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Microemulsion cyclosporine with C2 monitoring and tacrolimus in liver transplantation with or without hepatitis C virus infection

The introduction of calcineurin inhibitors has improved graft survival in the last 25 years. The superiority of tacrolimus over cyclosporine (CsA) was well established in preventing acute rejection and corticosteroid-resistant rejection from 3 large randomized trials after liver transplantation. However, these differences were studied with a conventional formulation of CsA and CsA monitoring with trough (C0) concentrations. 4-6 In addition, in those three studies, the indication of hepatitis C virus (HCV)-related end-stage liver disease is relatively low: it accounts for more than 40% of liver transplantations in the United States. It is now clear that C2 monitoring of CsA better reflects the area under the concentration curve of the drug and has a better safety and efficacy profile in renal transplantation. Also, the microemulsion formulation of CsA (CsA ME) provides more predictable area under the concentration curve, and day-to-day fluctuations in concentration are less common. In liver transplantation, diversion of bile affects the absorption of CsA, which is less affected with CsA ME formulation. In vitro studies have shown anti-HCV activity of CsA at higher concentrations. Thus, several questions emerge. Does microemulsion formulation of CsA with C2monitoring provides better safety and efficacy in liver transplant patients as compared with tacrolimus? And is there any benefit of CsA ME with C2 monitoring over tacrolimus in HCV-positive patients undergoing liver transplantation? Both of these questions are important to clinicians in order to provide the best possible options for their patients. In a U.S. multicenter trial, Wiesner showed that the survival benefit of tacrolimus over CsA was maintained even in patients who were HCV positive with up to a 5-year follow-up. Ghobrial et al. reported the results of a retrospective data analysis of 190 CsA-treated and 132 tacrolimus-treated HCV-positive liver transplant recipients, with median follow-up of 22 months, and found no difference in patient or graft survival. In their study, conventional CsA and CsA ME were grouped together. A randomized study by Martin et al. of 77 patients examined the difference between CsA-treated or tacrolimus-treated HCV-positive liver transplant recipients. Although HCV RNA viral load in the CsA group were higher, histologically diagnosed HCV recurrence rate and survival rate were not different. However, CsA dose was not based on C2 monitoring. Similarly, Zervos et al. reported the results of a prospective study of tacrolimus-treated HCV-positive liver transplant recipients (n 25) with CsA ME–treated HCV-positive liver transplant recipients (n 24) with a median follow-up of 14 months. They found an increased incidence of acute rejection with CsA ME compared with tacrolimus but did not find any difference in patient survival or graft survival. A prospective study conducted in Europe, which included more than 600 cases, found a benefit with tacrolimus over CsA ME. However, in both studies, C0 concentrations were measured. 22,23