Since the first successful liver transplant in 1967, immunosuppression has allowed liver transplantation to become the standard treatment of end-stage liver disease. Over the decades, the rates of rejection have decreased, and patient survival outcomes have significantly improved in large part due to the introduction and advancements of immunosuppression medications. However, the adverse effects associated with long-term immunosuppression have created new challenges facing liver transplantation and added significantly to posttransplantation morbidity. This review presents the data and rationale for immunosuppression approaches, addresses the main controversies related to immunosuppression in liver transplantation, and explores some of the newer advancements in immunosuppressive drug therapy.

Optimal induction for kidney transplantation in patients with previous nonrenal organ transplantation is unclear. We aimed to evaluate the impact of induction therapy on the outcomes following kidney transplantation in patients who underwent prior heart or liver transplantation.

Using the UNOS database, patients who underwent isolated heart or liver transplant from 2000 to 2016 followed by subsequent kidney transplant and maintained on calcineurin inhibitor (CNI)/mycophenolic acid (MPA) regimen were identified and stratified into three groups according to the induction used for kidney transplant: No induction, induction with interleukin-2 receptor antibody (IL-2RA), or T-cell depleting induction with Thymoglobulin. The outcomes were compared between no induction vs. IL-2RA and T-cell depleting induction, and IL-2RA vs. T-cell depleting induction.

Adjusted risk for delayed graft function was significantly higher for T-cell depleting vs. no induction (OR 4.56, 95% CI 1.14-18.3, P = 0.03) and trended higher for IL-2RA vs. no induction (OR 2.96, 95% CI 0.84-10.33, P = 0.08) among kidney after heart group and significantly higher for T-cell depleting vs. no induction (OR 2.88, 95% CI 1.40-5.95, P = 0.004) and IL-2RA induction (OR 1.88, 95% CI 1.12-3.17, P = 0.02) among kidney after liver patients. Adjusted graft failure and patient death risks were similar in patients who got IL-2RA or depleting inductions vs. no induction and IL-2RA vs. depleting induction groups in kidney after heart and kidney after liver groups.

The use of induction was not associated with graft or patient survival benefits for kidney transplantation in patients who had prior heart or liver transplants and maintained on CNI and MPA regimen.

Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents.

To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy.

We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation.

We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections.

We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.

We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life.

the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear.

Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life.

Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects.

To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation.

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, Literatura Americano e do Caribe em Ciencias da Saude (LILACS), World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and The Transplant Library until May 2017.

Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids.

We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed; otherwise we reported only the results from the fixed-effect model. We assessed the risk of systematic errors using 'Risk of bias' domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table.

We included 17 completed randomised clinical trials, but only 16 studies with 1347 participants provided data for the meta-analyses. Ten of the 16 trials assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids (782 participants) and six trials assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). One additional study assessed complete post-operative glucocorticosteroid avoidance but could only be incorporated into qualitative analysis of the results due to limited data published in an abstract. All trials were at high risk of bias. Only eight trials reported on the type of donor used. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.15, 95% CI 0.90 to 1.46; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; very low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; low-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses.

Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.

Early allograft dysfunction (EAD) is a well-defined clinical syndrome that reflects overall graft function within the first week after transplant. The aim of this study was to further refine the definition for EAD.

In this study, 1124 patients were included for analysis. Logistic regression was performed to identify markers of liver injury associated with 6-month patient and graft failure.

Recursive partitioning identified cut-points for ALT/AST > 3000/6000 IU/dL observed within first week, with bilirubin ≥ 10 mg/dL and INR ≥ 1.6 on postoperative day 7 for the revised EAD model. The incidence of updated EAD was 15% (164/1124). Multivariable analysis identified eight risk factors associated with EAD: % macrosteatosis, donor location, donor weight, nonheart beating donors, type of organ transplanted, recipient-associated hepatocellular carcinoma, severity of postreperfusion syndrome, and the amount of transfused fresh frozen plasma. In the presence of EAD, the incidence of post-transplant renal replacement therapy and dialysis dependence increases. There was a significant association of the presence of EAD with 6-month mortality (12% vs 3%) and 6-month graft failure (8% vs 1%).

Higher AST/ALT level needed as cutoff in comparison with the old EAD definition.

Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.

Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects.

To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation.

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded and Social Sciences Citation Index, The Transplant Library, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2014.

Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver-transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding the perioperative period and excluding the occurrence of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids.

We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed. We assessed the risk of systematic errors using risk of bias domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table.

We included 16 completed randomised clinical trials with a total of 1347 participants. We found 10 trials that assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use and treatment of rejection) versus short-term glucocorticosteroids (782 participants) and six trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). We found one ongoing trial assessing complete postoperative glucocorticosteroid avoidance versus short-term glucocorticosteroids, which is expected to enrol 300 participants. All trials were at high risk of bias. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.16, 95% CI 0.91 to 1.48; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; moderate-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses.

Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.

Induction immunosuppression with anti-thymocyte globulin (ATG) provides potential benefits after liver transplantation (LT). However, its use in patients with LT and hepatitis C (HCV) is controversial.

To evaluate the 1- and 2-year patient survival and HCV recurrence rate in patients receiving ATG during the induction phase of immunosuppression (IPI) after LT.

A total of 49 patients undergoing their first LT for HCV were randomized to receive ATG during IPI. Patient survival and HCV recurrence were determined at 1 and 2 years. The frequency of acute cellular rejection (ACR), infections, and neoplasms was also evaluated.

Twenty-six patients were randomized to receive ATG (Arm-1) and 23 to standard induction therapy (Arm-2). Those given ATG had lower HCV recurrence (26.9 vs 73.9 %, p = 0.001). The 1- and 2-year patient survival rates were similar for both arms (p = 0.33). Infections occurred in 46.1 % subjects in Arm-1 and 34.7 % in Arm-2 (p = 0.562). There was a greater proportion of fungal infections in Arm-1 (19.2 vs 0 %, p = 0.032).

ATG during the IPI was associated with lower frequency of recurrence of HCV in patients undergoing LT. This, however, did not affect the 1- and 2-year survival and the frequency of ACR, infections, or neoplasms.

Hepatitis C virus (HCV)-related cirrhosis represents the leading cause of liver transplantation in developed, Western and Eastern countries. Unfortunately, liver transplantation does not cure recipient HCV infection: reinfection universally occurs and disease progression is faster after liver transplant. In this review we focus on what happens throughout the peri-transplant phase and in the first 6-12 mo after transplantation: during this crucial period a completely new balance between HCV, liver graft, the recipient's immune response and anti-rejection therapy is achieved that will deeply affect subsequent outcomes. Nearly all patients show an early graft reinfection, with HCV viremia reaching and exceeding pre-transplant levels; in this setting, histological assessment is essential to differentiate recurrent hepatitis C from acute or chronic rejection; however, differentiating the two patterns remains difficult. The host immune response (mainly cellular mediated) appears to be crucial both in the control of HCV infection and in the genesis of rejection, and it is also strongly influenced by immunosuppressive treatment. At present no clear immunosuppressive strategy could be strongly recommended in HCV-positive recipients to prevent HCV recurrence, even immunotherapy appears to be ineffective. Nonetheless it seems reasonable that episodes of rejection and over-immunosuppression are more likely to enhance the risk of HCV recurrence through immunological mechanisms. Both complete prevention of rejection and optimization of immunosuppression should represent the main goals towards reducing the rate of graft HCV reinfection. In conclusion, post-transplant HCV recurrence remains an unresolved, thorny problem because many factors remain obscure and need to be better determined.

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.

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.

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.

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)).

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.

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.

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).

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.

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

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.

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.

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).

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.

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.

The purpose of this review is to evaluate the historical and recent literature as it pertains to current immunosuppression regimens in hepatitis C virus (HCV)-positive (+) liver-transplant recipients.

Recent findings suggest that there are unique differences between HCV transplant recipients and non-HCV transplant recipients, not only in the graft's inflammatory response, but also to the treatments used to prevent and combat rejection.

HCV (+) transplant recipients present unique challenges. Over the years, there has been progress but there is clearly no consensus regarding the optimal immunosuppressive medications or drug regimens; however, there continues to be advancements in the management of patients with HCV. Though current studies do not provide clear evidence as to optimal immunosuppression, they do identify questions ideally addressed by large, randomized controlled trials.

Routine induction therapy in living donor liver transplantation (LDLT) has not been well described.

We reviewed outcomes of induction therapy with rabbit antithymocyte globulin (rATG) or basiliximab within 1 year of LDLT.

Between 2002 and 2007, 184 adults underwent LDLT and received induction therapy in addition to standard immunosuppression. Acute cellular rejection (ACR) developed in 17 of 130 patients (13.1%) who received rATG and 13 of 54 patients (24.1%) who received basiliximab (P = .066). The interval between transplantation and rejection as well as rejection severity was similar in patients who received rATG and those who received basiliximab. Hepatitis C (HCV) recurrence requiring initiation of antiviral therapy was more common in patients who received rATG compared with basiliximab (34.5% vs 8.7%; P = .021), and in those who received induction combined with tacrolimus as opposed to cyclosporine (38.5% vs 3.9%; P = .001). rATG and basiliximab were associated with excellent patient and graft survivals well as low rates of opportunistic infections and malignancies.

Induction with rATG or basiliximab was well tolerated and highly effective at preventing ACR within 1 year of LDLT, but may be associated with a higher risk of clinically significant HCV recurrence in some patients.

Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompensation. The use of poor quality organs, particularly from older donors, has a highly negative impact on the severity of recurrence and patient/graft survival. Although immunosuppressive regimens have a considerable impact on the outcome, the optimal regimen after liver transplantation for HCV-infected patients remains unclear. Disease progression monitoring with protocol biopsy and new noninvasive methods is essential for predicting patient/graft outcome and starting antiviral treatment with the appropriate timing. Antiviral treatment with pegylated interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. Living-donor liver transplantation is now widely accepted as an established treatment for HCV cirrhosis and the results are equivalent to those of deceased donor liver transplantation.

In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.

This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p=0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p=0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p=0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p=0.022, p<0.0001, p=0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients.

Non-renal transplant recipients who subsequently develop ESRD and undergo kidney transplantation are medically and immunologically complex due to comorbidities, high cumulative exposure to immunosuppressants, and sensitization to alloantigen from the prior transplant. Although prior non-renal transplant recipients are one of the fastest growing segments of the kidney wait list, minimal data exist to guide the use of antibody induction therapy (IT+) at the time of kidney after lung (KALu), heart (KAH), and liver (KALi) transplant.

This retrospective cohort study used national registry data to examine IT use and survival after kidney transplantation. Separate multivariate Cox regression models were constructed to assess patient survival for IT+ and IT- KALu (n=232), KAH (n=588), and KALi (n=736) recipients.

Use of IT increased during the study period. The percentage of patients considered highly sensitized (panel reactive antibody ≥20%) was not statistically significant between IT+ and IT- groups. IT+ was not associated with improvement in 1- and 10-year patient survival for KALu (P=0.20 and P=0.22, respectively) or for KAH (P=0.90 and P=0.14, respectively). However, IT+ among KALi was associated with inferior patient survival at 1 and 10 years (P=0.04 and P=0.02, respectively).

Use of IT for kidney transplantation among prior non-renal transplant recipients may not offer a survival advantage in KALu or KAH. However, due to limited power, these findings should be interpreted cautiously. IT+ was associated with inferior outcomes for KALi. Use of IT should be judicially reconsidered in this complex group of recipients.

The introduction of calcineurin inhibitor (CNI) based immunosuppression has revolutionized the field of liver transplantation by dramatically reducing the incidence of acute cellular rejection and prolonging patient and allograft survival. However, the introduction of CNIs has also come at the price of increased patient morbidity, particularly with regard to the well-known nephrotoxic effects of the medications. In an effort to minimize the adverse effects, immunosuppression regimen have evolved to include the use of various induction agents and purine synthesis inhibitors to limit the dose of CNI necessary to achieve low acute cellular rejection rates. Careful assessments of risks and benefits are needed as these newer agents have their own side effect profiles. In addition, the impact of newer immunosuppression regimen on hepatitis C (HCV) recurrence has not been completely elucidated. This review will provide an overview of the most common immunosuppression regimen used in liver transplantation and discuss their impact on acute cellular rejection, patient and allograft survival, and HCV recurrence.

We used the United Network for Organ Sharing Database to determine the influence of antibody-based induction therapy on patient and graft survival in orthotopic liver transplant (OLT) recipients with and without hepatitis C (HCV). We identified all initial OLT patients with HCV serology. Patients were divided into four groups: HCV positive without induction (17 362), HCV positive with induction (3479), HCV negative without induction (20 417) and HCV negative with induction (4357). Both HCV positive and negative patients who received induction did better than those who did not. For HCV positive patients, 5-year patient survival was 70.8% versus 68.7% (p = 0.004) and graft survival was 65.2% versus 62.1% (p < 0.001). For HCV negative patients, 5-year patient survival was 78.8% versus 76.7% (p < 0.001) and graft survival was 74.0% versus 70.8% (p < 0.001). On multivariate analysis, induction was associated with improved patient (HR = 0.91: p = 0.024) and graft (HR = 0.88: p < 0.001) survival in HCV positive patients and improved patient (HR = 0.87: p = 0.003) and graft survival (HR = 0.87: p < 0.001) in HCV negative patients. The benefit of induction occurred early and largely dissipated when patients with death within a year were censored. The benefit of induction therapy appeared most pronounced in patients with renal insufficiency or on organ-perfusion support at transplant.

Therapeutic drug monitoring of mycophenolate mofetil (MMF) was found to be beneficial in preventing acute rejection after kidney transplantation. The aim of this pilot prospective study was to evaluate the efficacy of MMF dose adjustment in de novo liver transplant patients receiving MMF at fixed versus concentration-controlled doses [ie, adapted to mycophenolic acid (MPA) AUC0-12h] and tacrolimus during the first 12 months posttransplant. Twenty-nine patients received steroids only up to day 10, induction therapy by lymphoglobulins followed by tacrolimus and MMF. In all patients, MPA AUC0-12h were measured on posttransplant days 7 and 14 and at months 1, 2, 3, 6, and 12. From March 2006 to March 2007, 15 patients received MMF at a fixed dose of 1 g twice a day for 12 months. From April 2007 to December 2007, MMF was given to 14 patients at a dose of 1 g twice a day until day 7 and was then adapted to reach an MPA AUC0-12h target of 30-60 mg x h/L. The proportion of MPA AUC0-12h values within the target range was similar in both groups. The proportion of patients with MPA AUC0-12h below 30 mg x h/L tended to be higher in the fixed dose group within the first month posttransplant. However, MMF dose did not differ significantly between the 2 groups at any period except month 1. MPA AUC0-12h tended to be higher in the concentration-controlled group at day 14 and month 2 and was significantly so at month 1. Tacrolimus trough concentrations tended to be lower in the concentration-controlled group at all study periods and was significantly so at month 3. At 12 months posttransplant, patient and graft survivals, acute rejection rate, and adverse events were similar in both groups. We concluded that adapting the dose of MMF resulted in a significant increase in MPA AUC0-12h at month 1. There was a trend toward a lower proportion of patients with MPA AUC0-12h below 30 mg x h/L in the concentration-controlled group. No difference in outcome was found between both groups.

Because of the markedly improved short-term results of liver transplantation (LT) and persistently high number of long-term complications, the attention of transplant physicians should be focused on minimizing immunosuppressive therapy as much as possible. Steroid-based immunosuppression is responsible for a substantial post-LT morbidity and mortality, hence, minimization of its use is of utmost importance to improve the quality of life of the successfully transplanted liver recipient. This literature review shows that LT can be performed safely with steroid-minimal immunosuppression without compromising graft and patient survival. The tendency in clinical practice is to move more and more from steroid withdrawal to steroid avoidance protocols.

Hepatitis C is one of the most common indications for liver transplantation in the United States, accounting for approximately 40%-45% of all liver transplants. Unfortunately, recurrent disease is universal in patients who are viremic before transplantation. This can lead to cirrhosis in at least 25% of patients 5 years after liver transplantation, and recurrent hepatitis C is now emerging as an important but occasionally contentious indication for retransplantation. Several attempts have been undertaken to identify patients at high risk for severe recurrent disease who may benefit from treatment, but unfortunately antiviral therapy frequently is ineffective and often is associated with numerous side effects. Although we have made significant strides in understanding the natural history of this disease in nontransplant patients, this does not hold true for the transplant population in which several uncertainties covering virtually the entire spectrum of liver transplantation persist. Despite these concerns, on a more practical level, it is usually only in the postoperative setting that clinicians truly can assess the impact of their interventions on the natural history of recurrent hepatitis C, for example, by adjusting immunosuppression or prescribing antiviral therapy. Preoperative and perioperative (including donor) factors often are outside the control of hepatologists and transplant surgeons. This review is not an inclusive review of the literature but summarizes what we believe are the more controversial topics of this disease.

Steroid use after liver transplantation (LT) has been associated with diabetes, hypertension, hyperlipidemia, obesity, and hepatitis C (HCV) recurrence. We performed meta-analysis and meta-regression of 30 publications representing 19 randomized trials that compared steroid-free with steroid-based immunosuppression (IS). There were no differences in death, graft loss, and infection. Steroid-free recipients demonstrated a trend toward reduced hypertension [relative risk (RR) 0.84, P = 0.08], and statistically significant decreases in cholesterol (standard mean difference -0.41, P < 0.001) and cytomegalovirus (RR 0.52, P = 0.001). In studies where steroids were replaced by another IS agent, the risks of diabetes (RR 0.29, P < 0.001), rejection (RR 0.68, P = 0.03), and severe rejection (RR 0.37, P = 0.001) were markedly lower in steroid-free arms. In studies in which steroids were not replaced, rejection rates were higher in steroid-free arms (RR 1.31, P = 0.02) and reduction of diabetes was attenuated (RR 0.74, P = 0.2). HCV recurrence was lower with steroid avoidance and, although no individual trial reached statistical significance, meta-analysis demonstrated this important effect (RR 0.90, P = 0.03). However, we emphasize the heterogeneity of trials performed to date and, as such, do not recommend basing clinical guidelines on our conclusions. We believe that a large, multicenter trial will better define the role of steroid-free regimens in LT.

Hepatitis C represents more than 35% of liver transplant candidates worldwide. Meanwhile, hepatitis B continues to be an important cause of end-stage liver disease and hepatocellular carcinoma in Asia and Africa. Recurrent viral liver disease is a significant event after liver transplantation and continues to be one of the main causes of graft dysfunction and loss in the middle and long-term follow-up. Mechanisms of liver reinfection and disease recurrence vary between these two viruses and pre-emptive as well as the therapeutic approaches are different. Hepatitis B patients can be managed with immune globulin immediately after liver transplant and various agents such as nucleotide and nucleoside analogues can be associated. As a result, disease recurrence has been delayed or prevented in these patients. Individuals transplanted for hepatitis C are known to have universal reinfection and a high rate of disease recurrence has been reported in the literature. Strategies to treat hepatitis C recurrence are limited to the use of pegylated interferon and ribavirin when disease is demonstrated histologically and biochemically, although other strategies have been described with limited or no success. We herein review the mechanisms of disease recurrence and the current as well as the future therapeutic approaches to prevent and to treat these diseases.

Recurrent hepatitis C virus (HCV) infection after orthotopic liver transplantation (OLT) has been associated with progression to cirrhosis in approximately 20% of patients, 5 years postoperatively. Accelerated decompensation has also been noted when compared with cirrhosis in non-transplant patients. Different treatment strategies are available for recurrent HCV infection post-OLT, but efforts are hindered by the modest response rates, poor tolerability and the risk of rejection as well as graft loss. Anti-HCV immunoglobulin therapy to prevent graft infection with HCV has no established role at present but studies are ongoing. Treatment prior to transplantation in patients with decompensated cirrhosis has been evaluated but the results are too preliminary to make firm recommendations. Prophylactic interferon-based antiviral therapy in the early postoperative period to prevent graft infection was shown to have low response rates and high rates of adverse effects. Treatment of established recurrent HCV infection with combination peginterferon (pegylated interferon) and ribavirin is associated with 10-59% sustained virological response and the predictive value of a positive early virological response has been validated in the post-transplant setting. Improvement in inflammatory activity after viral eradication is well established, but fibrosis regression or stabilisation is less predictable and factors such as rejection and biliary complications may still contribute to graft loss. Most studies have initiated therapy at least 6 months postoperatively in order to optimise patient tolerance and enable the addition of ribavirin. The use of adjuvant agents to treat drug-induced neutropenia and anaemia in this population is evolving and becoming a crucial part of therapy. Determination of optimal doses of both pegylated interferon and ribavirin, and guidance on when to stop treatment, as well as improving tolerability are important steps in achieving higher response rates and minimising drug toxicity.

Antilymphocyte antibody induction has been used in liver transplantation for decades, initially as part of a triple or quadruple immunosuppressive protocol to prevent rejection or in the treatment of steroid-resistant rejection. More recently there has been renewed interest in antibody induction in liver transplantation as part of a strategy to eliminate or reduce one or more immunosuppressive agents. This review highlights recent advances in the role of antibody induction in liver transplantation.

Primary interest in antibody induction now falls into four major categories: steroid avoidance; calcineurin inhibitor reduction as a renal sparing protocol; minimal immunosuppression protocols (tolerance); and limiting hepatitis C recurrence. These protocols usually involve short courses of antibody induction in the peritransplant period, with decreased reliance on other agents after transplantation. Recent reports demonstrate several beneficial effects of antibody induction and suggest that, in the Model for End-Stage Liver Disease era, antibody induction in immunosuppressive strategies in liver transplantation will become increasingly important.

Antibody induction in liver transplantation confers valuable benefit in limiting the adverse effects of maintenance immunosuppression. Antibodies allow the subsequent reduction or elimination of other agents to minimize overall immunosuppression.

While early surgical success made organ transplantation possible in the 1950s and 1960s, the breakthrough in clinical organ transplantation was achieved through the discovery and invention of modern immunosuppressive agents in the early/mid-1980s. Especially during the 1990 s, a large array of immunosuppressants has expanded the armamentarium used to prevent and treat allograft rejection, resulting in an excellent short-term and an acceptable long-term outcome. However, these drugs have potent but still non-specific immunosuppressive properties and frequently show severe acute and chronic side effects, sometimes questioning the overall success.

As the "Holy-Grail" of the transplant community, the induction of "true donor-specific tolerance" has not been achieved yet; current immunosuppressive strategies, in particular in Europe, include "individually tailored immunosuppressive" protocols, mostly based on specific immunologic and non-immunologic risk factors. These protocols allow for optimal immunosuppressive protocols for each patient group according to their needs by choosing the most suitable, well-tolerated combination of agents and the most effective doses to avoid acute rejection episodes (incidence and severity) and minimise drug-related toxicity to reduce long-term drug-related morbidity and mortality. Nevertheless, transplant recipient are still being forced to take a life-long course of chemical immunosuppressive agents to keep their graft, knowing about the possible life-threatening side effects.

We review current trends of immunosuppressive protocols in liver and kidney transplantation, focusing on calcineurin-inhibitor-sparing protocols, mammalian-target-of-rapamycin (mTOR) inhibitor based-protocols and corticosteroid-avoidance protocols, being aware of the fact, that most of these strategies could be applicable for other transplanted organs, too. Finally, we describe future trends and new developments that are rising on the horizon.

Churg-Strauss disease (CSD) is a rare allergic disorder that is associated with vasculitis, peripheral eosinophilia and allergic asthma. We report on successful liver transplantation in a patient with CSD who suffered from chronic hepatitis C. Recurrent hepatitis C and CSD were ultimately managed by the application of pegylated interferon.

Corticosteroid avoidance is feasible and may be desirable in liver transplantation. Approximately 50% of liver transplant recipients who use calcineurin inhibitors and azathioprine do not need corticosteroids. The availability of newer agents, such as mycophenolate mofetil and antibody therapy, has increased the percentage of patients who do not need to use corticosteroids to about 75%. The feasibility of corticosteroid-free immunosuppression has been established by controlled trials demonstrating non-inferiority with respect to patterns of rejection as well as patient and graft survival. However, the evidence available to date does not unequivocally establish the benefits of corticosteroid-free immunosuppression, although some advantage has been established relating to post-transplant diabetes mellitus, cytomegalovirus infection and growth patterns in children. The effect of corticosteroid-free immunosuppression in hepatitis C liver transplant recipients is yet to be resolved.