A Randomized Multicenter Study Comparing a Tacrolimus-Based Protocol with and without Steroids in HCV-Positive Liver Allograft Recipients

Abstract

Allograft reinfection with hepatitis C virus (HCV) occurs universally in liver transplant recipients. Corticosteroids can contribute to HCV recurrence. This randomized study evaluated HCV recurrence in HCV-positive liver allograft recipients using steroid-free immunosuppression. All patients received tacrolimus (TAC) at an initial dose of 0.10-0.15 mg/kg. The steroid-free arm (TAC/daclizumab (TAC/DAC, n = 67)) received daclizumab induction, and the steroid arm (TAC/steroid (TAC/STR, n = 68)) received a steroid bolus (≤ 500mg) followed by 15-20 mg/day with discontinuation after month 3. Median HCV viral load at month 12, the primary endpoint, was similar at 5.46 (0.95-6.54) IU/mL with TAC/DAC and 5.91 (0.95-6.89) IU/mL with TAC/STR. Small numerical differences in the estimated rate of freedom from HCV recurrence (19.1 versus 13.8%) and freedom from biopsy proven rejection (78.4 versus 66.1%) were observed between TAC/DAC and TAC/STR. Patient survival estimates were significantly lower with TAC/DAC than with TAC/STR (83.1 versus 95.5%; 95% CI, -0.227 to -0.019%), and graft survival was numerically lower (80.1 versus 91.1%, P = NS). Completion rates (45 versus 82%) indicated poorer tolerability with TAC/DAC than with TAC/STR. Steroid-free immunosuppression had no real impact on HCV viral load. HCV recurrence was higher with TAC/STR. Results are inconclusive due to the unexpected lower completion rates in the TAC/DAC arm.

Figure 1

Progress of liver transplant recipients through the phases of the randomized study comparing a tacrolimus-based protocol with and without steroids. The rate of study completion was lower with TAC/DAC than with TAC/STR. Most commonly, patients in the TAC/DAC arm prematurely discontinued the study due to an adverse event. TAC: tacrolimus; DAC: daclizumab; STR: steroids; FAS: full analysis set; PAS: primary analysis set.

Figure 2

Estimated rate of patients free from recurrence of HCV Infection (Kaplan-Meier Method) at 12 months as confirmed by central biopsy. Freedom from HCV recurrence at 12 months was 19.1% with the TAC/DAC steroid-free protocol and 13.8% with the TAC/STR protocol (Kaplan-Meier method) with a significant difference in survival curves between treatments (95% CI, −0.105 to 0.211%; P = 0.020, Wilcoxon Gehan test). Protocol biopsies were performed at months 6 and 12 accounting for the higher number of events reported at these time points. TAC: tacrolimus; DAC: daclizumab; STR: steroids.