Seminar

Virology of hepatitis C virus infection after liver transplantation

Sofia Perez del Pulgar, PhD.

End-stage liver disease due to chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation (LT) in the Americas, Europe, and Japan. Unfortunately, infection of the graft is universal in patients with detectable viral load at the time of LT. Furthermore, the course of recurrent HCV infection is accelerated after LT, with approximately 30% of patients developing chronic hepatitis and liver cirrhosis within 5 years after LT. The LT setting is a unique model to study the pathogenesis of HCV infection for several reasons: (1) tissue and serum samples can be obtained before and after HCV infection; (2) infection can be monitored from the beginning and thus, it is possible to obtain data on HCV kinetics and host factors; (3) hepatitis C recurrence after LT is a rapidly progressive disease and patients with mild or very severe hepatitis recurrence can be well characterized. Studies on early kinetics have shown that HCV replication starts a few hours after reperfusion of the graft and that HCV-RNA concentrations increase within the first days after LT, despite the presence of anti-HCV antibodies. The main source of HCV infection is circulating virions. Nevertheless, some data suggest that HCV present in extrahepatic compartments may contribute to hepatitis C recurrence. Recent data suggest that escape from neutralizing antibodies and efficient entry into hepatocytes play a major role in reinfection of the liver graft. Indeed, HCV receptor levels at the time of LT may modulate early HCV kinetics and hepatitis C recurrence is associated with increased levels of claudin-1 and occludin at the tight-junctions. To date, the proportion and distribution of HCV-infected hepatocytes remain unclear. Some studies have shown that infection is not random. Clustering of HCV-positive hepatocytes suggest a localized mechanism of intrahepatic propagation and control (cell-to-cell transmission and innate immune responses, respectively) and may have implications for HCV therapy. On the other hand, the quasispecies population changes significantly after LT, most likely because of the strong immunosuppression and the need to adapt to a new environment. However, there are no conclusive data supporting the role of HCV quasispecies composition and disease outcomes. Treatment of recurrent HCV infection after LT is often compromised by adverse effects and limited efficacy of interferon-based therapies. The advent of direct-acting antivirals, particularly in interferon-free regimens, is very likely to improve the prognosis and outcome of patients with severe hepatitis C recurrence.