G105 Profibrogenic Chemokines and Viral Evolution Predict Rapid Progression of Hepatitis C to Cirrhosis

Abstract

The clinical presentation and outcomes of chronic hepatitis C are highly variable, and it is not possible to predict which individuals will rapidly evolve to severe fibrosis and liver failure. Using serial serum samples prospectively collected from 6 patients with transfusion-associated hepatitis C (followed from the day of transfusion for up to 30 years), we identified outcome-specific features that predict long-term disease severity. We found that stable or slowly progressive disease correlated with an earlier ALT peak and antibody seroconversion, transient control of viremia and significant induction of IFN- and MIP-1, all indicative of an effective, albeit insufficient, adaptive immune response. By contrast, rapidly progressive disease was associated with persistent and significant elevations of ALT and the profibrogenic chemokine MCP-1 (CCL-2), a major chemotactic factor for hepatic stellate cells, which play a central role in fibrogenesis. Rapidly progressive disease was also associated with greater viral diversity and divergence, and a higher rate of synonymous substitutions. Strikingly a strong genetic bottleneck occurred in all patients around one year post-infection. This study suggests that the long-term course of chronic hepatitis C is determined early in infection and that disease severity is predicted by the evolutionary dynamics of HCV and the level of MCP-1, a chemokine that appears critical to the induction of progressive fibrogenesis and, ultimately, the ominous complications of cirrhosis. In this proposed model for the pathogenesis of chronic HCV-related liver disease, rapid disease progression may result from an excess of soluble mediators of inflammation and fibrosis rather than from T-cell-mediated hepatotoxicity.