Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity.

Abstract

Side effects of interferon–ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin–ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV‐3) induced viral hepatitis. HRC 203 had greater anti‐viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro‐inflammatory cytokines interferon gamma (IFN‐γ) and tumor necrosis factor alpha (TNF‐α) by macrophages. In vivo, untreated MHV‐3–infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin‐ and HRC 203–treated mice with a marked reduction in biochemical [ALTmax 964 ± 128 IU/L (ribavirin); 848 ± 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203–treated mice behaved normally, in contrast to ribavirin‐treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV‐3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro. (Hepatology 2006;43:581–591.)