Cyclosporine suppresses hepatitis C virus and increases the chance of a sustained virological response after liver transplantation

Liver transplant patients with hepatitis C virus (HCV) achieved significantly better long-term viral response when taking the immunosuppressive agent Cyclosporine along with interferon-ribavirin combination therapy. Cyclosporine also showed efficacy against Hepatitis C virus in vitro.

The results of this study appear in the January 2006 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS). The journal is published on behalf of the societies by John Wiley & Sons, Inc. and is available online via Wiley InterScience.

Hepatitis C always recurs after liver transplantation, often damaging the new organ and rendering patients ineligible for retransplantation. To address this problem, patients with hepatitis C often undergo interferon-ribavirin combination therapy after receiving a liver transplant in hopes of a sustained virologic response. At the same time, of course, the patients must take immunosuppressive agents to guard against transplant rejection.

The most commonly used anti-rejection medication is Tacrolimus, although Cyclosporine is also used. The latter drug has been shown to have anti-viral activity against HIV, herpes simplex and vaccinia virus, leading researchers to speculate it might also inhibit hepatitis C virus. To examine this hypothesis, they analyzed the impact of the drug in a liver transplant population. They also studied its effect on hepatitis C in vitro.

For the in vitro study, the researchers, led by Roberto J. Firpi, M.D. of the University of Florida, treated the HCV replicon line, GSB1, with varying doses of Cyclosporine for 48 hours and examined the results. They found that Cyclosporine reduced HCV replication by 20 percent, compared to no reduction with Tacrolimus. Furthermore, the Cyclosporine appeared to work through a different pathway compared to interferon.

Then, the researchers retrospectively examined the cases of 115 people infected with hepatitis C who had undergone liver transplantation at the University of Florida between 1991 and November 2002 and had received interferon-based therapy alongside their anti-rejection medications. After 48 weeks, 46 percent of the patients taking Cyclosporine had achieved a sustained virological response, compared with just 27 percent of the patients taking Tacrolimus.

"Our study suggests that Cyclosporine may play a beneficial role as primary immunosuppression for patients transplanted for HCV infection and may offer an advantage to Tacrolimus in those patients undergoing IFN-based therapy," the authors report. In addition, they confirm antiviral activity by the drug in cell cultures, having found that, "combination of Cyclosporine and interferon achieve better antiviral effect than either one alone."

Of note, considerably more patients taking Tacrolimus had to reduce or stop the therapy due to side effects. Also of possible significance, more patients taking Cyclosporine died, mostly due to infections and hepatitis complications, though this may be attributable to a longer follow-up period for that group.

Still, the indication that Cyclosporine had novel antiviral properties invites further investigation, the authors write. A prospective randomized comparative trial between cyclosporine and TAC should further evaluate their observations.

"Due to the accelerated rate of disease progression and graft failure after liver transplantation in HCV patients," the authors conclude, "it will be very important to determine the ideal immunosuppression regimen."