REFINE: A Randomized Trial Comparing Cyclosporine A and Tacrolimus on Fibrosis After Liver Transplantation for Hepatitis C

Abstract

REFINE was a 12‐month, prospective, open‐label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL‐2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA‐treated patients (71.6%) and 52/77 tacrolimus‐treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between‐group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid‐free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus‐ and CsA‐treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy‐proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV‐induced liver fibrosis between patients treated with CsA or tacrolimus in steroid‐containing regimens, whereas CsA in steroid‐free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Systematic Review and Meta-Analysis of Tacrolimus versus Ciclosporin as Primary Immunosuppression After Liver Transplant

“…The two studies with the lowest assessed risk of bias were amongst the top three largest studies included in the meta-analysis [24,25], with a combined weight of 60.2% in the mortality analysis.…”

“…Graft loss was reported in 5 of the 11 included studies, with a total of 80 events over 12 months of follow-up in 1,168 patients (Fig 3) [25–28,32]. Of the 594 patients on ciclosporin-based immunosuppression, 41 patients experienced graft loss, compared with 39 of 574 patients on tacrolimus, yielding a graft loss RR of 1.20 (95% CI 0.57, 2.53; P = 0.63) with ciclosporin relative to tacrolimus.…”

“…Eight of the included studies reported acute rejection at 12 months as an endpoint, with 970 and 943 patients at risk in the ciclosporin and tacrolimus arms respectively [25–29,32,33]. There were a total of 281 acute rejection events in patients on ciclosporin compared with 245 events in patients on tacrolimus, resulting in a risk ratio of 1.15 (95% CI 0.99–1.32; P = 0.06) for ciclosporin relative to tacrolimus (Fig 4).…”

Tacrolimus-Based versus Cyclosporine-Based Immunosuppression in Hepatitis C Virus-Infected Patients after Liver Transplantation: A Meta-Analysis and Systematic Review

“…In addition, the number of deaths is inferior to the number of graft loss in four manuscripts [24], [31], [37], [38]. However, the number of deaths is superior to the number of graft loss in three manuscripts [17], [25], [26]. It's a hint that the definition of graft loss in their manuscripts might be different,which may lead to different result of the meta-analysis of graft loss.…”

Is there such a thing as protocol immunosuppression in liver transplantation?

“…A recent RCT indicated less severe recurrence in cyclosporine-treated patients but no difference in survival at 2 years [15]. In contrast, a retrospective review of almost 9000 patients in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database suggested better outcomes in tacrolimus-treated patients [16].…”