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To report 5-year outcomes of the CERTITUDE study.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.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 mThe CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

More data on resistance of HCV genotype (GT) 3 and 4 to direct-acting antivirals (DAAs) are still needed. Here we investigated the presence of resistance-associated substitutions (RASs) pre- and post-treatment and their emergence under DAAs in HCV GT3- and GT4-infected patients failing DAA regimens by next-generation sequencing (NGS). Sanger sequencing and NGS were performed on NS5B and NS5A in plasma samples prior to and post treatment of 13 patients. Positions implicated in resistance to anti-NS5A and anti-NS5B in the literature were analysed. No baseline RASs was detected in NS5B but one GT4r virus developed the mutation S282T at failure. In NS5A, pre-existing RASs or polymorphisms were detected in viruses of 6/10 patients (L28M for a GT4a, M28V for a GT4r, L30R for a GT4a, 2 GT4d and 1 GT4r, and T58P for a GT4d) by Sanger sequencing and in viruses of 7/10 patients by NGS. Additional baseline minority substitutions detected by NGS were Y93H in a GT3a, L28M in a GT4a and GT4d, and L28F in a GT4d virus. At failure, these substitutions were found at a frequency of 100%. Y93H was detected alone at baseline, whilst L28M and L28F were accompanied by polymorphisms L30R or L30R + T58P. Use of NGS in patients failing DAAs and infected by HCV GT3 and GT4 revealed the emergence of specific patterns of substitutions in NS5A and NS5B, in particular substitutions at position 28 in NS5A in GT4 virus, highlighting the need to list these substitutions in guidelines for resistance interpretation.

Normothermic perfusion provides a means to rescue steatotic liver grafts, including by pharmacological defatting. In this study, we tested the potential of new drug combinations to trigger defatting in three human culture models, primary hepatocytes with induced steatosis, primary hepatocytes isolated from steatotic liver, and precision-cut liver slices (PCLS) of steatotic liver. Forskolin, L-carnitine and a PPARα agonist were all combined with rapamycin, an immunosuppressant that induces autophagy, in a D-FAT cocktail. D-FAT was tested alone or in combination with necrosulfonamide, an inhibitor of mixed lineage kinase domain like pseudokinase involved in necroptosis. Within 24 h, in all three models, D-FAT induced a decrease in triglyceride content by 30%, attributable to an upregulation of genes involved in free fatty acid β-oxidation and autophagy, and a downregulation of those involved in lipogenesis. Defatting was accompanied by a decrease in endoplasmic reticulum stress and in the production of reactive oxygen species. The addition of necrosulfonamide increased the efficacy of defatting by 8%-12% in PCLS, with a trend towards increased autophagy. In conclusion, culture models, notably PCLS, are insightful to design strategies for liver graft rescue. Defatting can be rapidly achieved by combinations of drugs targeting mitochondrial oxidative metabolism, macro-autophagy and lipogenesis., Summary: This study describes a defatting cocktail that has been proven to function in three relevant steatotic human culture models without cytotoxicity, and which could be employed in the reduction of steatosis in donor livers during liver transplantation.

Hepatitis C virus (HCV) infection and alcohol abuse are leading causes of chronic liver disease and frequently coexist in patients. The unfolded protein response (UPR), a cellular stress response ranging along a spectrum from cytoprotection to apoptosis commitment, has emerged as a major contributor to human diseases including liver injuries. However, the literature contains conflicting reports as to whether HCV and ethanol activate the UPR and which UPR genes are involved. Here we have used primary human hepatocytes (PHH) to reassess this issue and address combined impacts. In this physiologically relevant model, either stressor activated a chronic complete UPR. However, the levels of UPR gene induction were only modest in the case of HCV infection. Moreover, when combined to the strong stressor thapsigargin, ethanol exacerbated the activation of pro-apoptotic genes whereas HCV tended to limit the induction of key UPR genes. The UPR resulting from HCV plus ethanol was comparable to that induced by ethanol alone with the notable exception of three pro-survival genes the expressions of which were selectively enhanced by HCV. Interestingly, HCV genome replication was maintained at similar levels in PHH exposed to ethanol. In conclusion, while both HCV and alcohol activate the hepatocellular UPR, only HCV manipulates UPR signalling in the direction of a cytoprotective response, which appears as a viral strategy to spare its own replication.

International audience; Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR

International audience; The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR-treated patients and 78 TAC-treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR-treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3-12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m2 , respectively (P = 0.90) and adjusted mean change in eGFR from randomization was -8.0 versus -13.5 mL/minute/1.73 m2 (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR-treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC-treated patients (P = 0.05). Treated biopsy-proven acute rejection affected 4 EVR-treated patients and 2 TAC patients during months 6-24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR-treated and TAC-treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI-free EVR-based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.

Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.

To increase the donor pool, the strategy of transplantation from "marginal" donors was developed though patients' preferences about these donors were insufficiently known. The preferences of patients registered on the waiting list or already transplanted in eight transplant teams covering four main organs (i.e., kidney, liver, heart, and lung) were evaluated using the discrete choice experiment method. In each left during 2 days, patients were interviewed on four scenarios. Of 178 eligible patients, 167 were interviewed; 40% accepted marginal graft in their own situation and 89% at least in one of the scenarios. Imagining urgent situations or rare profiles with difficult access to transplantation, respectively, 86% and 71% accepted these grafts. Most (76%) preferred to be informed about these grafts and 43% preferred to be involved in decision. The emergency [OR = 1.24; 95% CI: (1.06-1.45)] and the hazardousness [OR = 0.88; 95% CI: (0.78-0.99)] of the transplantation were factors independently associated with marginal graft acceptance. Most patients preferred to be informed and to be involved in the decision. Marginal grafts could be more accepted by patients in critical medical situations or perceiving their situation as critical. Physicians' practices in transplantation should be reconsidered taking into account individual preferences. This study was performed in a single country and thus reflects the cultural bias and practice thereof.

Resume La transplantation hepatique (TH) s’est accrue en France ces dernieres annees grâce a l’augmentation du nombre d’organes preleves, l’utilisation de greffons marginaux et l’elargissement des criteres cliniques et biologiques des patients figurant sur liste d’attente. L’evaluation d’un patient candidat a la TH fait appel a des scores clinico-biologiques tels que le score MELD (Model for End Stage Liver Disease). Ce score peut etre modifie, en lien avec la pathologie hepatique concernee (composante expert, natremie), ou en association a d’autres scores comme le score α-foetoproteine. La clairance au vert d’indocyanine, par sa mesure simplifiee, gagne un nouvel interet pour evaluer la fonctionnalite du foie. Il n’existe pas encore de « Donor Risk Index» evaluant avec fiabilite la qualite du foie du donneur. Dans les suites immediates de la TH, la biologie joue un role essentiel pour surveiller les receveurs a haut risque de mortalite, pour depister en urgence la non-fonction primaire du greffon, la thrombose de l’artere hepatique et pour contribuer au diagnostic des infections. La biologie joue un role moindre dans les lesions d’ischemie-reperfusion et les stenoses biliaires. Apres le premier mois post-TH, la surveillance biologique reguliere permet le diagnostic de recidive de la maladie initiale et du rejet chronique. Elle estime la fonctionnalite du foie et pourrait evaluer le developpement de fibrose avec l’aide de marqueurs sanguins non invasifs associes ou non a l’elastometrie.

Portopulmonary hypertension (PoPH) is diagnosed in 2-6% of liver transplantation (LT) candidates. We studied outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, and within 6 months and beyond 6 months after LT. Forty-nine patients (35 males, 48 ± 8 years) were analyzed (median Model for End-Stage Liver Disease score 20). At baseline, mean pulmonary artery pressure (mPAP) was 44 ± 10 mm Hg (range 26-73 mm Hg), cardiac index was 3.5 ± 0.9 L/min/m2, and pulmonary vascular resistance was 5.6 ± 2.8 Wood units. Hemodynamic reassessment performed in 35 patients who were treated with pulmonary arterial hypertension–targeted therapies before LT resulted in significant decreases in both mPAP (36 ± 7 versus 47 ± 10 mm Hg, P < 0.0001) and pulmonary vascular resistance (3.0 ± 1.4 versus 6.1 ± 3.1 Wood units, P < 0.0001). Fourteen patients (29%) died without having had access to LT. Thirty-five patients underwent LT and were followed up for a median of 38 months. Eight patients (23%) died after LT including 5 due to PoPH (after 1 day to 6 months). Among survivors (n = 27), all patients treated with intravenous epoprostenol were weaned off post-LT, and endothelin receptor antagonist or phosphodiesterase type 5 inhibitors were continued in 15/27 patients (55%). At last evaluation, 20/27 patients (74%) had mPAP

Because of global epidemics of obesity and type 2 diabetes, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing both in Europe and the United States, becoming one of the most frequent causes of chronic liver disease and predictably, one of the leading causes of liver transplantation both for end-stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms of pre- and post-transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease, and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for liver transplantation both in Europe and the United States; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to liver transplantation and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis on the correction and control of metabolic comorbidities.

Chronic renal disease (CKD) jeopardizes the long-term outcomes of liver transplant recipients. In patients with end-stage liver graft disease and CKD, liver retransplantation associated with kidney transplantation (ReLT-KT) might be necessary. Yet, this specific subset of patients remains poorly described.Indications, perioperative characteristics, and short- and long-term outcomes of patients undergoing ReLT-KT at 2 transplantation units from 1994 to 2012 were analyzed. Risk factors for postoperative mortality and long-term survivals were evaluated.Among 3060 patients undergoing liver transplantation (LT), 45 (1.5%) underwent ReLT-KT. The proportion of ReLT-KT among LT recipients continuously grew throughout the study period from 0.3% to 2.4% (P0.001). Median time from primary LT to ReLT-KT was 151.3 (7.5-282.9) months. The most frequent indications for liver retransplantation were recurrence of the primary liver disease and cholangitis in 15 (33.3%) cases each. CKD was related to calcineurin inhibitors toxicity in 38 (84.4%) cases. Twelve (26.7%) patients died postoperatively. D-MELD (donor age × recipients' MELD) was associated with postoperative mortality (HR: 8.027; 95% CI: 2.387-18.223; P = 0.026) and optimal cut-off value was 1039 (AUC: 0.801; P = 0.002). Overall 1, 3, and 5 years survivals were 68.8%, 65.9%, and 59.5%, respectively. D-MELD1039 was the only factor associated with poor survival (P = 0.021).ReLT-KT is a highly morbid increasingly performed procedure. Refinements in the selection of grafts and transplant candidates are required to limit the postoperative mortality of these patients.

International audience

International audience; Concerns related to equity and efficacy of our previous center-based allocation system have led us to introduce a patient-based allocation system called the "Liver Score" that incorporates the MELD score. The main objective of this study was to compare waitlist and post-transplant survivals before and after implementation of the "Liver Score" using the French transplant registry (period before: 2004-2006 and period after: 2007-2012). Patients transplanted during the second period were sicker and had a higher MELD. One-year waitlist survival (74% versus 76%; p=0.8) and one-year post-transplant survival (86.3% vs 85.7%; p=0.5) were similar between the 2 periods. Cirrhotic recipients with MELD>35 had lower one-year post-transplant survival compared to those with MELD35, patients presenting 2 or 3 risk factors (dialysis, intubation or infection) had a lower 1-year survival compared to those with none of these risk factors (61.2% vs 92%; p35 should be completed to allow safe transplantation. This article is protected by copyright. All rights reserved.

Purpose Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells. Methods A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration–time data (N = 221) were analyzed by using nonlinear mixed effects modeling. Findings A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration–time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6–598.7] vs 224.6 ng/mL · h [95% CI, 117.6–421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/106 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/106cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/106 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups. Implications This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results. ClinicalTrials.gov identifier: NCT02105155 .

Background: The role of regulatory T cells (Tregs) is now well established in the progression of hepatocellular carcinoma (HCC) linked to Hepatitis C virus (HCV) infection. However, nothing is known about the potential interplay between Tregs and HCV. In this pilot study, we have investigated the ability of Tregs to hang HCV on and the subsequent effect on their suppressive function and phenotype. Moreover, we have evaluated how HCV could promote the recruitment of Tregs by infected primary human hepatocytes. Methods: Tregs of healthy donors were incubated with JFH-1/HCVcc. Viral inoculation was assessed using adapted assays (RT-qPCR, Flow Citometry (FACS) and Western Blot (WB). Expression of Tregs phenotypic (CD4, CD25, CD127 and Foxp3) and functional (IL-10, GZMB, TGF-&beta, 1 and IL-2) markers was monitored by RT-qPCR, FACS and ELISA. Suppressive activity was validated by suppressive assays. Tregs recruitment by infected primary hepatic cells was evaluated using Boyden Chamber. Results: Tregs express the classical HCV receptors (CD81, CLDN1 and LDLR) and some co-receptors (CD5). HCV inoculation significantly increases the suppressive phenotype and activity of Tregs, and raises their anergy by inducing an unexpected IL-2 production. Moreover, HCV infection induces the expression of chemokines (CCL17, CXCL16, and CCL20) by primary hepatic human hepatocytes and chemokine receptors (CCR4, CXCR6 and CCR6) by Tregs. Finally, infected hepatocytes have a significantly higher potential to recruit Tregs in a seemingly CCL20-dependent manner. Conclusions: Direct interaction between HCV and Tregs represents a newly defined mechanism that could potentiate HCV immune evasion and favor intratumoral recruitment contributing to HCC progression.

The mammalian target of rapamycin (mTOR) inhibitor everolimus is approved for rejection prophylaxis after liver transplantation. The current article pools the experience of French liver transplant surgeons and physicians in use of everolimus and, particularly, practical guidance on dosing, appropriate concomitant immunosuppression and management of adverse events. In terms of indication, introduction of everolimus from week 4 after liver transplantation, with or without concomitant calcineurin inhibitor (CNI) therapy, offers a significant renal benefit without loss of immunosuppressive efficacy. De novo treatment with everolimus, either selectively or systematically, may play a role in the prevention and treatment of recurrence of hepatocellular cancer and de novo malignancies. For maintenance patients, the most frequent indications for introducing everolimus are in response to renal dysfunction, recurrent hepatocellular cancer, diabetes, hypertension, or neurotoxicity, or as a preventative approach to avoid malignancies. Of these, the strongest evidence exists for a renoprotective effect. However, the low rate of acute rejection following switch of maintenance patients from CNI-based to everolimus-based therapy means that this can be considered even where robust data are not yet available. Most adverse events associated with mTOR inhibitors can usually be managed successfully, often with concentration-controlled dose reductions. Dosing algorithms are provided, with suggestions for target ranges in specific settings, and treatment strategies for the most common side effects are proposed. Although further research is required, everolimus has become an established part of the immunosuppressive arsenal for liver transplant recipients over the last decade. Sharing experience from units which have embraced its use may help other centers develop their own protocols.

BACKGROUND & AIMS Equality of access to organ transplantation is a mandatory public health requirement. Referral from a local to a university hospital and then registration on the national waiting list are the two key steps enabling access to liver transplantation (LT). Although the latter procedure is well defined using the Model for End-stage Liver Disease score that improves equality of access, the former is mostly reliant on the practices of referring physicians. The aim of this study was to clarify the factors determining this initial step. METHODS This observational study included consecutive inpatients with cirrhosis of whatever origin in a cohort constituted between 2003 and 2008, using medical records and structured questionnaires concerning patient characteristics and the opinions of hospital clinicians. Candidates for LT were defined in line with these opinions. RESULTS Four hundred and thirty-three patients, mostly affected by alcoholic cirrhosis, were included, 21.0% of whom were considered to be candidates for LT. Factors independently associated with their candidature were: physician empathy [odds ratio (OR) = 10.8; 95% CI: 4.0-29.5], adherence to treatment (OR = 16.6; 95% CI: 3.7-75.2), geographical area (OR = 6.8; 95% CI: 2.2-21.3) and the patient's physiological age (OR = 2.3; 95% CI: 1.1-4.7). CONCLUSIONS Several subjective markers restrict the referral of patients from local hospitals to liver transplant centres. Their advancement to this second step is thus markedly weakened by initial subjectivity. The development of objective guidelines for local hospital physicians to assist them with their initial decision-making on LT is now necessary.

Hepatitis C viral infection persists and becomes chronic in a majority of affected individuals. Numerous factors have been described to explain how the virus manages to escape the host immune system. One important escape mechanism is the increase in regulatory T cells induced by the virus. In this review, we will focus on the status of regulatory T cells throughout the natural history of hepatitis C infection and after liver transplantation. The molecular mechanisms involved in increasing the number of regulatory T cells are also discussed, as are data regarding the impact of regulatory T-cells on hepatic fibrosis in the context of hepatitis C viral infection.

Hepatitis E virus (HEV) can induce chronic infections in the case of immunosuppression, which are sometimes not cured with ribavirin. Furthermore, sofosbuvir is a highly potent inhibitor of HCV polymerase and was shown to inhibit HEV genotype-3 replication in vitro. We report here the outcome of sofosbuvir/ribavirin therapy on a chronic HEV infection in a heart transplant recipient non-responder to ribavirin. After 24 weeks, the regimen failed to cure the persistent HEV infection, highlighting the need of therapeutic options for HEV-infected immunosuppressed patients.

Background Liver transplantation (LT) remains the best curative option for early hepatocellular carcinoma (HCC) but is limited by the ongoing graft shortage. The present study aimed at defining the population in which primary liver resection (LR) could represent the best alternative to LT. Methods An exploration set of 357 HCC patients (LR n = 221 and LT n = 136) operated between 2000–2012 was used in order to identify factors associated with survival following LR and define a good prognosis (GP) group for which LR may challenge the results of upfront LT. These factors were validated in an external validation set of 565 HCC patients operated at another center (LR n = 287 LR and LT n = 278). Results In the exploration set, factors associated with survival on multivariate analysis were a solitary lesion, a diameter

Metabolic diseases that involve the liver represent a heterogeneous group of disorders. Apart from the metabolic defect, the subject's liver functions may be normal. With the increasing need for organs, livers from donors with metabolic diseases other than familial amyloid polyneuropathy might be possibly used for transplantation. However, whether such livers qualify as grafts and how they might impact recipient outcome are still unanswered questions. This review of the literature summarizes current experience in the use of such grafts in the context of cadaveric, domino, and living-related liver transplantation.

International audience; BACKGROUND & AIMS: Liver transplantation (LT) is the therapeutic option for severe complications of Wilson's disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS: The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS: Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS: Liver failure associated with WD is a rare indication for LT (\textless1%), which achieves an excellent long-term outcome, including renal function.

International audience; SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. −13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p 3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

An intent-to-treat analysis of overall survival (ITT-OS) of cirrhotic patients with hepatocellular carcinoma (HCC) listed for living donor liver transplantation (LDLT) or brain-dead donor liver transplantation (BDLT) across 5 French liver transplant (LT) centers.Comparisons of HCC outcomes after LDLT and BDLT measured from time of transplantation have yielded conflicting results.Records from 861 cirrhotic patients with HCC consecutively listed for either LDLT (n = 79) or BDLT (n = 782) from 2000 to 2009 were analyzed for ITT-OS using a Cox model; and tumor recurrence using 2 competitive risk models.Tumor staging was similar between groups. In total, 162 patients dropped out (20.7%), all from Group BDLT (P0.0001). The postoperative mortality rate and the retransplantation rate were similar between LDLT and BDLT. At 5 years, no statistically significant difference was found in ITT-OS between LDLT and BDLT groups (73.2% vs 66.7%; P = 0.062). LDLT waitlist inclusion (hazard ratio: 0.61 (0.39-0.96); P = 0.034) and a time-of-listing MELD score ≥ 25 (hazard ratio: 1.93 (1.15-3.26); P = 0.014) were independent predictors of ITT-OS. Similar 5-year post-LT OS rates (73.2% and 73.0% for Group LDLT and Group BDLT, respectively; P = 0.407) and HCC recurrence rates (10.9% and 11.2% for Group LDLT and Group BDLT, respectively; P = 0.753) were found. Upon explant analysis, tumors exceeding the Milan criteria, macroscopic vascular invasion, and AFP score2 were independent predictors of recurrence, whereas LT type was not.LDLT improves ITT-OS, and it is not a risk factor for tumor recurrence. Therefore, LDLT and BDLT should be equally encouraged in countries where both are available.

We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose-intensified mycophenolate mofetil (MMF) further adjusted individually.Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant.One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12-month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P0.001) in arm A.Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence.

Regulatory T cells (Treg) may play an important role in operational (clinical) tolerance (OT), a stable graft function without immunosuppression in an otherwise immunocompetent host, that is spontaneously observed in some patients many years after transplantation. Several ongoing clinical trials are currently testing the effects of donor-specific or non-specific Treg infusion with the goal to induce this state of OT a few months after liver transplantation (LT). The preliminary results of two of these trials have been recently published, and raise a number of comments and issues: (1) These two papers demonstrate that a 100 to 1000-fold ex-vivo expansion of Treg is possible in humans after 2 weeks of culture. The optimal human Treg dose is however not clearly established, and might be higher than the dose that would be expected from translating murine data. (2) A lot of concerns are remaining regarding the Treg purity before expansion, the Treg stability during in vitro culture and the in vivo fate of infused cells. A strict monitoring of Treg should thus be done at each step. (3) Since Treg may play a detrimental role in some conditions, such as viral diseases and cancer, potential LT recipients with such diseases should probably be excluded from the initial trials of Treg infusion. (4) The follow-up of tolerant liver recipients should include repeated liver biopsies and detection of autoantibodies and humoral response, in addition to conventional liver graft assessment, in order to prevent the development of immune complications related to immunosuppression withdrawal. (5) The final issue raised by Treg therapy in LT is the choice of the immunosuppressive regimen used before tapering or withdrawal, appropriate to preserve OT establishment.

Induction therapy is used relatively infrequently in liver transplantation, but developments in induction regimens and strategies for their use are prompting a re-examination of its benefits. Rabbit antithymocyte globulin (rATG) induces protracted, dose-dependent lymphocytopenia with preferential reconstitution of regulatory T-lymphocytes. Non-depleting interleukin-2 receptor antagonists (IL-2RA) act selectively on activated T-lymphocytes with a shorter duration of effect. IL-2RA induction with delayed and reduced calcineurin inhibitor (CNI) exposure appears to preserve efficacy, while more aggressive CNI minimisation has been attempted successfully using rATG. Steroid-free tacrolimus monotherapy with rATG or IL-2RA induction is effective if adequate tacrolimus exposure is maintained. Early concerns that addition of induction to a conventional maintenance regimen could lead to accelerated progression of hepatitis C disease, or to an increased risk of hepatocellular cancer recurrence, now appear unfounded using modern regimens. Similarly, with routine use of systemic prophylaxis, recent prospective and retrospective data have not shown a higher rate of infections overall, or cytomegalovirus infection specifically, using rATG or IL-2RA induction. Historical evidence that lymphocyte-depleting agents increased the risk of non-Hodgkin lymphoma has not been confirmed for rATG. Wider use of induction in liver transplantation is now merited, using individualized strategies to support reduced CNI exposure or steroid-free immunosuppression.

Split liver transplantation (SLT) using extended right grafts is associated with complications related to ischemia of hepatic segment 4 (S4), and these complications are associated with poor outcomes. We retrospectively analyzed 36 SLT recipients so that we could assess the association of radiological, biological, and clinical features with S4 ischemia. The overall survival rates were 84.2%, 84.2%, and 77.7% at 1, 3, and 5 years, respectively. The recipients were mostly male (24/36 or 67%) and had a median age of 52 years (range = 13-63 years), a median body mass index of 22.9 kg/m2 (range = 17.3-29.8 kg/m2), and a median graft-to-recipient weight ratio of 1.3% (range = 0.9%-1.9%). S4-related complications were diagnosed in 22% of the patients (8/36) with a median delay of 22 days (range = 10-30 days). Secondary arterial complications were seen in 3 of these patients and led to significantly decreased graft survival in comparison with the graft survival of patients without complications (50.0% versus 85.6%, P = 0.017). Patients developing S4-related complications had significantly elevated aspartate aminotransferase (AST) levels (>1000 IU/L) on postoperative day (POD) 1 and elevated gamma-glutamyl transpeptidase (GGT) levels (>300 IU/L) on PODs 7 and 10 (P < 0.05). These AST and GGT elevations conferred a significantly high risk of developing these complications (odds ratio = 42, 95% confidence interval = 4-475, P < 0.05). The ischemic volume of S4 was extremely variable (0%-95%) and did not correlate with S4-related complications. In conclusion, our results suggest that S4-related complications are risk factors for worse graft survival, and the development of these complications can be anticipated by the early identification of a specific biological profile and a routine radiological examination. Liver Transpl 18:413–422, 2012. © 2011 AASLD.

Data on the conversion of patients to everolimus after liver transplantation are sparse. A multicenter, retrospective study followed 240 maintenance liver transplant patients to analyze the current indications for everolimus conversion, the employed regimens and exposure levels, and the impact on efficacy and safety. The mean time from transplantation to the introduction of everolimus was 4.9 ± 5.2 years. The mean everolimus trough level was 7.3 ± 4.1 ng/mL at month 1 and 8.1 ± 4.7 ng/mL at month 12. At 12 months, 61.6% of the patients were no longer receiving calcineurin inhibitor (CNI) therapy. The mean estimated glomerular filtration rate (eGFR) according to the Cockcroft-Gault formula was 64.2 ± 30.0 mL/minute on day 0 and 68.4 ± 32.5 mL/minute at month 12 (P = 0.007). Among patients with baseline serum creatinine levels ≥ 130 μmol/L, the eGFR values were 44.3 ± 15.7 mL/minute on day 0 and 53.7 ± 26.0 mL/minute at month 12 (P = 0.003). Four patients (1.6%) developed mild or moderate biopsy-proven acute rejection. Adverse events led to everolimus discontinuation in 12.9% of the patients. After the initiation of everolimus, the mean white blood cell count decreased significantly, and the total cholesterol and triglyceride levels increased significantly. In this retrospective analysis of the largest cohort of maintenance liver transplant patients analyzed after their conversion to everolimus, more than 60% of the patients were kept free of CNIs with a very low risk of acute rejection and with an acceptable safety profile. Randomized trials in which maintenance liver transplant patients are switched to everolimus in response to clinical indications or preemptively are warranted. Liver Transpl 17:905–913, 2011. © 2011 AASLD.

AIM: To generate a new score with improved accuracy compared with Milan criteria to select patients. PATIENTS: The training cohort comprised 373 patients transplanted for hepatocellular carcinoma (HCC) between 1988 and 1998 (cohort 1). An algorithm was derived from the analysis of patient data by the proportional hazard Cox regression model. The area under the receiver operating characteristic (AUROC) was used to determine a cut-off value. The validation cohort comprised 140 patients transplanted between 1999 and 2001 (cohort 2). RESULTS: Multivariate analysis identified three predictors of 5-year tumour-free survival: tumour differentiation (P=0.02), diameter (P

At present, no method is available for accurately monitoring the degree of immunosuppression induced by antirejection therapies. The aim of this study was to determine whether CD28 and CD38 expression by peripheral blood mononuclear cells could be useful in predicting the development of de novo malignancies after liver transplantation. Flow cytometry analysis was used to measure the expression of CD28 and CD38 by peripheral blood lymphocytes in 134 stable, long-term survivors of liver transplantation. Patients who developed a de novo malignancy after undergoing a medical checkup were entered into a cancer group. Twenty-two patients (16.4%) developed at least 1 de novo malignancy over a mean interval of 22 ± 14 months (1.2-49.4 months) after the checkup. The mean frequency of CD28+CD8+ cells was significantly lower in the cancer group versus the noncancer group (39% ± 22 versus 51% ± 21, P = 0.008), but CD38 expression was similar in the 2 groups. Multivariate analysis indicated that an age greater than 50 years (odds ratio = 5.81) and a low frequency of CD28+CD8+ cells at the time of the checkup (odds ratio =3.16) were the only significant predictors of the development of de novo malignancies (P = 0.027). The actuarial proportion of patients with de novo malignancies was significantly lower when the frequency of CD28+CD8+ cells was greater than or equal to 40% instead of less than 40% (P = 0.01). Flow cytometry measurements of CD28 expression by peripheral blood lymphocytes may facilitate the identification of patients at a high risk of developing de novo malignancies. Further prospective studies are necessary to determine whether such measurements could have a place in routine clinical practice to enable the intensity of immunosuppression to be minimized in patients who have an increased risk of developing cancer. Liver Transpl, 2011. © 2011 AASLD.

La Presse Medicale - In Press.Proof corrected by the author Available online since samedi 31 mai 2014

Background Management of anastomotic biliary strictures after liver transplantation deserves optimization. Objective To evaluate placement and removal of partially covered self-expandable metal stents (PCSEMSs) in this setting. Design Prospective, multicenter, uncontrolled study. Setting Three French academic hospitals with liver transplantation units and tertiary referral endoscopy centers. Patients Twenty-two patients (18 men, 4 women, aged 49.7 ± 12 years) with anastomotic biliary stricture. Seventeen (77.3%) presented stricture recurrence after plastic stenting. Interventions PCSEMSs were placed across the stricture for 2 months and then removed. Patients were followed by clinical examination and liver function tests 1, 3, 6, 9, and 12 months after PCSEMS removal. Main Outcome Measurement The ability to remove PCSEMS. Results PCSEMS placement was successful in all patients, after sphincterotomy in 21 patients. Stent-related complications included minor pancreatitis (3 patients), transient pain (1 patient), and cholangitis (1 patient). Stent removal was achieved in all patients but 2 whose stents had migrated distally. Partial stent dislocation was noted in 5 patients (upward in 4, downward in 1). Complications associated with stent removal were minor, including self-contained hemorrhage (1 patient) and fever (1 patient). The stricture persisted at the end of treatment in 3 patients (13.6%), all of whom had stent migration or dislocation. Recurrence of anastomotic stricture after initial success occurred in 9 of 19 patients (47.4%) within 3.5 ± 2.1 months. Sustained stricture resolution was observed in 10 of 19 patients (52.6%), 45.6% from an intent-to-treat perspective. Limitations Uncontrolled study with limited follow-up. Conclusions Temporary placement and removal of PCSEMSs in anastomotic biliary strictures after liver transplantation is feasible, although sometimes demanding. Stent migration may impair final outcome.

Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection.This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months.The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (or=100micromol/L or100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time.Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.