A2 Molecular Evolution of Hepatitis C Virus (HCV) and Clinical Outcome in Patients With Hepatitis C

HCV causes persistent infection in up to 85% of infected individuals, and about 30% of them develop long-term sequelae, such as cirrhosis or hepatocellular carcinoma. The mechanisms of viral persistence as well as the reason why some patients develop a stable, non-progressive disease whereas others develop a rapidly progressive disease remain unknown. Previously, we demonstrated that the evolutionary dynamics of the HCV quasispecies early in the course of HCV infection predicts whether the infection will resolve or become chronic. However, little is known about the correlation between viral evolution and clinical outcome in chronic hepatitis C. A well-defined cohort of patients with post-transfusion hepatitis C provided a unique opportunity to study how the HCV population evolves over time within individuals and its relationship with the clinical outcome. Six patients representing two different clinical outcomes were selected: 3 had a mild and stable disease for >20 years (slow progressors, SP) and 3 had a rapidly progressive disease leading to liver-related death (rapid progressors, RP). The HCV quasispecies was studied from the first PCR-positive sample, within 2 weeks of infection, for up to 23 years. During the acute phase, viral diversity initially decreased but increased dramatically after seroconversion. Phylogenetic analysis documented a genetic bottleneck during the critical transition from the acute to the chronic phase with a single lineage passing through to the next sample and evidence of a strong positive selection, a pattern indicative of viral immune escape. The relationship among the sequences present after this bottleneck correlated with the clinical outcome. Sequences in SP were different from earlier sequences, whereas RP had sequences identical to those pre-bottleneck. In both SR and RP, genetic diversity sharply increased 5 to 6 years after infection, although substitution rates were higher in RP. Altogether, these data suggest that the effectiveness of the host immunologic control may critically affect the pace of disease progression in patients with chronic hepatitis C.