Immunosuppression withdrawal following liver transplantation: The older, the wiser… but maybe too late
Authors: Josh Levitsky
Journal: Hepatology (2013)

Life-long immunosuppressive (IS) therapy is the current standard of care approach in liver transplant (LT) recipients. In the early years of LT, the majority of deaths occurred due to graft loss from rejection related to suboptimal IS therapy. With the advent of more effective IS agents and therapeutic modalities in the last 20 years, graft rejection rates have decreased and patient and graft survivals have improved significantly. However, adverse effects such as chronic kidney disease, recurrent and de novo infections and malignancy, and cardiovascular events associated with long-term IS, particularly the calcineurin inhibitors (CNIs), have now become primary concerns as patients are living longer to experience these complications. The search for improved treatment algorithms includes conversion to non-CNI therapy, trial-and-error dose minimizations, or even full IS withdrawal after some "safe" interval post-LT. The current inability to immunologically predict successful minimization or withdrawal of IS has compelled clinicians to maintain long-term IS therapy at clinically recommended "therapeutic" doses, despite the toxicities. However, distinct from other organ recipients, LT recipients have an increased propensity toward tolerance and the ability to wean IS therapy with fewer consequences. Donor-specific immunoregulatory effects, clonal deletion of alloreactive cells, dilution or inhibition of alloantibody, local presence of regulatory T and dendritic cells, and mixed donor-recipient hematopoietic chimerism are all components of liver immunoregulation.1-3 This is translated clinically into the relative insignificance of human leukocyte antigen (HLA) matching, lower incidence and impact of rejection, reduced amount of IS required, and immunological protection conferred by the liver on other organs in combined transplants. Although the percentage of relatively unselected LT recipients able to undergo simple IS withdrawal is the highest (∼20%) of all organ recipients, this rate has still been deemed clinically unacceptable, emphasizing the need to develop more effective tolerance induction strategies and predictive biomarkers.4 The current timely report by Benitez et al. (this issue of Hepatology5) truly stands in the crossroad of LT tolerance investigation. The approach was not distinctly different than previous studies, enrolling patients >3 years from LT without autoimmune disease, recent rejection, significant liver biochemistry or histological abnormalities prior to withdrawal, and high-risk behavior or comorbidities. Long-term follow-up and biopsies performed 3 years after IS discontinuation were key aspects providing important safety measures. Patients with hepatitis C virus (HCV) were included, but disappointingly the follow-up biopsies showed progression of HCV fibrosis whether tolerance was achieved or not. With these and other data,6 and that HCV+ recipients are difficult to enroll and maintain in withdrawal studies due to histological recurrence,7 the risk of IS withdrawal in viremic HCV+ recipients appears to outweigh any alleged benefit. The non-HCV recipients could be included in this study even if their prewithdrawal biopsy showed up to Metavir stage 2 fibrosis and up to 50% portal or perivenular inflammation. While these changes generally remained stable on follow-up biopsies, future studies should perhaps favor inclusion of patients with "cleaner" biopsies, as prewithdrawal inflammatory changes might be a barrier for tolerance.8 A recent review from the Banff Working Group proposed a number of preweaning biopsy findings that might preclude IS withdrawal, such as greater than mild portal, lobular, or perivenular inflammation, more than mild fibrosis, and the presence of abnormal biliary or vascular pathology.9 Finally, unlike previous trials, they only included selected patients believed to be at most risk of IS complications, such as cardiovascular disease, chronic kidney disease, and/or malignancy. This begs the ethical debate as to whether withdrawal should be considered in all LT patients or only in those at higher risk of IS-related complications. Regardless, it is important to keep in mind that their results may not be universally valid for the LT population as a whole. The novel "take-home" message from this trial is that there appears to be a near linear correlation between the likelihood of successful IS withdrawal and both age and time from transplantation. The authors infer that these two clinical variables could predict success or failure of drug withdrawal, with a high percentage of success in patients >10 years from LT and a low rate in those less than 50 years old or 5 years from LT. Knowing that an attempt at drug withdrawal is usually without penalty, i.e., rare instance of steroid-refractory or chronic rejection, it is reasonable that those at high likelihood of success should be considered for such an intervention, keeping in mind the study inclusion criteria. So if the risk is low and success is high in older patients further out from LT, then why not universally institute such a clinical withdrawal protocol? At face value, it sounds attractive, but a central issue is that the clinical benefits of drug withdrawal are not well known. Most studies, including this current article in which patients were enrolled if they were at higher risk for IS complications, have not shown clinically significant reductions in drug-related complications, i.e., metabolic disorders, infections, or malignancy.6, 10 Understandably, hundreds of patients with appropriate IS-maintained controls followed for many more years would need to be enrolled to realize such benefits. Thus, while the high percentage of success in this trial may be an "eye opener," there may be little to no clinical benefit of drug withdrawal in such long-term recipients in whom the toll of IS has already been established. In addition, IS by practice is often minimized over time by transplant providers, leaving the benefit of minimal versus no IS therapy less distinguishable. While this study is commendably the first to identify such direct clinical predictors, the approach of simple drug withdrawal does not apply to those who may need it the most—the young and naïve (i.e., more recently transplanted). Thus, to achieve similar success rates earlier after LT (i.e., <5 years) with a greater potential for clinical impact, alternative strategies are needed to (1) more specifically identify ideal drug withdrawal candidates and (2) promote immune adaptation and regulation. For the former, available prewithdrawal biomarkers could ultimately augment or replace more subjective clinical predictors of success. Studies have found immunophenotypic and genomic differences between patients on or off IS therapy, but the key is to differentiate them by such biomarkers before drug withdrawal is attempted. Only a few studies have attempted to do so in LT recipients, including this current trial in a prior publication by the same authors.11 Unexpectedly, the tolerant patients were found to have differential intragraft expression of genes and proteins involved in iron hemostasis, with the gene expressions being most predictive of successful withdrawal. This finding is not mechanistically well explained and requires further investigation. That said, it would have been useful in this current report to have combined the most promising clinical (age, sex, time from LT) and blood/graft biomarker predictors into an even more accurate, prognostic model for successful withdrawal. This approach alone, however, may still not identify early withdrawal candidates. A number of strategies might result in clinically acceptable (i.e., >50%) IS withdrawal rates (Fig. 1). Ideally, careful patient selection parameters and immunophenotypic, proteogenomic and functional biomarkers predictive of tolerance would guide the selection of the most suitable candidates.4, 11-14 Based on the current study, this strategy may be enough to withdraw IS from older patients further out from LT, in conjunction with close laboratory and biopsy monitoring over time. Long-term biopsies following IS withdrawal, even later than those performed in this trial (i.e., >5 years), are critical in any tolerance intervention, as there have been some reports of late, progressive histological abnormalities in recipients labeled as operationally tolerant.9 For HCV+ recipients, a high percentage will hopefully soon achieve viral eradication with novel direct-acting antiviral therapies and thus be in a better position to more safely enroll in IS withdrawal protocols. In considering early withdrawal, where the benefit is likely the greatest but the barrier for tolerance higher, a number of strategies are actively being investigated. These include donor hematopoietic cell infusions with or without nonmyeloablative induction, ex vivo Treg expansion and infusion, and conversion to more immunoregulatory IS therapy, such as mammalian target of rapamycin (mTOR) inhibitor agents.12, 15-17 The latter approach might be most favorable in LT recipients to avoid toxicities of potent ablative agents and is perhaps supported by this study's findings of more effective IS withdrawal from non-CNI therapy, as well as other in vivo and in vitro studies.12, 18, 19 Ultimately, the field will need to be guided by clinical and biomarker predictors, safer and more optimal immune manipulation strategies, and data showing the clinical benefits of withdrawal over maintenance of IS therapy. Josh Levitsky, M.D., M.S. Division of Gastroenterology & Hepatology Department of Medicine Northwestern University Feinberg School of Medicine Chicago, IL