Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients

Background
Antibodies against T-cells are used to induce immunosuppression after liver transplantation. These antibodies are intended to reduce rejection of the transplanted liver and are 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 antibodies have been used: interleukin-2 receptor antagonists (BT563, daclizumab, or basiliximab), monoclonal antibodies specific for the CD3 receptor (muromonab-CD3) or the CD52 surface protein (alemtuzumab), or polyclonal antibodies of horse or rabbit (antithymocyte globulin (ATG) or antilymphocyte globulin (ALG)). The benefits and harms of these antibodies are unclear.

This systematic review aimed to evaluate the use of antibodies against T-cells after liver transplantation. The question is whether T-cell antibody induction has a role after liver transplantation, and which antibody works best with the least number of adverse events.

Aim
We wanted to discover whether antibody induction therapy was better or worse than therapy without T-cell specific antibodies for induction of immunosuppression after liver transplantation, and whether one type of antibody is better than another type of antibody. We systematically searched medical databases and found 19 randomised clinical trials including 25 comparisons that investigated the use of different types of T-cell specific antibodies in 2067 patients after they had received their liver transplant. All of these trials had high risk of bias (that is, risk of overestimation of benefits and underestimation of harms). We compared randomised clinical trials assessing T-cell specific antibody induction versus no T-cell specific antibody induction or versus another type of T-cell specific antibody induction. These trials assessed interleukin-2 receptor antagonists versus no antibody induction (1454 patients, 10 trials); monoclonal T-cell specific antibody versus no antibody induction (398 patients, five trials); polyclonal T-cell specific antibody versus no T-cell specific antibody induction (145 patients, three trials); interleukin-2 receptor antagonist versus monoclonal T-cell specific antibody induction (87 patients, one trial); and interleukin-2 receptor antagonist versus polyclonal T-cell specific antibody induction (112 patients, two trials).

Results
From our results we were unable to determine the effects of antibody induction on mortality, graft loss including death, adverse events, infection, CMV infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, or hypertension for any of the comparisons. Acute rejection may be reduced when any kind of T-cell specific antibody induction was compared with no induction and when trial sequential analysis, which we used to control for random errors, was applied. Furthermore, serum creatinine was statistically significantly higher in the T-cell specific antibody induction group compared with the no induction group, as well as in the polyclonal T-cell specific antibody induction group compared with the no induction group.

Conclusion
The effects of T-cell antibody induction remain uncertain because of high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risk of systematic error (bias) and low risk of random error (play of chance).

Authors' conclusions: 

The effects of T-cell antibody induction remain uncertain because of the high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risks of systematic error (bias) and low risk of random error (play of chance).

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 antibody induction for preventing rejection after liver transplantation.

Objectives: 

To assess the benefits and harms of immunosuppressive T-cell specific antibody induction compared with placebo, no induction, or another type of T-cell specific antibody 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) until September 2013.

Selection criteria: 

Randomised clinical trials assessing immunosuppression with T-cell specific antibody induction compared with placebo, no induction, or another type of antibody induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. We planned to include trials with all of the different types of T-cell specific antibodies that are or have been used for induction (ie., polyclonal antibodies (rabbit of horse antithymocyte globulin (ATG), or antilymphocyte globulin (ALG)), monoclonal antibodies (muromonab-CD3, anti-CD2, or alemtuzumab), and interleukin-2 receptor antagonists (daclizumab, basiliximab, BT563, or Lo-Tact-1)).

Data collection and analysis: 

We used RevMan analysis 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 the risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). We presented outcome results in a summary of findings table.

Main results: 

We included 19 randomised clinical trials with a total of 2067 liver transplant recipients. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants); monoclonal antibody versus no induction (five trials with 398 participants); polyclonal antibody versus no induction (three trials with 145 participants); IL-2 RA versus monoclonal antibody (one trial with 87 participants); and IL-2 RA versus polyclonal antibody (two trials with 112 participants). Thus, we were able to compare T-cell specific antibody induction versus no induction (17 trials with a total of 1955 participants). Overall, no difference in mortality (RR 0.91; 95% CI 0.64 to 1.28; low-quality of evidence), graft loss including death (RR 0.92; 95% CI 0.71 to 1.19; low-quality of evidence), and adverse events ((RR 0.97; 95% CI 0.93 to 1.02; low-quality evidence) outcomes was observed between any kind of T-cell specific antibody induction compared with no induction when the T-cell specific antibody induction agents were analysed together or separately. Acute rejection seemed to be reduced when any kind of T-cell specific antibody induction was compared with no induction (RR 0.85, 95% CI 0.75 to 0.96; moderate-quality evidence), and when trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed before the required information size was obtained. Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 μmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small difference was not clinically significant. We found no statistically significant differences for any of the remaining predefined outcomes — infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension — when the T-cell specific antibody induction agents were analysed together or separately. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were found on quality of life.

When T-cell specific antibody induction agents were compared with another type of antibody induction, no statistically significant differences were found for mortality, graft loss, and acute rejection for the separate analyses. When interleukin-2 receptor antagonists were compared with polyclonal T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude random errors. We found no statistically significant differences for any of the remaining predefined outcomes: infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension. No data were found on quality of life.

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