Antibody induction therapy compared with corticosteroids for induction of immunosuppression after liver transplantation

Background
Historically, corticosteroids have been the backbone of immunosuppression after liver transplantation, and corticosteroids are typically started immediately before or during transplantation. However, the use of corticosteroids is associated with several complications such as infection, hepatitis C virus recurrence, diabetes mellitus, hypertension, obesity, osteoporosis, fracture, and reduced quality of life. Hence, corticosteroid avoidance and corticosteroid reduction regimens for liver transplant recipients have been developed.

Antibodies against T-cells are also used to induce immunosuppression after liver transplantation. This T-cell specific antibody induction therapy is intended to reduce rejection of the transplanted liver and is given within the first two weeks after transplantation. Furthermore, these antibodies may allow for delayed introduction of calcineurin inhibitors to protect kidney function.

Different types of T-cell specific antibody induction therapy have been used for liver transplant recipients: interleukin-2 receptor antagonists (BT563, daclizumab, or basiliximab), monoclonal antibodies specific for the CD3 receptor (muromonab-CD3) or the CD52 surface protein (alemtuzumab), and polyclonal antibodies (rabbit or horse antithymocyte globulin (ATG) or antilymphocyte globulin (ALG)). A novel approach has been to replace corticosteroids with T-cell specific antibody induction as part of a corticosteroid reduction or avoidance regimen. The benefits and harms of this T-cell specific antibody induction therapy remain unclear.

Aim
We wanted to discover whether antibody induction therapy was better or worse than therapy with corticosteroids for induction of immunosuppression after liver transplantation. In specific, we wanted to establish the role of T-cell specific antibody induction therapy as part of corticosteroid-free immunosuppression after liver transplantation, and to find out which type of T-cell specific antibody induction therapy works best with the fewest adverse effects. We systematically searched medical databases (date of last search September 2013) and found 10 randomised clinical trials with 1589 liver transplant recipients, which investigated the use of antibodies compared with corticosteroids for induction in 1589 participants after they had undergone liver transplant. These trials studied antithymocyte globulin and the interleukin-2 receptor antagonists basiliximab and daclizumab. All of these trials had high risk of bias (i.e., risks of overestimation of benefits and underestimation of harms), which means that the quality of the evidence included in the review is low.

Results
Our analyses showed no significant differences regarding mortality, graft loss, acute rejection, infection, hepatitis C virus recurrence, malignancy, and post-transplantation lymphoproliferative disorder. Cytomegalovirus infection was less frequent in patients receiving any kind of T-cell specific antibody induction compared with corticosteroid induction (low-quality evidence). This finding was also observed when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (low-quality evidence) and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (low-quality evidence). However, when trial sequential analysis regarding cytomegalovirus infection was applied, random errors could not be excluded. Furthermore, diabetes mellitus occurred less frequently when T-cell specific antibody induction was compared with corticosteroid induction (low-quality evidence), when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (low-quality evidence). When trial sequential analysis was applied, we could exclude random errors regarding a reduction in diabetes mellitus by T-cell specific antibodies compared with corticosteroids.

Conclusion
As a result of the low quality of the current evidence, the effects of T-cell antibody induction remain uncertain. T-cell specific antibody induction seems to reduce diabetes mellitus and may reduce cytomegalovirus infection when compared with corticosteroid induction. No other clear benefits or harms were associated with the use of T-cell specific antibody induction compared with corticosteroid induction. For some analyses, the number of trials investigating the use of T-cell specific antibody induction after liver transplantation is small, and the numbers of participants and outcomes in these randomised trials are limited. Furthermore, the included trials are heterogeneous in nature and have applied different types of T-cell specific antibody induction therapy. All trials were with high risk of bias. Hence, additional high-quality randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with corticosteroid induction for liver transplant recipients.

Authors' conclusions: 

Because of the low quality of the evidence, the effects of T-cell antibody induction remain uncertain. T-cell specific antibody induction seems to reduce diabetes mellitus and may reduce cytomegalovirus infection when compared with corticosteroid induction. No other clear benefits or harms were associated with the use of T-cell specific antibody induction compared with corticosteroid induction. For some analyses, the number of trials investigating the use of T-cell specific antibody induction after liver transplantation is small, and the numbers of participants and outcomes in these randomised trials are limited. Furthermore, the included trials are heterogeneous in nature and have applied different types of T-cell specific antibody induction therapy. All trials were at high risk of bias. Hence, additional randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with corticosteroid induction for liver transplant recipients. Such trials ought to be conducted with low risks of systematic error and of random error.

Read the full abstract...
Background: 

Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell specific antibody induction compared with corticosteroid induction of immunosuppression after liver transplantation.

Objectives: 

To assess the benefits and harms of T-cell specific antibody induction versus corticosteroid induction for prevention of acute rejection in liver transplant recipients.

Search strategy: 

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 September 2013 together with reference checking, citation searching, contact with trial authors and pharmaceutical companies to identify additional trials.

Selection criteria: 

We included all randomised clinical trials assessing immunosuppression with T-cell specific antibody induction versus corticosteroid induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy.

Data collection and analysis: 

We used RevMan for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance).

Main results: 

We included 10 randomised trials with a total of 1589 liver transplant recipients, which studied the use of T-cell specific antibody induction versus corticosteroid induction. All trials were with high risk of bias. We compared any kind of T-cell specific antibody induction versus corticosteroid induction in 10 trials with 1589 participants, including interleukin-2 receptor antagonist induction versus corticosteroid induction in nine trials with 1470 participants, and polyclonal T-cell specific antibody induction versus corticosteroid induction in one trial with 119 participants.

Our analyses showed no significant differences regarding mortality (RR 1.01, 95% CI 0.72 to 1.43), graft loss (RR 1.12, 95% CI 0.82 to 1.53) and acute rejection (RR 0.84, 95% CI 0.70 to 1.00), infection (RR 0.96, 95% CI 0.85 to 1.09), hepatitis C virus recurrence (RR 0.89, 95% CI 0.79 to 1.00), malignancy (RR 0.59, 95% CI 0.13 to 2.73), and post-transplantation lymphoproliferative disorder (RR 1.00, 95% CI 0.07 to 15.38) when any kind of T-cell specific antibody induction was compared with corticosteroid induction (all low-quality evidence). Cytomegalovirus infection was less frequent in patients receiving any kind of T-cell specific antibody induction compared with corticosteroid induction (RR 0.50, 95% CI 0.33 to 0.75; low-quality evidence). This was also observed when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (RR 0.55, 95% CI 0.37 to 0.83; low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (RR 0.21, 95% CI 0.06 to 0.70; low-quality evidence). However, when trial sequential analysis regarding cytomegalovirus infection was applied, the required information size was not reached. Furthermore, diabetes mellitus occurred less frequently when T-cell specific antibody induction was compared with corticosteroid induction (RR 0.45, 95% CI 0.34 to 0.60; low-quality evidence), when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (RR 0.45, 95% CI 0.35 to 0.61; low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (RR 0.12, 95% CI 0.02 to 0.95; low-quality evidence). When trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed. We found no subgroup differences for type of interleukin-2 receptor antagonist (basiliximab versus daclizumab). Four trials reported on adverse events. However, no differences between trial groups were noted. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were available on quality of life.

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