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Through this multi-center study, we are striving to develop the necessary knowledge base from which to study non-adherence. Non-adherence is a critical contributor to the development of late acute rejection in children who have had a liver transplant, and thus is associated with graft loss, increased expenditures on care, and ultimately death. We are working to establish strategies that aggressively identify and treat non-adherence, as it is clinically imperative to do so. We previously applied the principles of statistical process control (SPC) to manage calcineurin inhibitors (CNI) blood levels. Utilization of SPC increased the proportion of CNI blood levels in target range and removed the unnecessary variation of drug levels in the system.

The results are expected to have broad implications, well beyond the specific field of pediatric liver transplant recipients. Our results will enable practitioners to routinely detect non-adherence: this will open the way to research about predictors for non-adherence and interventions to improve it. Results from those studies will be broadly applicable. Finally, through the improvement in the detection of adherence, our results are also expected to improve medical outcomes, as already suggested by our pilot findings.

The success of liver transplantation has traditionally been measured by survival rates. Assessment of health-related quality of life (HRQL) in those awaiting transplantation and liver transplant recipients will permit us to hear the voice and perspective of the patient and help us predict future health status, mortality, and resource utilization (Liver Transplantation 9:62-71, 2003; J Pediatr 2010;156:270-6; Am J Transplant 2011;11-303-11; Pediatr Transplant 2013;17:605-11).

Dr. Bucuvalas has published extensively both in single center studies and as part of the NIH supported Functional Outcome Group; we have reported deficits in intelligence and learning as early as 5 years of age (including specific deficits in cognitive executive functions such as planning, working memory, task initiation, and self-monitoring). While decreased cognitive function is by itself a critical outcome metric, it also poses a challenge to self-management and may ultimately adversely affect allograft health.

Single center retrospective studies report variable inflammation and progressive fibrosis in long-term pediatric liver allografts. In preliminary work as part of the IWITH trial (section D), we rigorously described and analyzed structural changes in liver allografts in a multi-center cohort of stable children with ALT and GGT <50IU/L.

Screening, pre-weaning liver biopsies done at 12 North American centers in an immunosuppression withdrawal study for children ≥4ys post-transplant were scored by a central pathologist for 48 histologic criteria. Hierarchical cluster analysis was performed on three dominant features: 1) periportal/portal fibrosis 2) perivenular fibrosis 3) interface activity. Multivariable logistic regression analysis with clinical covariates and backward variable selection (p<0.10 for retention) identified independent predictors of cluster assignment. Biopsies segregated into 3 distinct clusters : 1 no fibrosis no interface activity (n=52); 2 fibrosis but no interface activity (n=32); 3 interface activity +/- fibrosis (n=16).

We conclude that long-term pediatric liver transplant recipients with normal liver tests can harbor significant structural changes with/without inflammation. Distinct structural clusters and their clinical correlates suggest both non-immune and immune mechanisms of histologic allograft deterioration. Future data, including C4d score, donor specific antibody, and tolerant/non-tolerant phenotype, currently in analyses may confirm the mechanism of injury and guide future therapeutic trials.

While determining the success rate and safety profile of Immunosuppression (IS) withdrawal is important, the definition of an immune phenotype, or fingerprint, predictive of operational tolerance is arguably more important and more likely to result in a substantial impact on the well-being and longevity of pediatric liver transplant recipients. We seek to identify that subset of pediatric liver transplant recipients who can safely and durably withdraw from IS.

Our primary goal is to test the hypothesis that a defined subset of pediatric liver transplant recipients can safely and durably withdraw from immunosuppression (IS). It is believed that the majority of liver transplant recipients require chronic IS to ensure optimal graft function while the minority remains operationally tolerant and able to sustain normal graft function without immunosuppression. So, while determining the success rate and safety profile of ISW is foundational, the definition of an immune phenotype or fingerprint that can predict successful ISW is arguably more likely to impact both outcome and clinical practice. Consequently, we also aim to define and validate a cross-platform biomarker, comprised of clinical, histological, immunologic and / or gene expression (peripheral blood and/or tissue-based) profiles capable of reliably distinguishing tolerant from non-tolerant allograft recipients. We have successfully enrolled subjects in the trial and anticipate that all patients will have met the endpoint, rejection or safe immunosuppression withdrawal as defined by normal liver tests and histology by the end of 2015.