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Unlabelled: Cyclosporin A (CsA) inhibits replication of the HCV subgenomic replicon, and this effect is believed to not be mediated by its immunosuppressive action. We found that DEBIO-025, a novel non-immunosuppressive cyclophilin inhibitor derived from CsA, inhibited HCV replication in vitro more potently than CsA. We also examined the inhibitory effect of DEBIO-025 on naive HCV genotypes 1a or 1b in vivo using chimeric mice with human hepatocytes. These mice were treated for 14 days with DEBIO-025, pegylated-interferon alpha-2a (Peg-IFN), a combination of either drugs, or CsA in combination with Peg-IFN. In mice treated with Peg-IFN, serum HCV RNA levels decreased approximately 10-fold whereas DEBIO-025 treatment alone did not induce any significant change. In mice treated with both DEBIO-025 and Peg-IFN, HCV RNA levels decreased more than 100-fold. All mice treated with Peg-IFN combined with CsA died within 4 days. The combination treatment of DEBIO-025 and Peg-IFN reduced HCV RNA levels and core protein expression in liver, indicating that the HCV RNA levels reduction in serum was attributable to intrahepatic inhibition of HCV replication., Conclusion: We demonstrated that DEBIO-025 was better tolerated than CsA, and that its anti-HCV effect appeared to be synergistic in combination with Peg-IFN in vivo.

Background: Only 15% to 20% of patients with chronic hepatitis C have a sustained virological response to interferon monotherapy. The aim of the present study was to compare the efficacy and safety of interferon, in combination with oral cyclosporin A, with interferon monotherapy in the treatment of chronic hepatitis C., Methods: We assigned 120 patients with chronic hepatitis C to receive the standard Japanese dose of interferon alpha2b alone for 24 weeks or that dose of interferon alpha2b in combination with cyclosporin A, at doses of 200 mg daily for the first 4 weeks and 100 mg daily for the following 20 weeks. All patients were assessed for drug safety, tolerance, and efficacy at the end of weeks 4, 12, 24, and 48. Efficacy was assessed by the disappearance of serum hepatitis C virus (HCV)-RNA by polymerase chain reaction and normalization of serum aminotransferase. The primary endpoint was a sustained virological response; i.e., sustained undetectable serum HCV RNA at 48 weeks., Results: The sustained virological response rate was significantly higher in the combination therapy group (42/76) than in the monotherapy group (14/44; P = 0.01). The sustained biochemical response rate was also higher in the combination therapy group (46/76) than in the 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., Conclusions: In patients with chronic hepatitis C; combined interferon and cyclosporin A treatment was more effective than interferon monotherapy. The benefit was mostly achieved in patients with a high viral load and HCV genotype 1.

Background. Only 15% to 20% of patients with chronic hepatitis C have a sustained virological response to interferon monotherapy. The aim of the present study was to compare the efficacy and safety of interferon, in combination with oral cyclosporin A, with interferon monotherapy in the treatment of chronic hepatitis C. Methods. We assigned 120 patients with chronic hepatitis C to receive the standard Japanese dose of interferon a2b alone for 24 weeks or that dose of interferona2b in combination with cyclosporin A, at doses of 200mg daily for the first 4 weeks and 100 mg daily for the following 20 weeks. All patients were assessed for drug safety, tolerance, and efficacy at the end of weeks 4, 12, 24, and 48. Efficacy was assessed by the disappearance of serum hepatitis C virus (HCV)-RNA by polymerase chain reaction and normalization of serum aminotransferase. The primary endpoint was a sustained virological response; i.e., sustained undetectable serum HCV RNA at 48 weeks. Results. The sustained virological response rate was significantly higher in the combination therapy group (42/76) than in the monotherapy group (14/44; P = 0.01). The sustained biochemical response rate was also higher in the combination therapy group (46/76) than in the 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. Conclusions. In patients with chronic hepatitis C; combined interferon and cyclosporin A treatment was more effective than interferon monotherapy. The benefit was mostly achieved in patients with a high viral load and HCV genotype 1. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor on prevention of fulminant hepatic failure in four children with acute severe hepatitis.