Caregivers' and providers' perspectives of social and medical care after pediatric liver transplant: Results from the multicenter SOCIAL-Tx study.

Disparities exist in pediatric liver transplant (LT). We characterized barriers and facilitators to providing transplant and social care within pediatric LT clinics. This was a multicenter qualitative study. We oversampled caregivers reporting household financial strain, material economic hardship, or demonstrating poor health literacy. We also enrolled transplant team members. We conducted semistructured interviews with participants. Caregiver interviews focused on challenges addressing transplant and household needs. Transplant provider interviews focused on barriers and facilitators to providing social care within transplant teams. Interviews were recorded, transcribed, and coded according to the Capability, Opportunity, Motivation-Behavior model. We interviewed 27 caregivers and 27 transplant team members. Fifty-two percent of caregivers reported a household income <$60,000, and 62% reported financial resource strain. Caregivers reported experiencing (1) high financial burdens after LT, (2) added caregiving labor that compounds the financial burden, (3) dependency on their social network's generosity for financial and logistical support, and (4) additional support being limited to the perioperative period. Transplant providers reported (1) relying on the pretransplant psychosocial assessment for identifying social risks, (2) discomfort initiating social risk discussions in the post-transplant period, (3) reliance on social workers to address new social risks, and (4) social workers feeling overburdened by quantity and quality of the social work referrals. We identified barriers to providing effective social care in pediatric LT, primarily a lack of comfort in assessing and addressing new social risks in the post-transplant period. Addressing these barriers should enhance social care delivery and improve outcomes for these children.

Caregiver Perceptions of Social Risk Screening in Pediatric Liver Transplantation: From the Multicenter SOCIAL-Tx Study.

BACKGROUND: The social determinants of health contribute to adverse post-liver transplant outcomes. Identifying unmet social risks may enable transplant teams to improve long-term outcomes for at-risk children. However, providers may feel uncomfortable asking about household-level social risks in the posttransplant period because they might make their patients/families uncomfortable. METHODS: We conducted a mixed-methods analysis of caregiver participants (ie, parents/guardians of pediatric liver transplant recipients) in the Social and Contextual Impact on Children Undergoing Liver Transplantation study to assess their perceptions of provider-based social risk screening. Participants (N = 109) completed a 20-min social determinants of health questionnaire that included questions on the acceptability of being asked intimate social risk questions. A subset of participants (N = 37) engaged in an in-depth qualitative interview to share their perceptions of social risk screening. RESULTS: Of 109 participants across 9 US transplant centers, 60% reported financial strain and 30% reported at least 1 material economic hardship (eg, food insecurity, housing instability). Overall, 65% of respondents reported it very or somewhat appropriate and 25% reported being neutral to being screened for social risks in a liver transplant setting. In qualitative analyses, participants reported trust in the providers and a clear understanding of the intention of the screening as prerequisites for liver transplant teams to perform social risk screening. CONCLUSIONS: Only a small minority of caregivers found social risk screening unacceptable. Pediatric liver transplant programs should implement routine social risk screening and prioritize the patient and family voices when establishing a screening program to ensure successful implementation.

A review of racial, socioeconomic, and geographic disparities in pediatric liver transplantation.

Equity is a core principle in both pediatrics and solid organ transplantation. Health inequities, specifically across race, socioeconomic position, or geography, reflect a moral failure. Ethical principles of prudential life span, maximin principle, and fair innings argue for allocation priority to children related to the number of life years gained, equal access to transplant, and equal opportunity for ideal posttransplant outcomes. Iterative policy changes have aimed to narrow these disparities to achieve pediatric transplant equity. These policy changes have focused on modifying pediatric priority for organ allocation to eliminate mortality on the pediatric transplant waiting list. Yet disparities remain in pediatric liver transplantation at all time points: from access to referral for transplantation, likelihood of living donor transplantation, use of exception narratives, waitlist mortality, and inequitable posttransplant outcomes. Black children are less likely to be petitioned for exception scores, have higher waitlist mortality, are less likely to be the recipient of a living donor transplant, and have worse posttransplant outcomes compared with White children. Children living in the most socioeconomically deprived neighborhoods have worse posttransplant outcomes. Children living farther from a transplant center have higher waitlist mortality. Herein we review the current knowledge of these racial and ethnic, socioeconomic, and geographic disparities for these children. To achieve equity, stakeholder engagement is required at all levels from providers and health delivery systems, learning networks, institutions, and society. Future initiatives must be swift, bold, and effective with the tripartite mission to inform policy changes, improve health care delivery, and optimize resource allocation to provide equitable transplant access, waitlist survival, and posttransplant outcomes for all children.

Developing an adolescent and adult Fontan Management Programme.

Patients with single-ventricle CHD undergo a series of palliative surgeries that culminate in the Fontan procedure. While the Fontan procedure allows most patients to survive to adulthood, the Fontan circulation can eventually lead to multiple cardiac complications and multi-organ dysfunction. Care for adolescents and adults with a Fontan circulation has begun to transition from a primarily cardiac-focused model to care models, which are designed to monitor multiple organ systems, and using clues from this screening, identify patients who are at risk for adverse outcomes. The complexity of care required for these patients led our centre to develop a multidisciplinary Fontan Management Programme with the primary goals of earlier detection and treatment of complications through the development of a cohesive network of diverse medical subspecialists with Fontan expertise.

Acute Kidney Injury Following Pediatric Liver Transplant.

OBJECTIVE: To determine the incidence, severity, and risk factors of postoperative acute kidney injury in pediatric liver transplant patients with and without inborn errors of metabolism. DESIGN: Retrospective cohort study. SETTING: Single-center PICU. PATIENTS: All children less than or equal to 18 years old who received a liver transplant between January 2009 and July 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Following exclusion criteria there were 92 transplant encounters. After excluding patients who received combined kidney-liver transplantation, acute kidney injury occurred in 57% of patients (N = 49), with 25.6% (N = 22) stage 1, 15.1% (N = 13) stage 2, and 16.3% (N = 14) stage 3. In an adjusted analysis, metabolic indication for transplant was not significantly associated with presence of acute kidney injury (p = 0.45). For the subset of patients without inborn errors of metabolism, the odds of having acute kidney injury was 1.50 (95% CI: 1.00-2.26) for each 1-unit increase in preoperative INR after adjusting for the covariates of age, preoperative albumin, CMV status of donor, and preoperative creatinine. In the full cohort, as well as the sample of children without inborn errors of metabolism, presence of acute kidney injury was associated with longer total hospital stay as well as number of ICU days. CONCLUSIONS: Acute kidney injury in the early postoperative period is common in pediatric liver transplant patients (57%), 31.4% of whom had severe disease. In patients without inborn errors of metabolism, each unit increase in preoperative INR suggests a higher risk of acute kidney injury after adjusting for covariates including preoperative creatinine. This finding suggests an association between the severity of preoperative synthetic liver function and the risk of developing postoperative acute kidney injury which requires further investigation.

North American Biliary Stricture Management Strategies in Children After Liver Transplantation: A Multicenter Analysis From the Society of Pediatric Liver Transplantation (SPLIT) Registry.

Biliary strictures affect 4%-12% of pediatric liver transplantations. Biliary strictures can contribute to graft loss if left untreated; however, there remains no consensus on the best course of treatment. Study objectives included analyses of outcomes associated with biliary stricture management strategies via percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP), or surgery. We identified pediatric liver transplantation recipients (2011-2016) with biliary strictures from the Society of Pediatric Liver Transplantation (SPLIT) registry and retrieved imaging, procedural, and operative reports from individual centers. Subanalyses were performed to specifically evaluate PTC and ERCP for "optimal biliary outcome" (OBO), defined as graft survival with stricture resolution and without recurrence or surgery. A total of 113 children with a median follow-up of 3.9 years had strictures diagnosed 100 days (interquartile range, 30-290) after liver transplantation; 81% were isolated anastomotic strictures. Stricture resolution was achieved in 92% within 101 days, more frequently with isolated anastomotic strictures (96%). 20% of strictures recurred, more commonly in association with hepatic artery thrombosis (32%). Patient and graft survival at 1 and 3 years were 99% and 98% and 94% and 92%, respectively. In a subgroup analysis of 79 patients with extrahepatic strictures managed by PTC/ERCP, 59% achieved OBO following a median of 4 PTC, and 75% following a median of 3 ERCP (P < 0.001). Among patients with OBO, those with ERCP had longer time intervals between successive procedures (41, 47, 54, 62, 71 days) than for PTC (27, 31, 36, 41, 48 days; P < 0.001). Allograft salvage was successful across all interventions. Stricture resolution was achieved in 92%, with 20% risk of recurrence. Resolution without recurrence was highest in patients with isolated anastomotic strictures and without hepatic artery thrombosis.

Not everything that counts can be counted: Tracking long-term outcomes in pediatric liver transplant recipients.

For pediatric liver transplant (LT) recipients, an ideal outcome is to survive and thrive into adulthood. However, outcomes reporting for all LT recipients typically rely on much shorter-term outcomes, 1-5 years post-LT. Using Organ Procurement and Transplantation Network (OPTN) registry data from 1990 to 2018, this analysis seeks to determine if long-term follow-up and outcome data are complete for pediatric LT recipients age 0 to 12 years who survive at least 1 year post-LT without graft loss (n = 9309). Of the 7948 pediatric transplant recipients who did not die or require re-LT, 1 in 6 was reported as lost to follow-up by their transplant center during long-term follow-up. Rates of lost to follow-up were highest in those transplanted between 1990 and 1999 and increased in early adulthood for all recipients. Almost 10% of pediatric LT recipients who remained in follow-up required relisting for LT. 8% of children remaining in follow-up had graft failure. Lost to follow-up may bias estimates of long-term outcomes and risk factors for poor outcomes. For those remaining in follow-up, graft failure and death continue to occur in the decades after LT. Continued proactive monitoring, management, and innovations are needed to truly optimize post-LT survival for all children.

Addressing Social Adversity to Improve Outcomes for Children After Liver Transplant.

The social determinants of health, defined as the conditions in which we live, learn, work, and play, undoubtedly impact health outcomes. Social adversity in childhood perpetuates over the life course and has consequences extending into adulthood. This link between social adversity and adverse outcomes extends to children undergoing liver transplant, with children from socioeconomically deprived neighborhoods experiencing a greater burden of morbidity and mortality after transplant. Yet, we lack an in-depth understanding of how to address social adversity for these children. Herein, we lay out a strategy to develop and test interventions to address social adversity for children undergoing liver transplant. To do so, we believe that more granular data on how specific social risk factors (e.g., food insecurity) impact outcomes for children after liver transplant are needed. This will provide the liver transplant community with knowledge on the most pressing problems. Then, using the National Academies of Sciences, Engineering, and Medicine's framework for integrating social needs into medical care, the health system can start to develop and test health system interventions. We believe that attending to our patients' social adversity will realize improved outcomes for children undergoing liver transplant.

Neighborhood socioeconomic deprivation, racial segregation, and organ donation across 5 states.

One in 10 people die awaiting transplantation from donor shortage. Only half of Americans register as organ donors. In this cross-sectional study, we evaluated population-level associations of neighborhood socioeconomic deprivation and racial segregation on organ donor registration rates. We analyzed state identification card demographic and organ donor registration data from 5 states to estimate the association between a neighborhood socioeconomic deprivation index (range [0, 1]; higher values indicate more deprivation) and a racial index of concentration at the extreme (ICE) (range [-1, 1]; lower values indicate predominantly black neighborhoods, higher values indicate predominantly white neighborhoods) on organ donor registration rates within a specified geography (census tract or ZIP code tabulation area [ZCTA]). Among 26 720 738 registrants, 32% of the sample were registered organ donors. At the census tract level, with each 0.1 decrease in the deprivation index, the organ donor registration rate increased by 6.8% (95% confidence interval [CI]: 6.6%, 7.0%). With each 0.1 increase in the racial ICE, the rate increased by 1.5% (95% CI: 1.5%, 1.6%). These associations held true at the ZCTA level. Areas with less socioeconomic deprivation and a higher concentration of white residents have higher organ donor registration rates. Public health initiatives should consider neighborhood context and novel data sources in designing optimal intervention strategies.

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management.

BACKGROUND AND AIMS: Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. APPROACH AND RESULTS: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects. CONCLUSIONS: Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Liver Transplant Survivorship.

For both children and adults with end-stage liver disease, liver transplantation represents a lifelong treatment, not a cure. The physical and psychological process of undergoing transplantation begins well before the surgery itself. Concerns regarding suffering and death from end-stage liver disease are replaced by a lifelong need for multiple medications, ongoing monitoring of graft function, and heightened vigilance for complications related not only to the transplant itself but to longterm immunosuppression. The psychological toll from the entire transplant experience on the patient and caregivers, as well as the strain that such a major treatment places on these human interactions can leave emotional scars that persist longer than the surgical healing process itself. The concept of survivorship, originally applied to patients with cancer, acknowledges the ongoing spectrum of care and support that patients and their caregivers require to optimize longterm outcomes after serious medical treatment. Transplant survivorship would expand the focus of care of a patient with end-stage liver disease beyond disease-specific issues and survival alone. This viewpoint explores the need for such a construct in the field of liver transplantation to promote a more holistic approach that encompasses the overall physical, psychological, social, and spiritual well-being of the liver transplant patient.

Association Between Neighborhood-level Socioeconomic Deprivation and the Medication Level Variability Index for Children Following Liver Transplantation.

BACKGROUND: Neighborhood socioeconomic deprivation is associated with adverse health outcomes. We sought to determine if neighborhood socioeconomic deprivation was associated with adherence to immunosuppressive medications after liver transplantation. METHODS: We conducted a secondary analysis of a multicenter, prospective cohort of children enrolled in the medication adherence in children who had a liver transplant study (enrollment 2010-2013). Participants (N = 271) received a liver transplant ≥1 year before enrollment and were subsequently treated with tacrolimus. The primary exposure, connected to geocoded participant home addresses, was a neighborhood socioeconomic deprivation index (range 0-1, higher indicates more deprivation). The primary outcome was the medication level variability index (MLVI), a surrogate measure of adherence to immunosuppression in pediatric liver transplant recipients. Higher MLVI indicates worse adherence behavior; values ≥2.5 are predictive of late allograft rejection. RESULTS: There was a 5% increase in MLVI for each 0.1 increase in deprivation index (95% confidence interval, -1% to 11%; P = 0.08). Roughly 24% of participants from the most deprived quartile had an MLVI ≥2.5 compared with 12% in the remaining 3 quartiles (P = 0.018). Black children were more likely to have high MLVI even after adjusting for deprivation (adjusted odds ratio 4.0 95% confidence interval, 1.7-10.6). CONCLUSIONS: This is the first study to evaluate associations between neighborhood socioeconomic deprivation and an objective surrogate measure of medication adherence in children posttransplant. These findings suggest that neighborhood context may be an important consideration when assessing adherence. Differential rates of medication adherence may partly explain links between neighborhood factors and adverse health outcomes following pediatric liver transplantation.

Health-Related Quality of Life and Cognitive Functioning in Pediatric Liver Transplant Recipients.

The goal of this work was to examine the change in health-related quality of life (HRQOL) and cognitive functioning from early childhood to adolescence in pediatric liver transplantation (LT) recipients. Patients were recruited from 8 North American centers through the Studies of Pediatric Liver Transplantation consortium. A total of 79 participants, ages 11-18 years, previously tested at age 5-6 years in the Functional Outcomes Group study were identified as surviving most recent LT by 2 years and in stable medical follow-up. The Pediatric Quality of Life 4.0 Generic Core Scale, Pediatric Quality of Life Cognitive Function Scale, and PROMIS Pediatric Cognitive Function tool were distributed to families electronically. Data were analyzed using repeated measures and paired t tests. Predictive variables were analyzed using univariate regression analysis. Of the 69 families contacted, 65 (94.2%) parents and 61 (88.4%) children completed surveys. Median age of participants was 16.1 years (range, 12.9-18.0 years), 55.4% were female, 33.8% were nonwhite, and 84.0% of primary caregivers had received at least some college education. Median age at LT was 1.1 years (range, 0.1-4.8 years). The majority of participants (86.2%) were not hospitalized in the last year. According to parents, adolescents had worse HRQOL and cognitive functioning compared with healthy children in all domains. Adolescents reported HRQOL similar to healthy children in all domains except psychosocial, school, and cognitive functioning (P = 0.02; P < 0.001; P = 0.04). Participants showed no improvement in HRQOL or cognitive functioning over time. For cognitive and school functioning, 60.0% and 50.8% of parents reported "poor" functioning, respectively (>1 standard deviation below the healthy mean). Deficits in HRQOL seem to persist in adolescence. Over half of adolescent LT recipients appear to be at risk for poor school and cognitive functioning, likely reflecting attention and executive function deficits.

Predicting ideal outcome after pediatric liver transplantation: An exploratory study using machine learning analyses to leverage Studies of Pediatric Liver Transplantation Data.

Machine learning analyses allow for the consideration of numerous variables in order to accommodate complex relationships that would not otherwise be apparent in traditional statistical methods to better classify patient risk. The SPLIT registry data were analyzed to determine whether baseline demographic factors and clinical/biochemical factors in the first-year post-transplant could predict ideal outcome at 3 years (IO-3) after LT. Participants who received their first, isolated LT between 2002 and 2006 and had follow-up data 3 years post-LT were included. IO-3 was defined as alive at 3 years, normal ALT (<50) or GGT (<50), normal GFR, no non-liver transplants, no cytopenias, and no PTLD. Heat map analysis and RFA were used to characterize the impact of baseline and 1-year factors on IO-3. 887/1482 SPLIT participants met inclusion criteria; 334 had IO-3. Demographic, biochemical, and clinical variables did not elucidate a visual signal on heat map analysis. RFA identified non-white race (vs white race), increased length of operation, vascular and biliary complications within 30 days, and duct-to-duct biliary anastomosis to be negatively associated with IO-3. UNOS regions 2 and 5 were also identified as important factors. RFA had an accuracy rate of 0.71 (95% CI: 0.68-0.74), PPV = 0.83, and NPV = 0.70. RFA identified participant variables that predicted IO-3. These findings may allow for better risk stratification and personalization of care following pediatric liver transplantation.

Barriers to ideal outcomes after pediatric liver transplantation.

Long-term survival for children who undergo LT is now the rule rather than the exception. However, a focus on the outcome of patient or graft survival rates alone provides an incomplete and limited view of life for patients who undergo LT as an infant, child, or teen. The paradigm has now appropriately shifted to opportunities focused on our overarching goals of "surviving and thriving" with long-term allograft health, freedom of complications from long-term immunosuppression, self-reported well-being, and global functional health. Experts within the liver transplant community highlight clinical gaps and potential barriers at each of the pretransplant, intra-operative, early-, medium-, and long-term post-transplant stages toward these broader mandates. Strategies including clinical research, innovation, and quality improvement targeting both traditional as well as PRO are outlined and, if successfully leveraged and conducted, would improve outcomes for recipients of pediatric LT.

Posttransplant biopsy risk for stable long-term pediatric liver transplant recipients: 451 percutaneous biopsies from two multicenter immunosuppression withdrawal trials.

Although liver biopsy is the gold standard for assessing allograft health, its attendant risk has deterred its use in routine monitoring of stable liver transplant recipients during long-term follow-up. We utilized prospectively collected data on adverse events from 2 clinical trials of immunosuppression withdrawal to quantify the risk of liver biopsy in pediatric liver transplant recipients. The trials included 451 liver biopsies in 179 children. No biopsies led to bleeding requiring transfusion or intervention, suggesting a clinically significant bleeding risk of <0.8%. Complications were reported in 5.5% of biopsies (95% CI 3.6%-8.1%): 5.8% (21/363) of protocol biopsies and 4.5% (4/88) of for-cause biopsies (P = .80). Mild complications occurred in 1.8% of biopsies, moderate in 1.8%, and severe in 2.0%. The majority of complications (89%) resolved within 1 week. Six of 9 (67%) severe complications were related to biliary issues; 5 were episodes of cholangitis. Biopsy-related cholangitis occurred only in children with underlying biliary strictures. Overall, biopsy-related complications were infrequent and resolved quickly. Severe complications were rare, with occult biliary stricture as the dominant driver. Our study provides evidence for clinicians who are considering the risk vs benefit of surveillance liver biopsies in pediatric liver transplant recipients.

Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants.

BACKGROUND & AIMS: A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles. METHODS: We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data. RESULTS: The mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell-mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3. CONCLUSION: In an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.

Trajectory of adherence behavior in pediatric and adolescent liver transplant recipients: The medication adherence in children who had a liver transplant cohort.

Knowledge of the longterm trajectory of nonadherence to immunosuppressants can inform decisions regarding organ allocation, adherence monitoring, and intervention efforts. The Medication Adherence in Children Who Had a Liver Transplant (MALT) prospective multisite study followed 400 pediatric and adolescent liver transplant recipients for 2 years, using the Medication Level Variability Index to monitor adherence. We hypothesized that adherence is an unstable (fluctuating) phenomenon: that patients who are adherent in year 1 may become nonadherent in year 2, and vice versa. However, we also hypothesized that a majority (more than 50%) of nonadherent patients remain nonadherent over time. We further hypothesized that the longer nonadherence lasts, the higher the likelihood of adverse events (rejection). Finally, we explored the effect of socioeconomic factors on the evolution of adherence over time. Most (59.7%) of the MALT patients who were nonadherent in year 1 remained so in year 2; 18.5% of patients who were adherent in year 1 became nonadherent in year 2. Only 4.4% of patients who were adherent in both year 1 and year 2 had a rejection, compared with 22.9% of patients who were nonadherent during 1 of the years, and 34.9% of those who were nonadherent in both years (P < 0.001), establishing a "dose-dependent" effect of adherence on transplant outcomes. Single-parent households were associated with worsening adherence. Our results suggest that good baseline adherence does not guarantee adherence later on, that nonadherence is likely to persist in the absence of interventions, and that monitoring of adherence and interventions to improve it should be expected to last for years if transplant outcomes are to be improved. Liver Transplantation 24 80-88 2018 AASLD.