Personalizing Immunosuppression in Liver Transplantation

Current Perspectives on Personalizing Immunosuppression in Liver Transplantation

Amit K. Mathur, MD, MS

University of Michigan Hospital and Health System, Ann Arbor, Michigan

Liver transplantation is the only durable therapy for patients with cirrhosis related to various pathologies. Ever since cyclosporine was first used, the evolution of care delivered after liver transplant and immunosuppressive regimens were devised has been remarkable. Hepatologists and surgeons recognize the need for customized immunosuppression predicated on a given patient’s individual risks. This article describes the historic evolution of immunosuppression in liver-transplant recipients, particularly in the context of early clinical trials comparing cyclosporine with tacrolimus. This report also summarizes current thinking on how immunosuppression can be modified according to a recipient’s risk for specific long-term complications, such as renal failure, and how patients may be identified as candidates for immunosuppressant reduction or withdrawal. Because clinical tolerance occurs rarely in liver-transplant patients, healthcare professionals need to understand the challenges that arise from current immunosuppressive strategies and the basis for personalizing therapy.Liver transplantation is the only durable therapy for patients with cirrhosis related to various pathologies. Ever since cyclosporine was first used, the evolution of care delivered after liver transplant and immunosuppressive regimens were devised has been remarkable. Hepatologists and surgeons recognize the need for customized immunosuppression predicated on a given patient’s individual risks. This article describes the historic evolution of immunosuppression in liver-transplant recipients, particularly in the context of early clinical trials comparing cyclosporine with tacrolimus. This report also summarizes current thinking on how immunosuppression can be modified according to a recipient’s risk for specific long-term complications, such as renal failure, and how patients may be identified as candidates for immunosuppressant reduction or withdrawal. Because clinical tolerance occurs rarely in liver-transplant patients, healthcare professionals need to understand the challenges that arise from current immunosuppressive strategies and the basis for personalizing therapy.

Dr. Mathur Since its inception, the fundamental goal of organ transplantation is to replace the function of a failing organ while maintaining a state of immunologic homeostasis between the foreign graft and its recipient. Immunosuppressive therapy aims to suppress the host response to incompatible graft antigens and retain the body’s otherwise normal programmed response to foreign antigens.1 Although major strides have been made in the development and application of novel immunosuppressive regimens, the majority of liver-transplant recipients continue to be maintained on calcineurin inhibitor (CNI)–based therapy plus an antiproliferative agent, such as mycophenolate mofetil, given with or without corticosteroids. The general application of these “one-size-fits-all” immunosuppressive regimens, however, may result in detrimental infectious and organ-specific complications and ultimately may negatively affect allograft function. These concerns have prompted transplant clinicians and researchers to seek better solutions for liver-transplant recipients that safely protect allograft function and mitigate against other risks, such as infection and renal failure.

At the 2013 American Transplant Congress in Seattle, Washington, several speakers discussed the concept of personalizing immunosuppression in liver-transplant recipients. This strategy involves tailoring immunosuppressive regimens for individuals based upon diagnostic indications, concurrent medical conditions at the time of transplant, graft type and function, and post-transplant complications experienced. The absence of widespread clinical tolerance in liver-transplant patients obligates clinicians to provide appropriate immunosuppression to prevent acute and chronic graft rejection and to avoid serious complications related to the use of immunosuppressive medication. A key principle is identification of strategies to avoid renal failure, which portends a significant increase in mortality risk after liver transplant and is a significant complication of CNI-based regimens.

This exciting symposium was moderated by John Lake, MD, Professor of Medicine at the University of Minnesota Medical School in Minneapolis, and Richard Mangus, MD, MS, FACS, Assistant Professor of Surgery at Indiana University School of Medicine, Indianapolis, and delivered by three noted experts in the field. The discussion was framed in the historic context of liver-transplant immunosuppression, definition of customized immunosuppressive regimens to prevent complications, and identification of candidates for immunosuppressant minimization or withdrawal.

LIVER-TRANSPLANT IMMUNOSUPPRESSION: AN HISTORIC CONTEXT
Based on a presentation by John O’Grady, MD, FRCPI, Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, United Kingdom.

The most pivotal studies on immunosuppression performed during the early years of liver transplantation involved the development of CNI therapy using cyclosporine and, later, tacrolimus. Sir Roy Calne and his group at Cambridge University2,3 conducted the initial clinical studies of cyclosporine in solid organ-transplant patients, which led to the rapid expansion of clinical transplant programs across the world. The efficacy of cyclosporine therapy was recognized quickly, and it was adopted rapidly. In the 1980s, several clinical studies investigated the use of tacrolimus (FK506) as an alternative to cyclosporine in liver-transplant recipients. 4–6 Cyclosporine and tacrolimus represented giant leaps forward in clinical liver transplantation, and they soon were studied using various protocol designs to establish optimal therapy.

In the 1980s and 1990s, CNIs were identified as effective immunosuppressive therapy in liver transplantation. Studies performed were mostly retrospective cohort trials from single centers. Rejection rates in this research were much lower with administration of CNI therapy than with the use of traditional immunosuppressive treatment at that time.2,4–7 However, problems with the design of these studies led to a failure to demonstrate an actual survival benefit after liver transplantation when CNIs were used. Additionally, the rates of secondary complications such as renal failure were exceptionally low, which resulted in criticism that study patients were subject to selection bias and were not particularly representative of the population being transplanted at most centers at that time or, more important, now.

Comparisons of Tacrolimus with Cyclosporine
The promising data emerging from these early clinical trials eventually led to a head-to-head comparison of tacrolimus with cyclosporine in a landmark, multicenter, open-label, randomized clinical trial involving 478 adults and 51 children receiving a liver transplant for the first time. In an article published in The New England Journal of Medicine in 1994,8 the US Multicenter FK506 Liver Study Group reported that patient and graft survival rates 1 year after transplantation were statistically the same in both the tacrolimus and cyclosporine arms (patient survival, 88% for both tacrolimus and cyclosporine [P = 0.85]; graft survival, 82% for tacrolimus vs 79% for cyclosporine [P = 0.55]). However, compared with cyclosporine therapy, treatment with tacrolimus resulted in significantly fewer acute rejection episodes (154 for tacrolimus vs 173 for cyclosporine; P < 0.002), lower rates of corticosteroid-resistant rejection (16% for tacrolimus vs 31% for cyclosporine; P < 0.001), and fewer refractory rejection episodes (6 for tacrolimus vs 32 for cyclosporine; P < 0.001). But this improvement in immunosuppressive efficacy came with a cost: The use of tacrolimus led to higher rates of adverse events, including nephrotoxicity (14% for tacrolimus vs 5% for cyclosporine) and neurotoxicity (12% for tacrolimus vs 4% for cyclosporine), and resulted in treatment conversion or study withdrawal. In all, 37 patients in the tacrolimus arm (14%) and 13 in the cyclosporine arm (5%) discontinued the study because of adverse events (P < 0.001). Nonetheless, the positive results of this study ushered in an era wherein tacrolimus therapy rapidly supplanted the use of cyclosporine for long-term immunosuppression following liver transplantation.

A 5-year follow-up study of the patients enrolled in the US FK506 trial again showed comparable patient and graft survival rates for tacrolimus (79% and 72%, respectively) and cyclosporine (73% and 66%).9 However, half-life patient survival was significantly longer among the patients treated with tacrolimus (25.1 ± 5.1 years) than among those who had received cyclosporine (15.2 ± 2.5 years; P = 0.049). Survival of hepatitis C virus (HCV)-positive patients also was significantly better in the tacrolimus arm than in the cyclosporine arm (79% vs 61%; P = 0.041). Both treatments were associated with a low incidence of late acute rejection, late corticosteroid-refractory rejection, and death or graft loss related to rejection at 5 years after transplantation. Further, both treatments demonstrated an acceptable safety profile, with maintenance of adequate renal and liver function and a low incidence of malignancy and/or lymphoproliferative disease and serious infections.

About the same time as the US study was reported, data from a European multicenter, open-label, randomized clinical trial comparing cyclosporine with tacrolimus in 545 recipients of primary liver transplants confirmed the similarity between the two drugs in graft and patient survival at 1 year.10 As in the US trial, tacrolimus therapy was associated with fewer episodes of acute, refractory, and chronic graft rejection than was cyclosporine therapy. Despite a higher frequency of adverse events (renal impairment, disturbances in glucose metabolism, and neurologic complications) in the tacrolimus arm, the authors of this study concluded that tacrolimus therapy was superior to immunosuppression with cyclosporine in lowering rejection rates and, further, permitted a reduction in concomitant corticosteroid dosing.

More recently (2002), a similar clinical trial conducted at multiple centers in the United Kingdom and Ireland randomized 606 patients undergoing a first orthotopic liver transplant to receive treatment with either cyclosporine or tacrolimus.11 At 1 year post transplant, patients in the tacrolimus arm had lower rates of death (17% vs 24% for those treated with cyclosporine), retransplantation (4% vs 10%), and treatment failure due to immunologic causes (2% vs 4%). Although a higher frequency of renal dysfunction was noted in the tacrolimus arm, compared with the rate in patients taking cyclosporine, the superior efficacy of tacrolimus for patients receiving their first liver transplant was clear.

Results from a 3-year follow-up study of these patients confirmed the benefits of tacrolimus-based immunosuppression over the use of cyclosporine.12 A total of 62% of patients randomized to receive tacrolimus therapy were alive at 3 years with their original graft and still on their allocated study medication, as compared with only 42% of patients in the cyclosporine arm (P < 0.001). However, no difference between tacrolimus and cyclosporine was seen in HCV-positive patients.

Tacrolimus dosing in these trials was relatively high when compared with the regimens given today, and many clinicians attribute the greater nephrotoxicity of this drug, compared with that of cyclosporine, to the high drug plasma levels achieved using the trial protocol.

Rise in the Use of Tacrolimus
Subsequently, 10-year data from the Scientific Registry of Transplant Recipients were analyzed to establish the efficacy and relative safety of tacrolimus.13 In the tacrolimus era, liver-transplant patients have demonstrated stable graft and patient survival and rates of corticosteroid-resistant rejection episodes similar to those observed in patients receiving cyclosporine. These studies, along with the experiences gained within liver-transplant centers, led to widespread adoption of tacrolimus-based immunosuppressive protocols, which continue to be used to the present day in patients who have undergone liver transplantation.

The Current State of Immunosuppression
Currently, clinicians aim to limit the long-term degree of immunosuppression given to liver-transplant patients to decrease the risk of secondary complications. Prolonged maintenance immunosuppression in liver-transplant patients is tremendously diverse. Over the long term, more than 30% of liver transplant patients reportedly use tacrolimus monotherapy, but nearly 10% of patients remain on triple-immunosuppressant regimens that include tacrolimus, antimetabolites, and corticosteroids. Clear data about how to proceed in this phase of care are lacking, but the driving principle is to limit morbidity without sacrificing graft function.

On the whole, CNI therapy is related to widely recognized side effects, particularly renal failure. When patients have stable liver-graft function, the priority is to limit the risk of kidney failure following transplant surgery. Kidney dysfunction is a significant source of morbidity and mortality after liver transplant and accounts for a significant increase in long-term graft loss.14

The ReSPeCT study15 sought to determine the renal benefits of delayed tacrolimus initiation with induction of daclizumab-based immunosuppressive therapy. Patients treated with this regimen experienced less nephrotoxicity over time without suffering a significant change in efficacy or tolerability of therapy. However, this study was flawed—the lower renal failure rate among the daclizumab-treated cohort in this study may have been related to difficulty in achieving goal tacrolimus trough levels using low doses. Biopsy-proven acute rejection rates were lower among the daclizumab group even after 1 year, but immunosuppressive policies in liver transplantation typically are not based upon differences in acute rejection rates.

Summary
The future of liver-transplant immunosuppression is unclear. The types of agents being used over the next decade probably will not change appreciably, but drug combinations likely will be devised according to an individual’s risk profile for secondary complications, including the risk of corticosteroid-resistant graft rejection, renal failure, and recurrence of HCV infection. In this context, there may be a role for novel biologic therapies in other domains, which could modify traditional regimens by reducing CNI toxicity and promoting corticosteroid avoidance. Additionally, after they are studied carefully in clinical trials, dual-action antineoplastic drugs that reduce fibrosis may help to maintain immunosuppression in liver-transplant patients.

TAILORING IMMUNOSUPPRESSIVE STRATEGIES TO MINIMIZE COMPLICATIONS
Based on a presentation by James Trotter, MD, Medical Director of Liver Transplantation at Baylor University Medical Center, Dallas, Texas.

Over the past decade, there has been a significant decline in patients who have been placed on CNI monotherapy after receiving a liver transplant. This trend presumably has been associated with relative increases in acute rejection episodes. The number of patients receiving CNI-based therapy supplemented with mycophenolate-based antimetabolite therapy has grown significantly and has continued to characterize the maintenance phase of immunosuppression in liver transplantation. In fact, 8%–10% of patients are maintained completely off CNI-based therapies in favor of treatments based on mammalian target of rapamycin (mTOR) therapies using such drugs as sirolimus or everolimus. In the modern era, only 10%–15% of patients experience an acute rejection episode, which does not significantly affect the rate of graft failure. In the context of patients not losing liver grafts to rejection, modifications to immunosuppression can be introduced to prevent secondary side effects.

After liver transplant, there are several significant predictors of post-transplant mortality. Renal failure portends a nearly fourfold risk of post-transplant mortality when compared with the absence of renal failure. Graft loss requiring repeated transplant, HCV infection, and recurrent hepatocellular carcinoma (HCC) also are significantly associated with increased mortality after liver transplantation. In this context, developing an approach to immunosuppression should reflect these priorities.

HCV Infection
Mortality in liver recipients with HCV infections primarily is driven by disease recurrence over other factors. Several efforts have been used to tailor immunosuppressant therapy for patients infected with HCV to reduce the scourge of disease recurrence in the graft after liver transplant. One third of patients with HCV infection die of recurrent disease after transplant. Currently, therapy for infected patients is tailored by reducing or avoiding corticosteroid pulse therapy for suspected rejection, since such use of therapies may lead to HCV proliferation and graft injury.

Proliferation of HCV and disease recurrence have been the subject of novel treatment approaches that have been tested in several clinical trials over the past few years. Among these trials was a study investigating the use of protease inhibitors (telaprevir and boceprevir) in combination with interferon-based regimens. In patients with recalcitrant HCV infection who are candidates for post-transplant treatment with protease inhibitors, standard immunosuppression must be altered to accommodate changes in CNI metabolism that occur with antiviral administration. Telaprevir increases the serum levels of these drugs, and particularly those of tacrolimus: the concomitant administration of telaprevir can increase tacrolimus serum levels 100 fold. Accordingly, most transplant centers are converting their patients with HCV infections to cyclosporine before starting treatment of the infection. However, the side effects of these therapies still abound, and the holy grail of interferon-free antiviral treatment before or after liver transplant has not yet been realized.

Recurrent HCV infection and graft dysfunction related to progressive fibrosis are significant problems that may be solved by the use of immunosuppressive agents to prevent rejection and reduce fibrosis. The rapamycin pathway plays a central role in the pathophysiology of hepatic fibrosis in hepatic stellate cells.16,17 Sirolimus, the best known mTOR inhibitor, may be useful to correct this phenomenon.18 However, the package labeling for sirolimus carries a black-box US Food and Drug Administration (FDA) warning that the drug should not be used immediately after transplant due to its risk profile.19 Data support its antifibrotic properties. McKenna et al18 discovered less fibrosis on protocol-required liver-transplant biopsies among patients converted to sirolimus from CNIs than among those treated with tacrolimus for up to 2 years after transplant. The outcome also had a dose-dependent relationship, with patients given sirolimus for at least 300 days having the most delayed fibrosis and lack of fibrosis progression, although there was no significant difference in graft survival when sirolimus-treated patients were compared with controls. The limitations to this study were many, since it was a retrospective, single-center, nonrandomized study, although the potential benefit of sirolimus conversion is notable.

Kidney Failure
One of the most important priorities for clinicians involved in liver transplant is to limit the risk of renal failure related to the use of CNIs. Post-transplant renal failure has increased significantly in the era of application of the Model for End-Stage Liver Disease score and often manifests itself within the first year after transplant.20 Several studies have demonstrated the clear benefits of CNI avoidance on the risk of post-transplant renal dysfunction, but a question remains—how can CNI avoidance be accomplished safely without negatively affecting graft function?

In a recent prospective, randomized, controlled, open-label trial, Abdelmalek and others21 found that patients having an impaired glomerular filtration rate (GFR) of 40–90 mL/min at least 6 months after liver transplant who were converted to sirolimus therapy from using tacrolimus did not experience any tangible benefit on renal function at 1 year after conversion. Sirolimus-treated patients had higher rates of acute rejection (Table 1) and major side effects, compared with those who continued on tacrolimus.


Everolimus recently was approved by the FDA for use with reduced-dose tacrolimus in liver-transplant patients. In a recent multicenter, prospective clinical trial, patients given reduced-dose tacrolimus and everolimus had improved GFRs at 2 years post transplant when compared with patients using standard tacrolimus-based regimens, without incurring a higher risk of biopsy-proven acute rejection or major side effects.22,23 This improvement in GFR was identified retrospectively in patients converted to everolimus for maintenance immunosuppression.24 Everolimus holds significant promise in reducing renal toxicity from CNIs after liver transplant.

HCC
Aside from their immunosuppressive properties, the potential benefit of mTOR inhibitors in patients who have undergone liver transplant for HCC has achieved special attention due to their antineoplastic activity. Single-center data have suggested that the use of mTOR inhibitors for immunosuppression may reduce the recurrence of HCC in such patients, although this possibility has not been studied prospectively. A current, ongoing clinical trial is accruing patients to evaluate HCC recurrence as an endpoint.25 Although the use of mTOR inhibitors may be particularly beneficial in this patient population, the safety, efficacy, and usefulness of this drug class have not been fully explored.

Summary
In terms of the major predictors of mortality risk after transplant, there is a clear role for tailoring immunosuppression. The current literature primarily is aimed at reducing the risk of renal failure derived from CNI use, and new regimens containing everolimus hold promise. Retrospective clinical data demonstrate the potential benefits of sirolimus in reducing graft fibrosis, but prospective, randomized data do not show any benefit on graft survival and have revealed potential harm. The drug’s effects in prospective clinical studies in transplant patients with HCC remain unrealized, but clinical trials are under way to define more clearly the potential benefits and risks of using sirolimus in this population.

IMMUNOSUPPRESSION MINIMIZATION OR WITHDRAWAL
Based on a presentation by Sandy Feng, MD, PhD, Professor of Surgery, Division of Transplant Surgery, University of California at San Francisco Medical Center, San Francisco, California.

Perhaps the biggest goal in the evolution of solid-organ transplantation has been the achievement of clinical tolerance, which represents the ultimate tailoring of immunosuppressive therapy. Operational tolerance, or maintenance of graft function without immunosuppression, has been difficult to achieve. Several studies on the subject have estimated that ≤ 20% of liver-transplant patients could be operationally tolerant (Table 2).26 However, withdrawal of immunosuppression carries the risk of acute rejection, which reportedly is as high as 50%. This context framed the discussion on how to identify candidates for minimization or withdrawal of maintenance immunosuppressive therapies.


Many studies of operational tolerance seek to identify biomarkers in patients who have demonstrated the rare tolerant clinical phenotype. A post hoc analysis of previous trials revealed clinical factors and biomarkers found using gene analysis to help identify predictors of clinical tolerance. Most clinically tolerant patients were younger. However, the presence of these clinical factors and biomarkers has failed to predict tolerance prospectively.

In studies thus far, the dominant issues surrounding operational tolerance involve monitoring of graft function over the long term. There appears to be a trend toward more graft fibrosis over time, particularly in the presence of donor-specific antibody and complement (C4d) deposition on allograft biopsy. However, the timing of fibrotic onset has been inconsistent and has not had any major clinical effect on patients. Further, no patients in highly selected populations, such as recipients of living-donor liver transplants from parental donors, have returned to immunosuppression.

For the majority of liver transplant recipients, operational tolerance is not likely to be a clinical reality over the next several years. However, the results of several studies by the Immune Tolerance Network and others clearly have demonstrated the promise of minimizing or withdrawing immunosuppressive therapy. The challenge of monitoring graft function and identifying predictors of failure remains, particularly when attempting to identify good candidates for complete weaning from therapy.

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Dr. Mathur is a Clinical Lecturer/Multi-Organ Abdominal Transplant Fellow in the Department of Surgery, University of Michigan Hospital and Health System, Ann Arbor, Michigan.

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