Azathioprine in Liver Transplantation: A Reevaluation of Its Use and a Comparison with Mycophenolate Mofetil

The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, Royal Free Hospital, London, UK.
American Journal of Transplantation (Impact Factor: 5.68). 07/2009; 9(8):1725-31. DOI: 10.1111/j.1600-6143.2009.02705.x
Source: PubMed


Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF.

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    • "Seventeen studies have data on MMF and severity of HCV recurrence: only two found decreased severity, (in one there was no multivariate analysis), nine studies documented similar severity, and six had increased severity [57]. A prospective study [63] of 21 patients receiving quadruple induction CyA-based immunosuppression augmented by MMF "
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    ABSTRACT: HCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens. From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency. There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6 months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed.
    Journal of Hepatology 09/2011; 56(4):973-83. DOI:10.1016/j.jhep.2011.06.031 · 11.34 Impact Factor
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    • "MMF has widely replaced azathioprine in solid organ transplantation, mainly due to its faster onset of action and potentially greater immunosuppressive capacity reducing rejection episodes as seen after cardiac and renal transplantation, albeit at the cost of a higher rate of infections [9] [10]. In liver transplantation, the superiority of MMF over azathioprine is less clear [11]. Moreover, the exact role of MMF as compared to azathioprine in the treatment of autoimmune diseases and vasculitis syndromes still has to be defined [12] and a recent controlled treatment trial of ANCA associated vasculitis concluded that MMF was inferior to azathioprine for the maintenance of remission [13]. "

    Journal of Hepatology 09/2011; 55(3):510-1. DOI:10.1016/j.jhep.2011.01.012 · 11.34 Impact Factor
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    • "Interestingly, three studies in the mid-nineties also explored the efficacy and safety of azathioprine after CNI reduction/interruption [69] [70] [71] [72] in patients with renal impairment. Although limited , this experiment suggested here again that CNI interruption under the control of antiproliferative agents was associated with an improvement in renal function at the cost of rejection. "

    Journal of Hepatology 12/2010; 54(5):1041-54. DOI:10.1016/j.jhep.2010.12.001 · 11.34 Impact Factor
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