Volume 60, Issue 3, March 2014, Pages 500–507
Cover image
Research Article
Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration
Lena Allweiss1,
Tassilo Volz1,
Marc Lütgehetmann1, 2,
Katja Giersch1,
Till Bornscheuer1,
Ansgar W. Lohse1, 3,
Joerg Petersen4,
Han Ma5,
Klaus Klumpp5,
Simon P. Fletcher5, †,
Maura Dandri1, 3, Corresponding author contact information, E-mail the corresponding author
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 = Δ1 log; HBsAg = Δ1.4 log; 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.
Keywords
Corresponding author contact information
Corresponding author. Address: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-, 20246 Hamburg, Germany. Tel.: +49 40 7410 52949; fax: +49 40 7410 57232.
†
Present address: Gilead Sciences, Foster City, CA, USA.