TREATMENT WITH PEGYLATED INTERFERON-ALPHA INDUCES SUSTAINED SUPPRESSION OF BOTH VIRUS REPLICATION AND ANTIGENEMIA IN HUMANIZED uPA/SCID MICE STABLY INFECTED WITH HBV

The direct antiviral efficacy of interferon alpha (IFN-a) treatment on hepatic HBVreplication has not been well defined. Using HBV-infected humanized uPA/SCIDmice we recently showed that treatment with conventional IFN-a induced significant,but short-lived (<24 hours) suppression of HBV replication (Gastroenterology 2011).Aim of this study was to investigate whether the use of pegylated interferon-a (peg-IFN-a) could induce sustained and hence more effective antiviral effects in HBVinfectedmice. Methods: Human liver chimeric uPA/SCID mice with median viral titersof 3.5×10E8 HBV-DNA/ml received either peg-IFN-a (25ng/gr, twice per week) for 2(n=4) or 4 weeks (n=3), or were left untreated as controls (n=4) for the intrahepaticanalyses. Viremia was determined in each mouse prior to, and after 2 and 4 weeksof treatment. Results: Peg-IFN-a induced a significant decrease in viremia in all miceafter 2 weeks of treatment (median 1.3log reduction), although an additional 2 weeksof treatment did not lead to a further reduction in viral load. Similarly, although therewas no effect on cccDNA levels, virion productivity (measured by rcDNA/cccDNA ratio)was reduced ≈3–4 fold in mice treated with peg-IFN for 2 or 4 weeks. Notably, steadystatelevels of pgRNA (Δ0.8log) and subgenomic RNAs (Δ1.1log) were also loweredby peg-IFN-a treatment, and the decrease of all viral transcripts translated into a clearreduction of intrahepatic HBcAg levels, as determined by immunohistochemistry anda decline (up to 34%) in serum HBsAg levels (p=0.016). Conclusion: The sustainedvirological suppression and reduction of both HBcAg and HBsAg levels achievedin vivo in the absence of adaptive immune responses emphasizes the qualitativelydifferent antiviral effects induced by peg-IFN-a compared to polymerase inhibitors,thus providing a rationale for exploring the potential of therapeutic strategies basedon the combination of distinct types of antiviral agents.

HBV - Peg-IFN - uPA/SCID