INTERFERON COMBINED WITH CYCLOSPORIN A TREATMENT HAS A POSSIBILITY TO BE AN EFFECTIVE COUNTERMEASURE AGAINST RECURRENCE OF HCV AFTER LIVER TRANSPLANTATION IN PATIENTS WITH END-STAGE HCV RELATED LIVER DISEASE

Abstract

P546 Aims: Chronic hepatitis C virus (HCV) is a worldwide health problem. Approximately 100 million people in the world are chronically infected with HCV. It is estimated that 20% of patients developed cirrhosis within 20 years after establishment of persistent infection. Survival rate is poor once complications, such as hepatocellular carcinoma or hepatic failure develop and liver transplantation is the only reliable treatment option. Indeed, complication of chronic HCV are the most common indication for liver transplantation that account for more than 40% of transplants performed in western countries over recent years. After liver transplantation for HCV related liver diseases, the recurrence of HCV infection is almost universal and the risk of progression to cirrhosis is accelerated. The modalities and efficacy of antiviral treatment in this indication are still controversial. We show crucial clues to solve this problem based on our recent clinical trial. Method: We assigned 120 patients with chronic hepatitis C to receive IFN? 2b 10MU daily for the first 4 weeks and three times weekly for the following 20 weeks or that dose of IFN? 2b in combination with cyclosporin A at doses of 200mg daily for the first 4 week and 100mg daily for the following 20 weeks. CsA was given orally in four divided doses daily and blood cyclosporin A levels were closely monitored and dose reduction or discontinuation was instituted for early morning level exceeding 350 ng/ml or serious adverse events. Efficacy of the treatment was assessed by the disappearance of serum HCV RNA by polymerase chain reaction and normalization of serum transaminase. The primary end point was a sustained virological response. We also performed in vitro experiment using HCV replicon system and cell culture system to study the inhibitory effect of cyclosporin A and its derivatives on HCV replication. Results: The sustained virological response rate was significantly higher in combination therapy group (42/76) than in the monotherapy group (17/44: p=0.01). The sustained biochemical response rate was also higher in combination therapy group (46/76) than in monotherapy group (17/44; p=0.017). In patients with genotype 1 and high viral loads, the sustained virological response rate was markedly higher in the combination therapy group (16/38) than in the monotherapy group (1/21; p=0.006). Side effect profiles were similar in the two groups. Results of the experimental systems revealed that inhibition of cyclophilins is closely related to suppression of HCV replication. Conclusion: Interferon combined with cyclosporin A treatment has a possibility to be an effective countermeasure against recurrence of HCV after liver transplantation in patients with end-stage HCV related liver disease because of its higher sustained virological response. Higher sustained biochemical response is another clinical advantage that retard the progression of recurrent liver disease. Cyclophilins are ubiquitous intracellular proteins and their function is a peptidyl prolyl cis-trans isomerase(PPIase). To suppress the activity of the PPIase is required higher concentration of cyclosporin A than to suppress the activity of calcineurin. Administration of cyclosporin A divided four times a day is crutial to maintain to blood level of cyclosporin A.