Reply

Abstract

We thank Dr. Cross for his useful comments1 based on our work.2 In our study, we demonstrated that long-term maintenance immunosuppression with azathioprine and tacrolimus along with shorter term prednisolone [triple therapy (TT)] resulted in a slower onset of histologically severe fibrosis and portal hypertension in recipients with hepatitis C virus (HCV) and cirrhosis in comparison with tacrolimus monotherapy (MT). Indeed, there was no statistically significant difference in patient or graft survival between the 2 treatment arms according to our findings. Therefore, we did not conclude anywhere in our article that TT prolonged graft survival. However, we did show the impact of TT treatment through delayed progression to stage 4 fibrosis in recipients with HCV. There was also a statistically significant difference between MT-treated patients and TT-treated patients in terms of clinical decompensation (Fig. 1), which was defined as the first clinical manifestation of ascites/hydrothorax, variceal bleeding, jaundice (≥3 mg/dL; in the absence of other causes), or encephalopathy. Throughout the study period, 3 TT patients suffered decompensation (25, 54, and 60 months), whereas 7 MT patients suffered decompensation (12, 30, 50, 55, 60, 68, and 86 months). These results were even more apparent with longer follow-up. Two more MT patients suffered decompensation at 88 and 96 months post-LT. Kaplan-Meier curves of MT and TT with respect to the prediction of clinical decompensation. Although we do agree with Dr. Cross that the next step in clinical research could be considered a randomized trial comparing low-dose prednisolone and tacrolimus to TT, we pointed out in the Discussion section that in our study during the first year, virtually no patient stopped taking azathioprine, but steroids were tapered off in most. This could suggest that the effect of azathioprine is at least as important as, if not more important than, the effect of low-dose maintenance steroids. Indeed, in a recent randomized trial3 in which azathioprine was not used, the steroid group had more fibrosis. Moreover, azathioprine use has been associated with less fibrosis in comparison with mycophenalate,4 and this finding has been documented in our whole population5 and by others.6-11 Therefore, we believe that future clinical trials should include azathioprine in the control arm and that in vitro work should be encouraged with respect to HCV and azathioprine. Pinelopi Manousou*, Andrew K Dhillon , Andrew K Burroughs*, * The Royal Free Shiela Sherlock Liver Centre and Division of Surgery & International Sciences, University College London, London, United Kingdom, Department of Histopathology, Royal Free Hospital, London, United Kingdom.