Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19.

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

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.

Integrating an addiction team into the management of patients transplanted for alcohol-associated liver disease reduces the risk of severe relapse.

Background & Aims: Liver transplantation (LT) is a last resort treatment for patients at high risk of mortality from end-stage liver disease. Over the past years, alcohol-associated liver disease has become the most frequent indication for LT in the world. The outcomes of LT for alcohol-associated liver disease are good, but return to alcohol use is detrimental for medium-term survival because of cancer development, cardiovascular events, and recurrent alcohol-associated cirrhosis. Several strategies have been developed to prevent return to alcohol use during the pre- or post-LT period, but there are no specific recommendations. Therefore, the main objective of this study was to investigate if the integration of an addiction team in a LT unit affected the rate of severe alcohol relapse after LT. The secondary objectives were to assess the effects of addiction follow up on cardiovascular events, cancer, and overall survival. Methods: This study was a retrospective comparison between centres with or without addiction monitoring. Results: The study included 611 patients of which 79.4% were male with a mean age of 55.4 years at the time of LT, 190 were managed by an integrated addiction team. The overall alcohol relapse rate was 28.9% and the rate of severe relapse was 13.0%. Patients with addiction follow-up had significantly less frequent severe alcohol relapse than those in the control group (p = 0.0218). Addiction follow up (odds ratio = 0.19; p = 0.001) and age at LT (odds ratio = 1.23; p = 0.02) remained significantly associated with post-LT cardiovascular events. Conclusions: Our study confirms the benefits of integrating an addiction team to reduce return to alcohol use after LT. Clinical Trials registration: This study is registered at ClinicalTrials.gov (NCT04964687). Impact and implications: The main indication for liver transplantation is alcohol-associated cirrhosis. There are currently no specific recommendations on the addiction monitoring of transplant candidates, although severe return to alcohol use after liver transplantation has a negative impact on long-term survival of patients. In this study, we explored the impact of a systematic addiction intervention on the return to alcohol use rates. In our transplantation centre, we demonstrated the interest of an addiction follow up to limit the severe alcohol relapses rate. This information should be further investigated in prospective studies to validate these data.

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.

Risk of infection in elderly patients with inflammatory bowel disease under biologics: A prospective, multicenter, observational, one-year follow-up comparative study.

OBJECTIVES: The emergence of biologics has improved the course of inflammatory bowel diseases (IBD) in the elderly population despite a potential higher risk of infections. We conducted a one-year, prospective, multicenter, observational study to determine the frequency of occurrence of at least one infectious event in elderly IBD patients under anti-TNF therapy compared with that in elderly patients under vedolizumab or ustekinumab therapies. METHODS: All IBD patients over 65 years exposed to anti-TNF, vedolizumab or ustekinumab therapies were included. The primary endpoint was the prevalence of at least one infection during the whole one year follow-up. RESULTS: Among the 207 consecutive elderly IBD patients prospectively enrolled, 113 were treated with anti-TNF and 94 with vedolizumab (n=63) or ustekinumab (n=31) (median age 71 years, 112 Crohn's disease). The Charlson index was similar between patients under anti-TNF and those under vedolizumab or ustekinumab as well as the proportion of patients under combination therapy and under concomitant steroid therapy did not differ between both both groups. The prevalence of infections was similar in patients under anti-TNF and in those under vedolizumab or ustekinumab (29% versus 28%, respectively; p=0.81). There was no difference in terms of type and severity of infection and of infection-related hospitalization rate. In multivariate regression analysis, only the Charlson comorbidity index (≥ 1) was identified as a significant and independent risk factor of infection (p=0.03). CONCLUSION: Around 30 % of elderly patients with IBD under biologics experienced at least one infection during the one-year study follow-up period. The risk of occurrence of infection does not differ between anti-TNF and vedolizumab or ustekinumab therapies, and only the associated comorbidity was linked with the risk of infection.

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.

Mycophenolate mofetil decreases humoral responses to three doses of SARS-CoV-2 vaccine in liver transplant recipients.

BACKGROUND AND AIMS: After 2 doses, the efficacy of anti-SARS-CoV-2 vaccination seems to be lower in solid organ transplant recipients than in the immunocompetent population. The objective of this study was to determine the humoral response rate after vaccination, including with a booster dose, and to identify risk factors for non-responsiveness in liver transplant recipients. METHODS: We included all patients seen in consultation in two French liver transplant centres between January 1, 2021, and March 15, 2021. RESULTS: 598 liver transplant recipients were enrolled and 327 were included for analysis. Sixteen patients received one dose, 63 patients two doses and 248 patients three doses. Anti-SARS-Cov-2 antibodies were detected in 242 out of 327 (74.0%) liver transplant patients after vaccination. Considering an optimal serologic response defined as an antibody titre >260 BAU/ml, 172 patients (52.6%) were responders. Mycophenolate mofetil (MMF) treatment was an independent risk factor for a failure to develop anti-SARS-CoV-2 antibodies after vaccination (OR 0.458; 95%CI 0.258-0.813; p = .008). Conversely, male gender (OR 2.247, 95%CI 1.194-4.227; p = .012) and receiving an mRNA vaccine (vs a non-mRNA vaccine) (OR 4.107, 95%CI 1.145-14.731; p = .030) were independent predictive factors for developing an optimal humoral response after vaccination. None of the patients who received the vaccine experienced any serious adverse events. CONCLUSIONS: Even after a third booster dose, response rate to vaccination is decreased in liver transplant recipients. MMF appears to be a major determinant of seroconversion and optimal response to vaccination in these patients.

Impact of calcineurin inhibitor-free immunosuppression on de novo donor-specific antibody formation in liver transplant recipients.

BACKGROUND & AIMS: Low calcineurin inhibitor (CNI) levels expose liver transplant recipients to rejection episodes and potentially to antibody-mediated rejection. There are little data on the impact of CNI-free immunosuppression on de novo donor-specific HLA antibody (dnDSA) development. Here we evaluated the prevalence of dnDSA in liver transplant recipients on CNI-free maintenance regimens and their associations with histopathological abnormalities of allografts. METHODS: Seven hundred and twenty-seven liver transplant recipients underwent a first liver transplant between 2000 and 2018 in three French transplant centres and had protocolized follow-up with dnDSA screening and allograft biopsy 1, 5 and 10 years after transplantation. RESULTS: CNIs were withdrawn in 166 (22.8%) patients with or without conversion to mammalian target of rapamycin inhibitors and/or maintenance with mycophenolic acid. DSA were present after withdrawal in 30.1% (50/166) patients on CNI-free immunosuppression compared with 16% (90/561) on CNI maintenance therapy (p < 0.001). The cumulative incidence of dnDSA 10 years after transplant was 20% in the CNI group versus 28% in the CNI-free group (p < 0.01). dnDSAs were associated with histological graft abnormalities (significant allograft fibrosis or rejection) (HR 2.24, 95% CI 1.2-4.1; p = 0.01). In univariate Cox regression analysis, being on a CNI-free regimen did not impact graft histology. CONCLUSIONS: Patients on a CNI-free IS regimen have a higher prevalence of dnDSA than patients on a standard IS regimen. dnDSAs but not CNI-free immunosuppression were associated with abnormal allograft histology.

Programmable receptors enable bacterial biosensors to detect pathological biomarkers in clinical samples.

Bacterial biosensors, or bactosensors, are promising agents for medical and environmental diagnostics. However, the lack of scalable frameworks to systematically program ligand detection limits their applications. Here we show how novel, clinically relevant sensing modalities can be introduced into bactosensors in a modular fashion. To do so, we have leveraged a synthetic receptor platform, termed EMeRALD (Engineered Modularized Receptors Activated via Ligand-induced Dimerization) which supports the modular assembly of sensing modules onto a high-performance, generic signaling scaffold controlling gene expression in E. coli. We apply EMeRALD to detect bile salts, a biomarker of liver dysfunction, by repurposing sensing modules from enteropathogenic Vibrio species. We improve the sensitivity and lower the limit-of-detection of the sensing module by directed evolution. We then engineer a colorimetric bactosensor detecting pathological bile salt levels in serum from patients having undergone liver transplant, providing an output detectable by the naked-eye. The EMeRALD technology enables functional exploration of natural sensing modules and rapid engineering of synthetic receptors for diagnostics, environmental monitoring, and control of therapeutic microbes.

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS).

BACKGROUND & AIMS: Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe. METHODS: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019. RESULTS: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p <0.0001). The 1-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3. CONCLUSION: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes.

Alcohol Consumption the Day of Liver Transplantation for Alcohol-Associated Liver Disease Does Not Affect Long-Term Survival: A Case-Control Study.

Alcohol abstinence before liver transplantation (LT) for alcohol-associated liver disease (ALD) is required for every candidate. Some listed patients might relapse, resulting in LT for patients nonabstinent during the pretransplant period. Long-term survival outcomes of these patients have never been studied. We sought to determine whether alcohol consumption on the day of the LT influenced long-term survival after LT. We conducted a retrospective case-control study among French LT centers. Cases were defined as recipients between January 1995 and December 2007 having positive blood and/or urine alcohol levels the day of LT. Each case was paired with 2 controls corresponding to patients transplanted for ALD during the same trimester. Patients were classified into 3 categories per alcohol consumption: abstainers, occasional or transitory excessive consumers, or patients with a sustained excessive consumption (daily consumption >20-30 g/day). During the study period, 3052 LTs for ALD were conducted in France. We identified 42 cases paired with 84 controls. Median blood alcohol level was 0.4 g/L (range 0.1-4.1 g/L) and median urine alcohol level was 0.2 g/L (range 0.1-2.0 g/L). Median follow-up period until death or censoring was 12.9 years (CI95% = [12.3; 13.6]). Long-term survival was not different between the groups. Relapse to any alcohol consumption rate was higher in the case group (59.5%) than in the control group (38.1%, odds ratio 2.44; CI95% = [1.13; 5.27]), but sustained excessive consumption was not significantly different between the groups (33.3% versus 29.8% in case and control groups respectively, χ2  = 0.68). Rates of recurrent cirrhosis and cirrhosis-related deaths were more frequent in the case group. Liver transplantation for nonabstinent patients during the immediate pretransplant period does not result in impaired long-term survival despite higher relapse and recurrent cirrhosis rates.

Abnormal liver tests in patients hospitalized with Coronavirus disease 2019: Should we worry?

While several studies from China have reported COVID-19-related liver injury, there are currently no data on liver dysfunction in hospitalized COVID-19 patients in Europe. The aim of this study was to describe the prevalence and predictive value of abnormal liver function in patients hospitalized with COVID-19. This was a retrospective cohort study of confirmed COVID-19 patients hospitalized in two referral hospitals in France. Clinical, biological and radiological data were collected and analysed. In all, 234 patients confirmed to have COVID-19 by RT-PCR were included. Liver function was abnormal in 66.6% of patients on admission. In multivariate logistic regression, abnormal liver test on admission were associated with in-hospital aggravation (OR = 4.1, 95% CI 1.5-10.8; P = .004) and mortality (OR 3.3; 95% CI = 1.04-10.5; P = .04). This study of liver tests in a European COVID-19 population confirms a high prevalence of abnormal liver tests on admission that are predictive of severe disease course and higher in-hospital mortality.

Predictive value of HLAMatchmaker and PIRCHE-II scores for de novo donor-specific antibody formation after adult and pediatric liver transplantation.

Production of de novo DSA (dnDSA) is associated with an increased risk of antibody mediated rejection after liver transplantation. Antibodies not only recognize the entire antigen but are able to bind specific functional epitopes present on the HLA molecule surface. The HLAMatchmaker and the PIRCHE-II (predicted indirectly recognizable HLA epitopes) algorithms are able to determine predictive epitope mismatches scores and de novo DSA (dnDSA) synthesis based on alloreactive eplets' identification. The aim of the present study was to assess, for the first time in liver transplantation, the complementarity between these two algorithms. We retrospectively analyzed a cohort of 407 adult and 133 pediatric liver transplant patients without preformed DSA, transplanted between 1991 and 2019 in Lyon and Montpellier. HLA antibodies were detected by single antigen bead assay. HLA typing of the donor-recipient pair was achieved by serological and/or DNA-based techniques. PIRCHE-II and HLAMatchmaker algorithms were then applied on both groups. During follow-up, 27.3% of adults and 38.3% of children developed dnDSA. HLA-DRB1 and DQB1-PIRCHE-II and HLAMatchmaker scores were significantly higher in dnDSA group compared to no DSA group for both pediatric and adult patients (except for PIRCHE-II HLA-DRB1 locus score in pediatrics). ROC curves allowed determining score thresholds classifying patients in low- and high-risk of dnDSA synthesis. The two algorithms' Kaplan-Meier curves showed a predicted incidence of dnDSA 20 years after transplantation significantly lower in the low-risk group compare with the high-risk group (log rank <0.05), in both cohorts, with a good negative predictive value. In conclusion, HLAMatchmaker and PIRCHE-II algorithms both are effective tools to identify anti-HLA immunization risk and to predict dnDSA formation after liver transplantation.