- Email: [email protected]
Retrospective Analysis of the Impact of Immunosuppression on the Course of Recurrent Hepatitis C After Liver Transplantation
Retrospective Analysis of the Impact of Immunosuppression on the Course of Recurrent Hepatitis C After Liver Transplantation M.J. Bahr, J.G.P. Beckermann, K. Rifai, L. Gehrmann, J. Rosenau, J. Klempnauer, C.P. Strassburg, and M.P. Manns ABSTRACT Introduction. In a substantial proportion of patients, recurrent hepatitis C after liver transplantation (OLT) rapidly progresses to graft cirrhosis. The role of different immunosuppressive schemes is not well evaluated. Patients and methods. The clinical course of 130 patients with recurrent hepatitis C after OLT was retrospectively analyzed. Mean trough levels of calcineurin inhibitors and cumulative doses of the remaining immunosuppressants were calculated. The results were compared with liver function tests, histological fibrosis progression, and survival. Results. Survival and fibrosis progression were similar in patients with tacrolimus and cyclosporine and did not correlate with mean trough levels. In contrast, the application of azathioprine (mean dose of more than 25 mg/d during the first 3 months after OLT) was associated with significantly less progression of fibrosis (P ⫽ .01). Administration of azathioprine after the early postoperative phase was not related to the long-term outcome. The dose of prednisolone in the long-term course after OLT significantly correlated with the rate of fibrosis progression (P ⫽ .008). Conclusions. The clinical course of recurrent hepatitis C was variable. Survival and fibrosis progression did not correlate with the type or trough level of calcineurin inhibitors. Azathioprine early in the course after OLT and prolonged administration of prednisolone were associated with less fibrosis progression.
T
HERE IS ACCUMULATING EVIDENCE that recurrent hepatitis C after liver transplantation (OLT) rapidly progresses to liver cirrhosis in a substantial proportion of patients.1,2 Graft cirrhosis quickly leads to decompensation, and survival in hepatitis C virus (HCV)-positive patients is significantly worse than in HCV-negative patients.3,4 Several studies addressed the underlying mechanisms of fibrosis progression in patients with recurrent hepatitis C after OLT. Besides others, the date of transplantation and donor age emerged as predictive factors for an accelerated course after OLT.2,5 Recent data also suggested a role of immunosuppression for the prognosis of posttransplantation hepatitis C.5 PATIENTS AND METHODS We retrospectively analyzed patients who received liver grafts at the Medizinische Hochschule Hannover. Data were taken from patients’ charts and the transplantation database including standard clinical and laboratory parameters. Histology was reevaluated
to provide data on the rate of fibrosis progression. Tacrolimus and cyclosporine were analyzed using the trough level database, which includes all whole-blood levels starting at the time of transplantation (n ⫽ 16,303). Mean trough levels for different time intervals after OLT (0 to 3 months, 3 to 24 months, 3 to 60 months, and 24 to 120 months) were calculated using area-under-the-curve analysis. Azathioprine, mycophenolate mofetil, and prednisolone were analyzed as cumulative doses. All patients received prednisolone initially after OLT; we therefore only analyzed prednisolone doses
From the Departments of Gastroenterology, Hepatology and Endocrinology (M.J.B., J.G.P.B., K.R., L.G., J.R., C.P.S., M.P.M.) and Visceral and Transplantation Surgery (J.K.), Medizinische Hochschule Hannover, Hannover, Germany. The work was supported by Fujisawa Deutschland GmbH (Munich, Germany). Address reprint requests to Matthias J. Bahr, MD, Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str 1, 30623 Hannover, Germany. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.02.103
Transplantation Proceedings, 37, 1703–1704 (2005)
1703
1704 given later than 24 months after OLT. Statistics were calculated using SPSS software.
RESULTS
Of 1250 patients receiving liver grafts during the period of analysis, 130 patients were identified HCV-positive (85 male, 45 female, 8 HBV coinfection, 2 HDV-positive; 37 hepatocellular carcinoma; median age at OLT 53 years). Mean follow-up time was 1863 days (maximum 6097 days). Five-year patient survival was 61%; 5-year graft survival was 56%. In patients with sufficient numbers of biopsies the rate of fibrosis progression was calculated. The more recently transplanted patients displayed a significantly higher rate of fibrosis progression (ANOVA, P ⬍ .001). Initial immunosuppression was cyclosporine in 83% and tacrolimus in 14% of the patients. All patients received additional prednisolone, 29% azathioprine, and 1% mycophenolate mofetil. The type of calcineurin inhibitor did not significantly influence graft survival. However, patients who required a switch of calcineurin inhibitor showed a significantly reduced graft survival (log-rank, P ⫽ .05). Likewise, mean trough levels were not related to survival. Fibrosis progression did not significantly correlate with the type of calcineurin inhibitor or the mean trough levels. For analysis of azathioprine effects, patients were split in two groups (⬎25 mg/d vs ⬍25 mg/d). For the time interval up to 3 months after OLT, higher azathioprine doses were associated with less fibrosis progression (U test, P ⬍ .02). Azathioprine given during later time periods after OLT was not associated with survival or fibrosis progression. A high proportion of patients received steroids during the first and second year after liver transplantation. We therefore analyzed differences in prednisolone doses in the long-term course (⬎24 months after OLT). Mean prednisolone doses did not correlate with graft or patient survival. There was a close correlation between fibrosis progression rate and prednisolone dose (Kruskal-Wallis test, P ⫽ .008). Patients with the lowest fibrosis progression rate received a mean dose of 7.7 ⫾ 1.6 mg/d prednisolone, while patients with highest fibrosis progression rate received 3.3 ⫾ 2.9 mg/d prednisolone. DISCUSSION
We analyzed the impact of immunosuppression on the course of recurrent hepatitis C after liver transplantation.
BAHR, BECKERMANN, RIFAI ET AL
Early reports suggested that steroid bolus therapy is associated with a worse outcome of recurrent hepatitis C.6 Recently, several reports addressed the role of other immunsuppressants.5,7–11 In our study, we found no evidence that the type or dose of calcineurin inhibitor influences the course of hepatitis C after liver transplantation. In contrast, induction therapy using azathioprine and prolonged administration of prednisolone were associated with an improved outcome. This is accordance with recently published data.5 However, prospective studies are required to optimize immunosuppression after OLT.
REFERENCES 1. Bahr MJ, Manns MP: Changing faces-natural course and treatment of hepatitis C after liver transplantation. J Hepatol 40:699, 2004 2. Berenguer M, Ferrell L, Watson J, et al: HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol 32:673, 2000 3. Berenguer M, Prieto M, Rayon JM, et al: Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 32:852, 2000 4. Forman LM, Lewis JD, Berlin JA, et al: The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 122:889, 2002 5. Berenguer M, Crippin J, Gish R, et al: A model to predict severe HCV-related disease following liver transplantation. Hepatology 38:34, 2003 6. Böker KHW, Dalley G, Bahr MJ, et al: Long-term outcome of hepatitis C virus infection after liver transplantation. Hepatology 25:203, 1997 7. Ben-Ari Z, Mor E, Bar-Nathan N, et al: Comparison of tacrolimus with cyclosporin as primary immunosuppression in patients with hepatitis C virus infection after liver transplantation. Transplant Proc 35:612, 2003 8. Ghobrial RM, Farmer DG, Baquerizo A, et al: Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience. Ann Surg 229:824, 1999 9. Herrero JI, de la Pena A, Quiroga J, et al: Risk factors for recurrence of hepatitis C after liver transplantation. Liver Transpl Surg 4:265, 1998 10. Martin P, Busuttil RW, Goldstein RM, et al: Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial. Liver Transpl 10:1258, 2004 11. Papatheodoridis GV, Davies S, Dhillon AP, et al: The role of different immunosuppression in the long-term histological outcome of HCV reinfection after liver transplantation for HCV cirrhosis. Transplantation 72:412, 2001
T
HERE IS ACCUMULATING EVIDENCE that recurrent hepatitis C after liver transplantation (OLT) rapidly progresses to liver cirrhosis in a substantial proportion of patients.1,2 Graft cirrhosis quickly leads to decompensation, and survival in hepatitis C virus (HCV)-positive patients is significantly worse than in HCV-negative patients.3,4 Several studies addressed the underlying mechanisms of fibrosis progression in patients with recurrent hepatitis C after OLT. Besides others, the date of transplantation and donor age emerged as predictive factors for an accelerated course after OLT.2,5 Recent data also suggested a role of immunosuppression for the prognosis of posttransplantation hepatitis C.5 PATIENTS AND METHODS We retrospectively analyzed patients who received liver grafts at the Medizinische Hochschule Hannover. Data were taken from patients’ charts and the transplantation database including standard clinical and laboratory parameters. Histology was reevaluated
to provide data on the rate of fibrosis progression. Tacrolimus and cyclosporine were analyzed using the trough level database, which includes all whole-blood levels starting at the time of transplantation (n ⫽ 16,303). Mean trough levels for different time intervals after OLT (0 to 3 months, 3 to 24 months, 3 to 60 months, and 24 to 120 months) were calculated using area-under-the-curve analysis. Azathioprine, mycophenolate mofetil, and prednisolone were analyzed as cumulative doses. All patients received prednisolone initially after OLT; we therefore only analyzed prednisolone doses
From the Departments of Gastroenterology, Hepatology and Endocrinology (M.J.B., J.G.P.B., K.R., L.G., J.R., C.P.S., M.P.M.) and Visceral and Transplantation Surgery (J.K.), Medizinische Hochschule Hannover, Hannover, Germany. The work was supported by Fujisawa Deutschland GmbH (Munich, Germany). Address reprint requests to Matthias J. Bahr, MD, Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg-Str 1, 30623 Hannover, Germany. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.02.103
Transplantation Proceedings, 37, 1703–1704 (2005)
1703
1704 given later than 24 months after OLT. Statistics were calculated using SPSS software.
RESULTS
Of 1250 patients receiving liver grafts during the period of analysis, 130 patients were identified HCV-positive (85 male, 45 female, 8 HBV coinfection, 2 HDV-positive; 37 hepatocellular carcinoma; median age at OLT 53 years). Mean follow-up time was 1863 days (maximum 6097 days). Five-year patient survival was 61%; 5-year graft survival was 56%. In patients with sufficient numbers of biopsies the rate of fibrosis progression was calculated. The more recently transplanted patients displayed a significantly higher rate of fibrosis progression (ANOVA, P ⬍ .001). Initial immunosuppression was cyclosporine in 83% and tacrolimus in 14% of the patients. All patients received additional prednisolone, 29% azathioprine, and 1% mycophenolate mofetil. The type of calcineurin inhibitor did not significantly influence graft survival. However, patients who required a switch of calcineurin inhibitor showed a significantly reduced graft survival (log-rank, P ⫽ .05). Likewise, mean trough levels were not related to survival. Fibrosis progression did not significantly correlate with the type of calcineurin inhibitor or the mean trough levels. For analysis of azathioprine effects, patients were split in two groups (⬎25 mg/d vs ⬍25 mg/d). For the time interval up to 3 months after OLT, higher azathioprine doses were associated with less fibrosis progression (U test, P ⬍ .02). Azathioprine given during later time periods after OLT was not associated with survival or fibrosis progression. A high proportion of patients received steroids during the first and second year after liver transplantation. We therefore analyzed differences in prednisolone doses in the long-term course (⬎24 months after OLT). Mean prednisolone doses did not correlate with graft or patient survival. There was a close correlation between fibrosis progression rate and prednisolone dose (Kruskal-Wallis test, P ⫽ .008). Patients with the lowest fibrosis progression rate received a mean dose of 7.7 ⫾ 1.6 mg/d prednisolone, while patients with highest fibrosis progression rate received 3.3 ⫾ 2.9 mg/d prednisolone. DISCUSSION
We analyzed the impact of immunosuppression on the course of recurrent hepatitis C after liver transplantation.
BAHR, BECKERMANN, RIFAI ET AL
Early reports suggested that steroid bolus therapy is associated with a worse outcome of recurrent hepatitis C.6 Recently, several reports addressed the role of other immunsuppressants.5,7–11 In our study, we found no evidence that the type or dose of calcineurin inhibitor influences the course of hepatitis C after liver transplantation. In contrast, induction therapy using azathioprine and prolonged administration of prednisolone were associated with an improved outcome. This is accordance with recently published data.5 However, prospective studies are required to optimize immunosuppression after OLT.
REFERENCES 1. Bahr MJ, Manns MP: Changing faces-natural course and treatment of hepatitis C after liver transplantation. J Hepatol 40:699, 2004 2. Berenguer M, Ferrell L, Watson J, et al: HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol 32:673, 2000 3. Berenguer M, Prieto M, Rayon JM, et al: Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 32:852, 2000 4. Forman LM, Lewis JD, Berlin JA, et al: The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 122:889, 2002 5. Berenguer M, Crippin J, Gish R, et al: A model to predict severe HCV-related disease following liver transplantation. Hepatology 38:34, 2003 6. Böker KHW, Dalley G, Bahr MJ, et al: Long-term outcome of hepatitis C virus infection after liver transplantation. Hepatology 25:203, 1997 7. Ben-Ari Z, Mor E, Bar-Nathan N, et al: Comparison of tacrolimus with cyclosporin as primary immunosuppression in patients with hepatitis C virus infection after liver transplantation. Transplant Proc 35:612, 2003 8. Ghobrial RM, Farmer DG, Baquerizo A, et al: Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience. Ann Surg 229:824, 1999 9. Herrero JI, de la Pena A, Quiroga J, et al: Risk factors for recurrence of hepatitis C after liver transplantation. Liver Transpl Surg 4:265, 1998 10. Martin P, Busuttil RW, Goldstein RM, et al: Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial. Liver Transpl 10:1258, 2004 11. Papatheodoridis GV, Davies S, Dhillon AP, et al: The role of different immunosuppression in the long-term histological outcome of HCV reinfection after liver transplantation for HCV cirrhosis. Transplantation 72:412, 2001