Long-term outcome following liver transplantation of patients with ACLF grade 3.

BACKGROUND AND AIMS: Utility, a major principle for allocation in the context of transplantation, is questioned in patients with acute-on chronic liver failure grade 3 (ACLF-3) who undergo liver transplantation (LT). We aimed to explore long-term outcomes of patients included the three-center retrospective French experience published in 2017. METHOD: All patients with ACLF-3 (n=73) as well as their transplanted matched controlled with ACLF-2 (n=145), 1 (n=119) and no ACLF (n=292) that have participated in the princeps study published in 2017 were included. We explored 5- and 10-year patient and graft survivals, causes of death and their predictive factors. RESULTS: Median follow-up of patients ACLF-3 patients was 7.5 years. At LT, median MELD was 40. In patients with ACLF-3, 2, 1 and no ACLF, 5-year patients' survivals were respectively 72.6% vs. 69.7% vs. 76.4% vs. 77.0% (p=0.31). Ten-year patients' survival ACLF-3 was 56.8% and was not different other groups (p=0.37) Leading causes of death in ACLF-3 patients were infections (33.3%), and cardiovascular events (23.3%). After exclusion of early death, UCLA futility risk score, age-adjusted Charlson comorbidity index and Chronic Liver Failure Consortium ACLF score were independently associated with 10-year patients' survival. Long-term grafts' survivals were not different across the groups. Clinical frailty scale and WHO performance status improved over time in patients alive after 5 years. CONCLUSION: 5- and 10-year patients' and grafts' survivals in ACLF-3 patients were not different from their controls. 5-year patients' survival is higher than that of the 50%-70% threshold defining the utility of liver graft. Efforts should focus on candidates' selection based on comorbidities as well as the prevention of infection and cardiovascular events standing as the main cause of death. IMPACT AND IMPLICATIONS: While short-term outcomes following liver transplantation in the most severely ill cirrhotic patients (ACLF-3) are known, long-term data are limited, raising questions about the utility of graft allocation in the context of scarce medical resources. This study provides a favorable long-term update, confirming no differences in 5- and 10-year patient and graft survival following liver transplantation in ACLF-3 patients compared to matched ACLF-2, ACLF-1, and no-ACLF patients. The study highlights the risk of dying from infection and cardiovascular causes in the long-term and identifies scores including comorbidities evaluation, such as the age-adjusted Charlson Comorbidity Index, as independently associated with long-term survival. Therefore, physicians should consider the cumulative burden of comorbidities when deciding to transplant these patients. Additionally, after transplantation, the study encourages mitigating infectious risk with tailored immunosuppressive regimens and managing tightly cardiovascular risk over time.

Autoimmune hepatitis recurrence after liver transplantation: "Les jeux sont faits".

Autoimmune hepatitis (AIH) may recur after liver transplantation (LT). The aims of this study were to evaluate the incidence and risk factors for recurrent autoimmune hepatitis (rAIH). A multicenter retrospective French nationwide study, including all patients aged ≥16 transplanted for AIH, with at least 1 liver biopsy 1 year after LT, was conducted between 1985 and 2018. Risk factors for rAIH were identified using a multivariate Cox regression model. Three hundred and forty-four patients were included (78.8% women) with a median age at LT of 43.6 years. Seventy-six patients (22.1%) developed recurrence in a median time of 53.6 months (IQR, 14.1-93.2). Actuarial risk for developing rAIH was 41.3% 20 years after LT. In multivariate analysis, the strongest risk factor for rAIH was cytomegalovirus D+/R- mismatch status (HR=2.0; 95% CI: 1.1-3.6; p =0.03), followed by associated autoimmune condition. Twenty-one patients (27.6% of rAIH patients) developed liver graft cirrhosis after rAIH. Independent risk factors for these severe forms of rAIH were young age at LT, IgG levels >20.7 g/L, and LT in the context of (sub)fulminant hepatitis. Immunosuppression, especially long-term maintenance of corticosteroid therapy, was not significantly associated with rAIH. Recurrence of AIH after LT is frequent and may lead to graft loss. Recurrence is more frequent in young patients with active disease at the time of LT, yet systematic corticosteroid therapy does not prevent it.

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors.

BACKGROUND AND AIM: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. APPROACH AND RESULTS: Retrospective multicenter analysis of liver disease (transaminases > 30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n = 1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological, and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease in 48% and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and HCC occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥ 3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group [80/396, (20%)], OR 12.9 (CI 95%: 7.8-21.3, p < 0.001). CONCLUSIONS: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild, they may be associated with severe disease. Porto-sinusoidal vascular disease and cirrhosis were the most frequent lesions, suggesting that the mechanism of action is multifactorial.

Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET).

BACKGROUND AND AIMS: Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. METHODS: Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. RESULTS: Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. CONCLUSIONS: Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.

The novel SALT-M score predicts 1-year post-transplant mortality in patients with severe acute-on-chronic liver failure.

BACKGROUND & AIMS: Twenty-eight-day mortality ranges from 30-90% in patients with acute-on-chronic liver failure grades 2/3 (severe ACLF). Though liver transplantation (LT) has demonstrated a survival benefit, the scarcity of donor organs and uncertainty regarding post-LT mortality among patients with severe ACLF may cause hesitancy. We developed and externally validated a model to predict 1-year post-LT mortality in severe ACLF, called the Sundaram ACLF-LT-Mortality (SALT-M) score, and estimated the median length of stay (LoS) after LT (ACLF-LT-LoS). METHODS: In 15 LT centers in the US, we retrospectively identified a cohort of patients with severe ACLF transplanted between 2014-2019, followed up to Jan'2022. Candidate predictors included demographics, clinical and laboratory values, and organ failures. We selected predictors in the final model using clinical criteria and externally validated them in two French cohorts. We provided measures of overall performance, discrimination, and calibration. We used multivariable median regression to estimate LoS after adjusting for clinically relevant factors. RESULTS: We included 735 patients, of whom 521 (70.8%) had severe ACLF (120 ACLF-3, external cohort). The median age was 55 years, and 104 with severe ACLF (19.9%) died within 1-year post-LT. Our final model included age >50 years, use of 1/≥2 inotropes, presence of respiratory failure, diabetes mellitus, and BMI (continuous). The c-statistic was 0.72 (derivation) and 0.80 (validation), indicating adequate discrimination and calibration based on the observed/expected probability plots. Age, respiratory failure, BMI, and presence of infection independently predicted median LoS. CONCLUSIONS: The SALT-M score predicts mortality within 1-year after LT in patients with ACLF. The ACLF-LT-LoS score predicted median post-LT stay. Future studies using these scores could assist in determining transplant benefits. IMPACT AND IMPLICATIONS: Liver transplantation (LT) may be the only life-saving procedure available to patients with acute-on-chronic liver failure (ACLF), but clinically instability can augment the perceived risk of post-transplant mortality at 1 year. We developed a parsimonious score with clinically and readily available parameters to objectively assess 1-year post-LT survival and predict median length of stay after LT. We developed and externally validated a clinical model called the Sundaram ACLF-LT-Mortality score in 521 US patients with ACLF with 2 or ≥3 organ failure(s) and 120 French patients with ACLF grade 3. The c-statistic was 0.72 in the development cohort and 0.80 in the validation cohort. We also provided an estimation of the median length of stay after LT in these patients. Our models can be used in discussions on the risks/benefits of LT in patients listed with severe ACLF. Nevertheless, the score is far from perfect and other factors, such as patient's preference and center-specific factors, need to be considered when using these tools.

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.

Treatment of donor-specific anti-HLA antibodies-mediated rejection after liver transplantation: A French nationwide retrospective study.

The deleterious effect of donor-specific anti-HLA antibodies (DSA) after liver transplantation (LT) has been increasingly recognized during the past decade. Antibody-mediated rejection (AMR) represents a rare but severe complication in the presence of DSA. However, little is known concerning the treatment of AMR after LT. The nationwide French study aimed to describe LT recipients who received specific treatment of AMR. We performed a multicenter retrospective study on 44 patients who were treated with B-cell targeting agents from January 2008 to December 2020. Median patient age at the time of AMR treatment was 51.6 years (range: 17.9-68.0). AMR was classified as acute (n = 19) or chronic (n = 25). The diagnosis of AMR was made after a median time of 16.8 months (range: 0.4-274.2) after LT. The main therapeutic combination was plasma exchange/rituximab/IVIG (n = 25, 56.8%). The median follow-up after the treatment of AMR was 32 months (range: 1-115). After the treatment, 1-, 5- and 10-year patient and graft survivals were 77%, 55.9%, and 55.9%, and 69.5%, 47.0%, and 47.0%, respectively. Initial total bilirubin (Q1-Q3 vs. Q4) was significantly associated with patient survival (log-rank test, p = 0.005) and graft survival (log-rank test, p = 0.002). After a median follow-up of 21 months (range: 12-107), DSA became undetectable in 15/38 patients (39.5%) with available DSA monitoring. In conclusion, specific treatment of AMR in LT recipients has slowly emerged in France during the past decade and has probably been considered in the most severe patients; this explains the global poor outcome, even if the outcome was favorable in some cases.

Liver support systems and liver transplantation in acute liver failure.

Acute liver failure (ALF) results in a multitude of complications that result in multi-organ failure. This review focuses on the pathophysiological processes and how to manage with these with artificial liver support and liver transplantation (LT). The pathophysiological sequence of events behind clinical deterioration in ALF comes down to two profound consequences of the failing liver. The first is the development of hyperammonemia, as the liver can no longer synthesize urea. The result is that the splanchnic system instead of removing ammonia becomes an ammonia-producing organ system that causes hepatic encephalopathy (HE) and cerebral oedema. The second complication is caused by the necrotic liver cells that release large molecules that originate from degrading proteins, that is damage associated molecular patterns (DAMPs) which causes inflammatory activation of intrahepatic macrophages and an overflow of DAMPs molecules into the systemic circulation resulting in a clinical picture that resembles septic shock. In this context the combined use of continuous renal replacement therapy (CRRT) and plasma exchange are rational and simple ways to remove ammonia and DAMPS molecules. This combination improve survival for ALF patients deemed not appropriate for LT, despite poor prognostic criteria, but also ensure a better stability of vital organs while awaiting LT. The combination of CRRT with albumin dialysis tends to have a similar effect. Currently, the selection criteria for LT for non-paracetamol cases appear robust while the criteria for paracetamol-intoxicated patients have become more unreliable and now consist of more dynamic prognostic systems. For patients that need LT for survival, a tremendous improvement in the post-LT results has been achieved during the last decade with a survival that now reach merely 90% which is mirroring the results seen after LT for chronic liver disease.

Liver transplantation for autoimmune hepatitis: Pre-transplant does not predict the early post-transplant outcome.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare indication (<5%) for liver transplantation (LT). The aim of this study was to describe the early outcome after LT for AIH. METHODS: A multicenter retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Occurrences of biliary and vascular complications, rejection, sepsis, retransplantation and death were collected during the first year after LT. RESULTS: A total of 344 patients (78.8% of women, 17.0% of (sub)fulminant hepatitis and 19.2% of chronic liver diseases transplanted in the context of acute-on-chronic liver failure [ACLF]) were included, with a median age at LT of 43.6 years. Acute rejection, sepsis, biliary and vascular complications occurred in respectively 23.5%, 44.2%, 25.3% and 17.4% of patients during the first year after LT. One-year graft and patient survivals were 84.3% and 88.0% respectively. The main cause of early death was sepsis. Pre-LT immunosuppression was not associated with an increased risk for early infections or surgical complications. Significant risk factors for septic events were LT in the context of (sub)fulminant hepatitis or ACLF, acute kidney injury at the time of LT (AKI) and occurrence of biliary complications after LT. AKI was the only independent factor associated with graft (HR = 2.5; 95% CI: 1.1-5.4; p = .02) and patient survivals (HR = 2.6; 95% CI: 1.0-6.5; p = .04). CONCLUSION: Early prognosis is good after LT for AIH and is not impacted by pre-LT immunosuppression but by the presence of AKI at the time of LT.

Long-term outcome of liver transplantation for autoimmune hepatitis: A French nationwide study over 30 years.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). The aims of this study were to evaluate long-term survival after LT for AIH and prognostic factors, especially the impact of recurrent AIH (rAIH). METHODS: A multicentre retrospective nationwide study including all patients aged ≥16 transplanted for AIH in France was conducted. Early deaths and retransplantations (≤6 months) were excluded. RESULTS: The study population consisted of 301 patients transplanted from 1987 to 2018. Median age at LT was 43 years (IQR, 29.4-53.8). Median follow-up was 87.0 months (IQR, 43.5-168.0). Seventy-four patients (24.6%) developed rAIH. Graft survival was 91%, 79%, 65% at 1, 10 and 20 years respectively. Patient survival was 94%, 84% and 74% at 1, 10 and 20 years respectively. From multivariate Cox regression, factors significantly associated with poorer patient survival were patient age ≥58 years (HR = 2.9; 95% CI, 1.4-6.2; p = 0.005) and occurrence of an infectious episode within the first year after LT (HR = 2.5; 95% CI, 1.2-5.1; p = 0.018). Risk factors for impaired graft survival were: occurrence of rAIH (HR = 2.7; 95% CI, 1.5-5.0; p = 0.001), chronic rejection (HR = 2.9; 95% CI, 1.4-6.1; p = 0.005), biliary (HR = 2.0; 95% CI, 1.2-3.4; p = 0.009), vascular (HR = 1.8; 95% CI, 1.0-3.1; p = 0.044) and early septic (HR = 2.1; 95% CI, 1.2-3.5; p = 0.006) complications. CONCLUSION: Our results confirm that survival after LT for AIH is excellent. Disease recurrence and chronic rejection reduce graft survival. The occurrence of an infectious complication during the first year post-LT identifies at-risk patients for graft loss and death.

Evidence for Alloimmune Sinusoidal Injury in De Novo Nodular Regenerative Hyperplasia After Liver Transplantation.

Posttransplant nodular regenerative hyperplasia (NRH) mostly remains unexplained. Microvascular injury due to antibody-mediated rejection (AMR) is suspected, but lack of donor specific antibody (DSA) testing makes it difficult to prove. Centered around a 1-year period of routine DSA testing, concomitant protocol, and indicated posttransplant liver biopsies (LB), recipients with NRH (n = 18) were compared with a matched control group (n = 36). All index, previous, and subsequent LB were reviewed. Both groups were similar in terms of demographics, timing of index LB, and DSA. In the index LB, the NRH group had higher sinusoidal C4d positivity (p = 0.029) and perisinusoidal fibrosis (p = 0.034), both independently associated with NRH (p = 0.038 and 0.050, respectively). Features of "possible" chronic AMR were detected in 28.5% of the NRH group without a known cause and 0% of the control group (p = 0.009). The NRH group had more preceding indicated LB with increased incidence of rejection and biliary obstruction pattern. In the follow-up histology, overall, sinusoidal and portal C4d positivity, sinusoidal microvasculitis, and perisinusoidal fibrosis were also higher (all p < 0.050). In conclusion, we provide evidence towards the hypothesis that some cases of posttransplant NRH are related to preceding active and persistent AMR. Large multicenter studies with protocol DSA testing are required to confirm.

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC0-24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC0-24 h (V4). AUC0-24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC0-24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

Invasive aspergillosis in liver transplant recipients.

BACKGROUND: Liver transplantation is increasing worldwide with underlying pathologies dominated by metabolic and alcoholic diseases in developed countries. METHODS: We provide a narrative review of invasive aspergillosis (IA) in liver transplant (LT) recipients. We searched PubMed and Google Scholar for references without language and time restrictions. RESULTS: The incidence of IA in LT recipients is low (1.8%), while mortality is high (∼50%). It occurs mainly early (<3 months) after LT. Some risk factors have been identified before (corticosteroid, renal, and liver failure), during (massive transfusion and duration of surgical procedure), and after transplantation (intensive care unit stay, re-transplantation, re-operation). Diagnosis can be difficult and therefore requires full radiological and clinicobiological collaboration. Accurate identification of Aspergillus species is recommended due to the cryptic species, and susceptibility testing is crucial given the increasing resistance of Aspergillus fumigatus to azoles. It is recommended to reduce the dose of tacrolimus (50%) and to closely monitor the trough level when introducing voriconazole, isavuconazole, and posaconazole. Surgery should be discussed on a case-by-case basis. Antifungal prophylaxis is recommended in high-risk patients. Environmental preventative measures should be implemented to prevent outbreaks of nosocomial aspergillosis in LT recipient units. CONCLUSION: IA remains a very serious disease in LT patients and should be promptly sought and, if possible, prevented by clinicians when risk factors are identified.

Maribavir for Preemptive Treatment of Cytomegalovirus Reactivation.

BACKGROUND: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known. METHODS: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment. RESULTS: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir. CONCLUSIONS: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).

Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe.

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I2 index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival.

Five-year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study.

BACKGROUND AND AIMS: To report 5-year outcomes of the CERTITUDE study. METHODS: An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up. RESULTS: Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m2 and EVR, -14.56 ml/min/1.73 m2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS: The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

Liver transplantation for NAFLD cirrhosis: Age and recent coronary angioplasty are major determinants of survival.

BACKGROUND AND AIMS: Liver transplantation (LT) is the treatment of end-stage non-alcoholic liver disease (NAFLD), that is decompensated cirrhosis and/or complicated by hepatocellular carcinoma (HCC). Few data on long-term outcome are available. The aim of this study was to evaluate overall patient and graft survivals and associated predictive factors. METHOD: This retrospective multicentre study included adult transplant patients for NAFLD cirrhosis between 2000 and 2019 in participating French-speaking centres. RESULTS: A total of 361 patients (69.8% of male) were included in 20 centres. The median age at LT was 62.3 years [57.4-65.9] and the median MELD score was 13.9 [9.1-21.3]; 51.8% of patients had HCC on liver explant. Between 2004 and 2018, the number of LT for NAFLD cirrhosis increased by 720%. A quarter of the patients had cardiovascular history before LT. Median follow-up after LT was 39.1 months [15.8-72.3]. Patient survival at 1, 5 and 10 years after LT was 89.3%, 79.8% and 68.1% respectively. The main causes of death were sepsis (37.5%), malignancies (29.2%) and cardiovascular events (22.2%). In multivariate analysis, three risk factors for overall mortality after LT were recipient pre-LT BMI < 32 kg/m2 at LT time (OR: 2.272; p = .012), pre-LT angioplasty during CV check-up (OR: 2.916; p = .016), a combined donor and recipient age over 135 years (OR: 2.020; 95%CI: p = .035). CONCLUSION: Survival after LT for NAFLD cirrhosis is good at 5 years. Donor and recipient age, and cardiovascular history, are major prognostic factors to consider.

Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation.

Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July-31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients' needs, and respondents' expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R- SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10-10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.

Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection : A Retrospective Cohort Study.

BACKGROUND: The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. OBJECTIVE: To assess the potential effect of donor or recipient HED on liver transplant rejection. DESIGN: Retrospective cohort study. SETTING: Liver transplant units. PATIENTS: 1154 adults and 113 children who had a liver transplant between 2004 and 2018. MEASUREMENTS: Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. RESULTS: In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. LIMITATION: The DSAs were measured only in children. CONCLUSION: Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. PRIMARY FUNDING SOURCE: Institut National de la Santé et de la Recherche Médicale.

Tumors located in the central column of the liver are associated with increased surgical difficulty and postoperative complications following open liver resection for colorectal metastases.

BACKGROUND: To assess the impact of difficult location (based on preoperative computed tomography) of liver metastases from colorectal cancer (LMCRC) on surgical difficulty, and occurrence of severe postoperative complications (POCs). METHODS: A retrospective single-centre study of 911 consecutive patients with LMCRC who underwent hepatectomy by the open approach between 1998 and 2011, before implementation of laparoscopic surgery to obviate approach selection bias. LMCRC with at least one of the following four features on preoperative imaging: tumor invading the hepatocaval confluence or retro-hepatic inferior vena cava, centrally located (Segments 4,5,8) and >10 cm in diameter, abutting the supra-hilar area, or involving the paracaval portion or caudate process of Segment 1; were considered as topographically difficult (top-diff). Independent predictors of surgical difficulty assessed by number of blood units transfused, duration of ischemia, and number of sessions of pedicle clamping during surgery and of severe POCs were identified by multivariate analysis before, and after propensity score matching. RESULTS: Top-diff tumor location independently predicted surgical difficulty. Severe POCs were associated with the tumor location [top-diff vs. topographically non difficult (non top-diff)], preoperative portal vein embolization, and variables related to surgical difficulty. CONCLUSION: LMCRC in difficult location independently predicts surgical difficulty and severe POCs.