Evaluation of a delayed liver transplantation strategy for patients with HCC receiving bridging therapy: the DELTA-HCC study.

INTRODUCTION: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015 in patients listed for any single HCC treated with resection or thermal-ablation during waiting phase, postponing LT until recurrence. The purpose of this study was to evaluate DS to make sure that it did not hamper pre and post-LT outcomes in DS patients. PATIENTS AND METHODS: Patients listed for HCC in France between 2015 and 2018 were studied. After data extraction from the national LT database, 2,025 patients were identified and classified according to 6 groups: single tumor entering DS, single tumor not entering DS, multiple tumors, no curative treatment, untreatable HCC or T1 tumors. 18-months Kaplan-Meier estimates of drop-out for death, too sick to be transplanted or tumor progression before LT, 5-year post-LT HCC recurrence and post LT-survival rates were compared. RESULTS: Median waiting-time in DS group was 910 days. Pre-LT drop-out probability was significantly lower in DS compare to other groups (13% vs 19%, p=0.0043) and significantly higher in the T1 group (25.4%, p=0.05). Post-LT HCC-recurrence rate in multiples nodules group was significantly higher (19.6%, p= 0.019) and post-LT 5-year survival did not differ among groups with 74% in DS group (p=0.22). CONCLUSION: The DELTA HCC study shows that DS does not negatively impact neither pre- nor post-LT patients 'outcomes, and has the potential to redistribute organs to patients in more urgent need of LT. It can reasonably be proposed and pursued. The unexpected high risk of drop out in T1 patients seems related to the MELD-based driving rules underserving this subgroup, calling for revision of allocation rules. IMPACTS AND IMPLICATIONS: To maximize utility and prevent premature liver transplantation (LT), a delayed LT strategy (DS) was adopted in France in 2015. It consists in postponing LT until recurrence in patients listed for any single HCC curatively treated by surgical resection or thermal ablation. The DELTA HCC study was conducted to evaluate this nationwide strategy. It shows in a non-US, European LT program that DS:- does not negatively impact pre- nor post-LT patients 'outcome,- concerns up to 20% of LT candidates-has therefore the potential to redistribute organs to patients in more urgent need of LT. Such a delayed strategy can reasonably be pursued and extended to other LT programs. Of note, an unexpected high risk of drop out in T1 patients, seemingly related to MELD-based offering rules which underserve these patients, calls for further scrutinization and revision of allocation rules in this subgroup.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplantant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

The liver in sickle cell disease.

Liver involvement in SCD patients is frequent but often misdiagnosed or underestimated, except in case of advanced liver diseases. Because of so far poorly recognized forms of chronic SCD-related vascular injury that can silently evolved towards end stages or facilitate ACLF, any persisting liver function tests abnormalities should be carefully investigated, following the above proposed algorithm. Work up and management must be considered multidisciplinary in relationship with a Hepatologist. Early SCD hepatopathy should prompt revision of SCD management to prevent further liver injury and decompensation, discussing transfusion exchanges and hydro urea when not yet initiated, and control for any cofactor of liver injury. The role of HSCT in early SCD hepatopathies also deserves evaluation. In advanced SCD hepatopathies, liver transplantation, which has been rarely performed so far, is the only therapeutic option associated with improved survival. It should definitely be discussed- either electively in case of decompensation in SCD cirrhosis or jaundice/recurrent cholangitis in cholestatic diseases, with excellent outcome, - or emergently in case of ALF or ACLF with more mitigate results. To improve knowledge and management of SCD liver diseases, creation of national and international registries, as well as longitudinal observational cohorts are encouraged.

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.

Artificial Intelligence and liver: Opportunities and barriers.

Artificial Intelligence (AI) has recently been shown as an excellent tool for the study of the liver; however, many obstacles still have to be overcome for the digitalization of real-world hepatology. The authors present an overview of the current state of the art on the use of innovative technologies in different areas (big data, translational hepatology, imaging, and transplant setting). In clinical practice, physicians must integrate a vast array of data modalities (medical history, clinical data, laboratory tests, imaging, and pathology slides) to achieve a diagnostic or therapeutic decision. Unfortunately, machine learning and deep learning are still far from really supporting clinicians in real life. In fact, the accuracy of any technological support has no value in medicine without the support of clinicians. To make better use of new technologies, it is essential to improve clinicians' knowledge about them. To this end, the authors propose that collaborative networks for multidisciplinary approaches will improve the rapid implementation of AI systems for developing disease-customized AI-powered clinical decision support tools. The authors also discuss ethical, educational, and legal challenges that must be overcome to build robust bridges and deploy potentially effective AI in real-world clinical settings.

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.

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.

Impact of direct antiviral agents for hepatitis C virus -induced liver diseases on registration, waiting list and liver transplant activity in France.

Direct-acting antivirals (DAA) has dramatically improved the prognosis of liver transplantation (LT) candidates for HCV end-stage liver disease (ESLD). We aimed to evaluate the impact of DAA on waiting list (WL) registration and LT activity in France. We evaluated all patients registered to the French WL for HCV ESLD between 2000 and 2018. Timespan was divided into two periods according to DAA availability: 2010-2013 versus 2014-2018. Changes in the indications of LT, outcome on WL were evaluated. Then, we evaluated the activity of LT and outcome for HCV recipients in France. Among 3,173 HCV candidates, registration on WL decreased by 33% between 2013 and 2018. The 1-year waitlist survival increased from 76.9% (95%CI: 74.2%-79.4%) in 2010-2013 to 79.8% (95%CI: 77.2%-82.1%) in 2014-2018 (p < 0.01). Regarding LT activity, the part of HCV ESLD decreased from 26% in 2010 to 16% in 2018. The 1-year graft survival rate in HCV recipients increased from 76.9% (95%CI: 73.7%-79.7%) in 2010-2012 to 84.9% (95%CI: 82.9%-86.7%) in 2013-2018 (p < 0.01). The availability of DAA to treat HCV infection is associated with a significant decrease of registration for LT, death and drop out for worsening condition on the LT. In addition, it has decreased the number of HCV+ LT and improved the 1-year graft survival in France.

Bariatric surgery and liver transplantation, here we are now: A French nationwide retrospective study.

At the time of the growing obesity epidemic worldwide, liver transplantation (LT) and metabolic syndrome are closely linked: non-alcohol-related fatty liver disease (NAFLD) is one of the leading indications for liver transplantation, and metabolic syndrome can also appear after liver transplantation, in relation to immunosuppressive medications and weight gain, whatever was the initial liver disease leading to the indication of LT. Therefore, the role of bariatric surgery (BS) is important due to its longer-lasting effect and efficacy. We performed a retrospective review of all 50 adult French liver transplant recipients who had a history of bariatric surgery, including 37 procedures before transplantation, and 14 after. There were three significantly different characteristics when comparing pre-and post-LT BS: patients were older (at the time of BS), presented more frequently arterial hypertension (at the time of LT), and the proportion of NAFLD as initial liver disease leading to LT was lower, in the post-LT group. Regarding pre-LT BS, in one case BS was complicated by liver failure leading to the rapid indication of LT; it was the single patient for whom the delay between BS and LT was less than 1 year; there was no patient who specifically underwent BS for the purpose of LT listing.

Economic Impact of European Liver and Intestine Transplantation Association (ELITA) Recommendations for Hepatitis B Prophylaxis After Liver Transplantation.

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.

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.

Long-Term Results of Endoscopic Metal Stenting for Biliary Anastomotic Stricture after Liver Transplantation.

(1) Background: Anastomotic biliary stricture (ABS) is a well-known complication of liver transplantation which can lead to secondary biliary cirrhosis and graft dysfunction. The goal of this study was to evaluate the long-term outcomes of endoscopic metal stenting of ABS in the setting of deceased donor liver transplantation (DDLT). (2) Methods: Consecutive DDLT patients with endoscopic metal stenting for ABS between 2010 and 2015 were screened. Data on diagnosis, treatment and follow-up (until June 2022) were collected. The primary outcome was endoscopic treatment failure defined as the need for surgical refection. (3) Results: Among the 465 patients who underwent LT, 41 developed ABS. It was diagnosed after a mean period of 7.4 months (+/-10.6) following LT. Endoscopic treatment was technically successful in 95.1% of cases. The mean duration of endoscopic treatment was 12.8 months (+/-9.1) and 53.7% of patients completed a 1-year treatment. After a mean follow-up of 6.9 years (+/-2.3), endoscopic treatment failed in nine patients (22%) who required surgical refection. Conclusions: Endoscopic management with metal stenting of ABS after DDLT was technically successful in most cases, and half of the patients had at least one year of indwelling stent. Endoscopic treatment long-term failure rate occurred in one fifth of the patients.

Inevitability of disease recurrence after liver transplantation for NAFLD cirrhosis.

Background & Aims: Liver transplantation (LT) is the only available treatment for end-stage non-alcoholic fatty liver disease (NAFLD) (related decompensated cirrhosis and/or hepatocellular carcinoma). The aim of our study was to evaluate the risk of disease recurrence after LT and the factors influencing it. Method: This retrospective multicenter study included adults transplanted for NAFLD cirrhosis between 2000 and 2019 in 20 participating French-speaking centers. Disease recurrence (steatosis, steatohepatitis and fibrosis) was diagnosed from liver graft biopsies. Results: We analyzed 150 patients with at least one graft liver biopsy available ≥6 months after transplantation, among 361 patients transplanted for NAFLD. The median (IQR) age at LT was 61.3 (54.4-64.6) years. The median follow-up after LT was 4.7 (2.8-8.1) years. The cumulative recurrence rates of steatosis and steatohepatitis at 5 years were 80.0% and 60.3%, respectively. Significant risk factors for steatohepatitis recurrence in multivariate analysis were recipient age at LT <65 years (odds ratio [OR] 4.214; p = 0.044), high-density lipoprotein-cholesterol <1.15 mmol/L after LT (OR 3.463; p = 0.013) and grade ≥2 steatosis on the graft at 1 year after LT (OR 10.196; p = 0.001). The cumulative incidence of advanced fibrosis (F3-F4) was 20.0% at 5 years after LT and significant risk factors from multivariate analysis were metabolic syndrome before LT (OR 8.550; p = 0.038), long-term use of cyclosporine (OR 11.388; p = 0.031) and grade ≥2 steatosis at 1 year after LT (OR 10.720; p = 0.049). No re-LT was performed for NAFLD cirrhosis recurrence. Conclusion: Our results strongly suggest that recurrence of initial disease after LT for NAFLD is inevitable and progressive in a large proportion of patients; the means to prevent it remain to be further evaluated. Impact and implications: Non-alcoholic fatty liver disease (NAFLD) is a growing indication for liver transplantation, but the analysis of disease recurrence, based on graft liver biopsies, has been poorly studied. Cumulative incidences of steatosis, steatohepatitis and NAFLD-related significant fibrosis recurrence at 5 years were 85.0%, 60.3% and 48.0%, respectively. Grade ≥2 steatosis on graft biopsy at 1 year (present in 25% of patients) is highly predictive of recurrence of steatohepatitis and advanced fibrosis: bariatric surgery should be discussed in these patients specifically.

Diagnosis and management of hepatic encephalopathy: The French recommendations.

Hepatic encephalopathy (HE) is a frequent and severe complication of liver disease with poor patient outcomes. However, it is a poorly understood complication, with no consensus for diagnosis. Therefore, HE is often underdiagnosed. Differential diagnosis may be cumbersome because of non-specific symptoms, such as confusion, cognitive disorders, the aetiological factors of cirrhosis and comorbidities, which are often observed in cirrhotic patients. Therefore, an overt or covert form of HE should be systematically investigated. Advice is provided to drive patient work-up. Effective treatments are available to prevent or treat HE bouts, but the issue of single or combination therapy has not been resolved. Transjugular intrahepatic portosystemic shunt (TIPS) placement largely improved the prognosis of cirrhotic patients, but HE occurrence of HE is often a fear, even when post-TIPS HE can be avoided by a careful selection of patients and preventive treatment. HE is an indication of liver transplantation. However, its reversibility post-transplantation and the consequences of transplantation in patients with other causes of neurological disorders remain controversial, which supports the performance of an extensive work-up in expert centres for this subset of patients. The present guidelines assist clinicians in the diagnosis of the overt or covert form of HE to implement curative and preventive treatments and clarify which patients require referral to expert centres for consideration for liver transplantation. These guidelines are very clinically oriented and address different frequent clinical issues to help physicians make bedside decisions.

AFP score and metroticket 2.0 perform similarly and could be used in a "within-ALL" clinical decision tool.

Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model's original thresholds. Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell's adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model's original thresholds. Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p <0.0001). At last tumor reassessment before LT, c-statistics did not significantly differ between the two composite models, either as original or threshold versions, for recurrence (0.72 vs. 0.68; p = 0.06), HCC survival, and overall survival after LT. We observed predictive gaps and overlaps between the model's thresholds, and no significant gain on reclassification. Patients meeting both models ("within-ALL") at last tumor reassessment presented the lowest 5-year cumulative incidence of HCC recurrence (7.7%; 95% CI 5.1-11.5) and higher 5-year post-LT survival (70.0%; 95% CI 64.9-74.6). Conclusions: In this multicenter cohort, Metroticket 2.0 and the AFP score demonstrated a similar ability to predict HCC recurrence post-LT. The combination of these composite models might be a promising clinical approach. Impact and implications: Composite models were recently proposed for the selection of liver transplant (LT) candidates among individuals with hepatocellular carcinoma (HCC). We found that both the AFP score and Metroticket 2.0 predicted post-LT HCC recurrence and survival better than Milan criteria; the Metroticket 2.0 did not result in better reclassification for transplant selection compared to the AFP score, with predictive gaps and overlaps between the two models; patients who met low-risk thresholds for both models had the lowest 5-year recurrence rate. We propose prospectively testing the combination of both models, to further optimize the LT selection process for candidates with HCC.

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.

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.

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 resection for single large hepatocellular carcinoma: a prognostic factors study.

INTRODUCTION AND OBJECTIVES: Liver resection is the only curative therapeutic option for large hepatocellular carcinoma (> 5 cm), but survival is worse than in smaller tumours, mostly due to the high recurrence rate. There is currently no proper tool for stratifying relapse risk. Herein, we investigated prognostic factors before hepatectomy in patients with a single large hepatocellular carcinoma (HCC). MATERIAL AND METHODS: We retrospectively identified 119 patients who underwent liver resection for a single large HCC in 2 tertiary academic French centres and collected pre- and post-operative clinical, biological and radiological features. The primary outcome was overall survival at five years. Secondary outcomes were recurrence-free survival at five years and prognostic factors for recurrence. RESULTS: A total of 84% of the patients were male, and the median age was 66 years old (IQR 58-74). Thirty-nine (33%) had Child-Pugh A cirrhosis, and the mean Model for End-Stage Liver Disease (MELD) score was 6 (6-6). The aetiology of liver disease was predominantly alcohol-related (48%), followed by nonalcoholic steatohepatitis (22%), hepatitis B (18%) and hepatitis C (10%). The mean tumour size was 70 mm (55-110). The median overall survival was 72.5 months (IC 95%: 56.2-88.7), and the five-year overall survival was 55.1 ± 5.5%. The median recurrence-free survival was 26.6 months (95% CI: 16.0-37.1), and the five-year recurrence-free survival rate was 37.8 ± 5%. In multivariate analysis, preoperative prognostic factors for recurrence were baseline alpha-fetoprotein (AFP) > 7 ng/mL (p<0.001), portal veinous invasion (p=0.003) and cirrhosis (p=0.020). Using these factors, we created a simple recurrence-risk scoring system that classified three groups with distinct disease-free survival medians (p<0.001): no risk factors (65 months), 1 risk factor (36 months), and ≥2 risk factors (8.9 months). CONCLUSION: Liver resection is the only curative option for large HCC, and we confirmed that survival could be acceptable in experienced centres. Recurrence is the primary issue of surgery, and we proposed a simple preoperative score to help identify patients with the most worrisome prognosis and possible candidates for combined therapy.