Zhong; Don E Ganem; Meghan Holdorf Journal: Proc Natl Acad Sci U S A Date: 2015-10-05 Impact factor: 11.205