The clinical and immunologic impact of using interferon and ribavirin in the immunosuppressed host

1. Allograft infection with hepatitis C virus (HCV) in immunosuppressed adults results in decreased allograft and patient survival. 2. Risk factors for accelerated progression of hepatitis C related to immunosuppression include treated episodes of acute cellular rejection (ACR), pulse therapy with methylprednisolone, and use of OKT3. 3. Both interferon alfa (IFN-alpha) and ribavirin (RVN) show antiviral actions against HCV and stimulate innate and adaptive immunity to increase cytolysis and polarize T helper subtype 1 (T(H)1) responses. In addition, IFN-alpha inhibits fibrogenesis in the liver. 4. Both IFN-alpha and RVN have been studied in immunosuppressed liver transplant recipients as prophylaxis or treatment of established hepatitis C to reduce allograft failure and patient mortality. Reported protocols include monotherapies with RVN, standard IFN-alpha, and pegylated IFN-alpha and combination therapies using RVN and either standard IFN-alpha or pegylated IFN-alpha. 5. The clinical impact of using IFN-alpha and RVN in highly selected immunosuppressed patients varied among studies. Combination therapy with standard IFN-alpha and RVN resulted in the greatest sustained biochemical and virological responses. However, no therapy prevented progression of acute cholestatic hepatitis C despite evidence of virological responses. Substantial proportions of patients developed adverse events requiring dose reduction or discontinuation that compromised efficacy. RVN monotherapy was not only virologically ineffective, but may have stimulated hepatic fibrosis. Current data regarding monotherapy or combination therapy with pegylated IFN-alpha are limited, but encouraging. 6. Despite potent immunostimulatory actions of both IFN-alpha and RVN that enhance natural killer, T(H)1, their use did not significantly increase the incidence of ACR. 7. Additional studies are needed to resolve the controversy over prophylaxis versus treatment of established disease and the potential utility of low-dose maintenance IFN-alpha therapy to retard fibrogenesis without clearing HCV. 8. After new, less toxic, and more potent antiviral agents become available, they should be tested immediately in patients with hepatitis C post-liver transplantation.