January 8, 2013

After Liver Transplant for HCV, Better Antiviral Results With Cyclosporine

Reuters Health Information

Jan 02, 2013

By Will Boggs MD and Nancy Lapid

NEW YORK (Reuters Health) Jan 02 - In patients transplanted for hepatitis C cirrhosis, the virus inevitably recurs. Now a new meta-analysis suggests that cyclosporine-based immunosuppression may be associated with a better response to antiviral therapy after transplant than tacrolimus-based protocols.

Recurrent hepatitis C virus (HCV) after transplant leads to cirrhosis in up to 30% of recipients within five years. Treatment with antivirals is less effective after transplant than before.

Dr. Eberhard L. Renner and colleagues from the University of Toronto, Canada pooled data from 18 studies of HCV-positive liver transplant recipients treated with interferon and ribavirin to investigate whether rates of sustained virological response (SVR) are higher with cyclosporine vs tacrolimus.

As reported December 27 online in Liver Transplantation, a random effects model confirmed that cyclosporine was associated with 18% higher efficacy (p=0.05) compared with tacrolimus. There was, however, significant heterogeneity across the studies.

In the four studies that reported genotype-specific SVR rates, SVR rates were consistently higher for G1 patients and for G1/G4 patients on cyclosporine than for G1 patients and G1/G4 patients on tacrolimus. Too few patients with G2/G3 were available for statistical analysis.

End of treatment response rates from six studies did not differ significantly between cyclosporine and tacrolimus patients, but relapse rates were lower with cyclosporine than with tacrolimus (19% vs 26%; p=0.02).

Rates of early discontinuation of antiviral therapy ranged from 11% to 17% for cyclosporine and from 8% to 24% for tacrolimus.

Results from the available studies did not allow definitive conclusions about rejection rates or patient and graft survival rates for the cyclosporine and tacrolimus groups.

"The mechanism or mechanisms by which cyclosporine improves the efficacy of interferon-based antiviral therapy in liver transplant recipients with recurrent HCV are not fully understood," the researchers note. "They may, however, include direct antiviral properties, with cyclosporine (but not tacrolimus) having been shown to inhibit HCV replication and to add to the antiviral efficacy of interferon in vitro."

"Although our results lend further support to a beneficial effect of cyclosporine in patients with recurrent HCV who are undergoing antiviral therapy, they are not conclusive with respect to an overall benefit of using one or another calcineurin inhibitor as the backbone of immunosuppression in HCV-positive liver transplant recipients," the authors continue.

"Confirmation of this marginal benefit in a randomized controlled trial is needed," they add, "although our results suggest that a very large study would be required to achieve the statistical power needed to definitively address this issue."

Dr. Renner did not respond to a request for comments on this report.

Dr. Patricia Sheiner, Director of Transplantation at Hartford Hospital in Hartford, Connecticut, who was not involved in the study, told Reuters Health that although this wasn't a randomized trial, the results are interesting.

Modern antiviral therapy for recurrent hepatitis C after liver transplantation generally consists of interferon, ribavirin, and one of the new protease inhibitors, she said. The problem, she continued, is that the protease inhibitors increase the blood levels of both cyclosporine and tacrolimus (Prograf), but to a far greater extent with tacrolimus.

"Almost no transplant programs are using Prograf when treating recurrent hepatitis C with triple antiviral therapy in these patients," Dr. Sheiner said. "They're putting people on cyclosporine."

"The drug-drug interaction makes Prograf almost unusable with the protease inhibitors," she added. "So in light of the fact that the new protease inhibitors need to be given with cyclosporine, this study is reassuring."

SOURCE: http://bit.ly/VvaQJG

Liver Transpl 2012.


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