Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes

Abstract

Objective: Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA).

Design: 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy.

Results: No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted.

Conclusions: Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.

Keywords: LIVER TRANSPLANTATION.

Figure 1

Hazard curves of Ishak stage 4. Hazard curves of reaching Ishak stage 4 in the two treatment arms (p=0.005 Mantel–Cox). In all, 19 MT patients reached stage ≥4 at a median of 32 months, while 11 TT reached stage ≥4 at a median of 49 months post-LT. Sixteen patients discontinued azathioprine between 10 and 37 months post-LT. MT, monotherapy; TT, triple therapy.

Figure 2

Hazard curves of collagen proportionate area (CPA) 6% and 7.2%. Hazard curves of reaching CPA 6% and 7.2% with those achieving sustained virological response censored (18 m MT, 36 m TT, 36 m MT, 38 m TT, 40 m TT, 52 m MT) in the two treatment arms (p=0.002 for CPA 6% and p=0.001 for CPA 7.2% by Mantel–Cox). Sixteen patients discontinued azathioprine between 10 and 37 months post-LT. MT, monotherapy; TT, triple therapy.

Figure 3

(A) Hazard curves of developing hepatic venous pressure gradient (HVPG)≥10 mm Hg and clinical decompensation. Hazard curves of developing HVPG≥10 mm Hg in the two treatment arms (p=0.019 by Breslow) in 33 MT and 31 TT. In all, 11 MT reached HVPG≥10 mm Hg, compared with four TT. Patients achieving sustained virological response (SVR) before reaching HVPG≥10 mm Hg were censored at the time of SVR. (B) Hazard curves of decompensation, defined as whichever occurred first of ascites/hydrothorax, variceal bleeding or encephalopathy, in our trial cohort (p=0.037 by Breslow). Decompensation occurred in 13 patients: nine MT at a mean of 70 m and four TT at a mean time of 91 m. Patients achieving SVR were censored at the time of SVR. MT, monotherapy; TT, triple therapy.

Figure 4

Fibrosis progression over time based on collagen proportionate area (CPA) and Ishak stage. Mean fibrosis according to time post-LT based on CPA and Ishak stage. Overall, 310 biopsies were evaluated in 49 MT and 48 TT: Median CPA fibrosis progression rate was 1.5%/year. Each box plot shows the median value, the IQR and the range of CPA each year. Ishak stage progression is presented as mean values ±2 SD to allow comparison with work from others. MT, monotherapy; TT, triple therapy.