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

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 marine 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-gamma) and tumor necrosis factor alpha (TNF-alpha) 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 [ALT(max) 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.