REFINE: A randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.
Levy G, Villamil FG, et al.American Journal of Transplantation 2014; 14(3): 635-646.
Aims
To investigate the development of liver fibrosis from hepatitis c related cirrhosis in liver transplant patients receiving cyclosporine A or tacrolimus.
Interventions
Patients received either CsA within 24 hours of liver transplant at a dose of 10-15mg/kg/day or tacrolimus within 24 hours post transplant at a starting dose of 0.1-0.15mg/kg/day.
Participants
361 hepatitis c virus (HCV)-positive adult first liver transplant recipients from a deceased or living donor.
Outcomes
The primary outcome was the rate of fibrosis stage ≥2 by 12 months. The secondary outcomes included fibrosis stage ≥2 at 24 months post transplant, fibrosis stage ≥1 and 12 and 24 months post transplantation, biopsy proven acute rejection, graft loss, death, treated acute rejection, the incidence of fibrosing cholestatic hepatitis, HCV RNA viral overload, liver enzymes, adverse events, serious adverse events and laboratory tests including serum creatinine.
Follow-up
24 months
CET Conclusions
This is an ambitious and interesting multicenter study investigating the role of cyclosporine vs. tacrolimus in the rate of development of fibrosis following liver transplantation in recipients with Hepatitis C. Whilst no difference in fibrosis rates was seen between the treatment arms, there is a suggestion that there is a reduced severity of fibrosis progression when cyclosporine A is combined with steroid withdrawal. These results should be interpreted with caution, however, as this appears to be a post-hoc analysis and the withdrawal of steroids was not randomised – rather it was selected on a per centre basis. Furthermore, steroid withdrawal was combined with the use of an IL2 antibody, which was not used in the patients maintained on steroids. The main problem with this study is the failure to recruit adequately, with an extremely high rate of dropouts from primary endpoint analysis (<50% underwent 12 month biopsy). Thus the sample size calculations are probably unsound and the study likely underpowered. This probably reflects the difficulty in achieving reliable protocol biopsy rates in such a large, multicenter study.
Data analysis
Modified intention-to-treat analysis
Trial registration
ClinicalTrials.gov NCT - 00260208