Author: | L. Allweiss1*, M. Lütgehetmann1,2, T. Volz1, T. Bornscheuer1, A.W. Lohse1, J. Petersen3, H. Ma4, K. Klumpp4, S. Fletcher4, M. Dandri1 |
Affiliation: | 1Internal Medicine, 2Medical Microbiology, Virology & Hygiene, University Medical Center Hamburg-Eppendorf, 3Liver Centre, Asklepiosklinik St. Georg, Hamburg, Germany, 4Hoffmann-La Roche, Nutley, NJ, USA. *[email protected] |
Background: The direct antiviral efficacy of interferon alpha (IFN-α) treatment on hepatic hepatitis B virus (HBV) replication has not been well defined. Using HBV-infected humanized uPA/SCID mice we recently showed that treatment with conventional IFN-α induced short-lived (< 24 hours) suppression of HBV replication and the responsiveness of infected human hepatocytes to IFN-α was impaired (Gastroenterology 2011:140;2074-83). Aim of this study was to investigate whether the use of pegylated interferon-α (peg-IFN-α), alone or in combination with entecavir (ETV), could induce more effective antiviral control in HBV-infected mice and improve hepatocyte responsiveness to IFN-α.
Methods: HBV-infected humanized uPA/SCID mice displaying median viral titers of 3.6x10E8 HBV-DNA/ml (n=23) received either peg-IFN-α monotherapy (25ng/gr, twice/week; n=6), ETV monotherapy (100ng/gr/day; n=6), or both drugs in combination (n=6), while 5 animals were left untreated as controls. Serological changes were determined prior to, and after 2 and 4 weeks of treatment. Intrahepatic analyses were performed by qRT-PCR and immunohistochemistry.
Results: After 4 weeks of therapy, the median reduction in viremia was 1.4Log, 3.4Log and 3.3Log in mice treated with peg-IFN-α, ETV or the combination thereof, respectively. Despite the larger viremia reduction provided by ETV, the reduction of intrahepatic HBcAg expression levels was more pronounced in mice receiving peg-IFN-α alone or combination therapy, than in mice receiving ETV monotherapy. Peg-IFN-α alone or in combination also reduced the levels of circulating HBsAg (0.21Log; 0.5Log) and HBeAg (0.55Log; 0.66Log), whereas the median decrease in these viral antigens was less pronounced in mice receiving ETV monotherapy (HBsAg=Δ0.13Log; HBeAg=Δ0.24Log). Remarkably, the progressive decrease of viral antigens was accompanied by an improved responsiveness to IFN-α, which was demonstrated by the ability to induce STAT translocation and enhancement of human interferon stimulated genes (ISG) in mice continuously treated with peg-IFN-α.
Conclusions: The strong reduction of intrahepatic viral loads and antigenemia achieved in vivo in the absence of adaptive immune responses emphasizes the qualitatively different antiviral effects induced by peg-IFN-α compared to polymerase inhibitors, thus providing a rationale for exploring the potential of therapeutic strategies based on the combination of distinct types of antiviral agents. |