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Data comparing long‐term effectiveness and safety of once‐daily tacrolimus formulations in de novo liver transplantation are scarce. We compared the effectiveness, pharmacokinetic profile, and safety of LCPT (Envarsus) and PR‐Tac (Advagraf) for up to 12 months post‐transplant. Adult de novo liver transplant recipients who started IR‐Tac (Prograf) and were converted to LCPT or PR‐Tac 3–5 days post‐transplant were included. Data from 163 patients were analyzed, 87 treated with LCPT and 76 with PR‐Tac. The incidence of treatment failure was 30.5% in the LCPT group versus 23.0% in the PR‐Tac group (p =.291). Biopsy‐proven acute rejection (BPAR) was reported in 26.8% of patients in the LCPT group and 17.6% in the PR‐Tac group (p =.166). Graft loss was experienced in one patient (1.2%) in the LCPT group and three patients (4.1%) in the PR‐Tac group (p =.346). Death was registered in three patients (3.7%) in the LCPT group and three patients (4.1%) in the PR‐Tac group (p >.999). Patients in the LCPT group showed 45.7% higher relative bioavailability (Cmin/total daily dose [TDD]; p <.01) with similar Cmin and 33.3% lower TDD versus PR‐Tac (p <.01). The evolution of renal function, safety profile, and the incidence of post‐transplant renal failure, dyslipidemia, obesity, hypertension, and diabetes mellitus were similar in patients treated with LCPT and PR‐Tac. In de novo liver transplant patients, LCPT and PR‐Tac showed comparable effectiveness with higher relative bioavailability, similar Cmin and lower TDD in the LCPT group. Renal function, safety, and post‐transplant complications were comparable in LCPT and PR‐Tac groups. [ABSTRACT FROM AUTHOR]

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Clinical management of transplant patients abruptly changed during the first months of COVID-19 pandemic (March to May 2020). The new situation led to very significant challenges, such as new forms of relationship between healthcare providers and patients and other professionals, design of protocols to prevent disease transmission and treatment of infected patients, management of waiting lists and of transplant programs during state/city lockdown, relevant reduction of medical training and educational activities, halt or delays of ongoing research, etc. The two main objectives of the current report are: 1) to promote a project of best practices in transplantation taking advantage of the knowledge and experience acquired by professionals during the evolving situation of the COVID-19 pandemic, both in performing their usual care activity, as well as in the adjustments taken to adapt to the clinical context, and 2) to create a document that collects these best practices, thus allowing the creation of a useful compendium for the exchange of knowledge between different Transplant Units. The scientific committee and expert panel finally standardized 30 best practices, including for the pretransplant period (n = 9), peritransplant period (n = 7), postransplant period (n = 8) and training and communication (n = 6). Many aspects of hospitals and units networking, telematic approaches, patient care, value-based medicine, hospitalization, and outpatient visit strategies, training for novelties and communication skills were covered. Massive vaccination has greatly improved the outcomes of the pandemic, with a decrease in severe cases requiring intensive care and a reduction in mortality. However, suboptimal responses to vaccines have been observed in transplant recipients, and health care strategic plans are necessary in these vulnerable populations. The best practices contained in this expert panel report may aid to their broader implementation. • Massive vaccination has greatly improved the outcomes of the COVID-19 pandemic. • Suboptimal responses to vaccines have been observed in transplant recipients. • Health care strategic plans are necessary in these vulnerable populations. • The best practices contained in this expert panel report may aid to their broader implementation. • Pretransplant, peritransplant and postransplant new practices are proposed. [ABSTRACT FROM AUTHOR]

Background: In recent years, interest in donation after cardiac death (DCD) has increased. Although DCD liver transplantation (LT) has demonstrated satisfactory long‐term outcomes, different studies have shown poorer patient and graft survival after DCD than after donation after brain death (DBD). This study aimed to evaluate the results of LT using controlled DCD (cDCD) donors, specifically the incidence of primary non‐function and ischemic cholangiopathy (IC), and to compare these results with those of LT using DBD in the same time period. Methods: Between June 2012 and July 2018, we performed 66 transplants using cDCD and 258 with DBD grafts. Results: The incidence of IC was similar in both groups (2% in DBD, 1.5% in DCD; P =.999). No significant differences were found for overall graft and patient survival rates between the groups at 1 and 2 years post‐transplantation. Conclusions: This study provided evidence that cDCD donors exhibit excellent graft and patient survival outcomes. When the warm ischemia time is <30 minutes and cold ischemia time is <6 hours, the graft and patient survival rates and the incidence of IC in DCD are similar to those in DBD, even when using donors without age restrictions. [ABSTRACT FROM AUTHOR]

Background & Aims There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. Methods 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. Results Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and –loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN = 0.80 vs. –MELD = 0.50; -D-MELD = 0.54; -P-SOFT = 0.54; -SOFT = 0.55; –BAR = 0.67 and -DRI = 0.42) and NN-MS (AUROC-ANN = 0.82 vs. –MELD = 0.41; -D-MELD = 0.47; -P-SOFT = 0.43; -SOFT = 0.57, -BAR = 0.61 and -DRI = 0.48). Conclusions ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models. [ABSTRACT FROM AUTHOR]

Fulminant hepatic failure is a rare complication of infection by varicella zoster virus that is favored by immunosuppression. Within 1 week, a 43-year-old male heart transplant recipient who was admitted with epigastric pain successively developed a generalized vesicular rash, hepatitis, and secondary multiorganic failure involving encephalopathy, despite treatment with acyclovir (since Day 2) and varicella zoster virus immunoglobulin (since Day 6). Emergency liver transplantation was performed on Day 9, and 36 months later, his heart and liver function are normal. [Copyright &y& Elsevier]

Background and Aim: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain., Methods: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels ≤ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated., Results: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups., Conclusion: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation.

BACKGROUND Self-administered subcutaneous hepatitis B immunoglobulin (s.c. HBIg) in combination with nucleos(t)ide analogs (NUCs) has proved to be effective and safe in preventing hepatitis B virus (HBV) reinfection after liver transplantation. MATERIAL AND METHODS This non-interventional, prospective, single-arm, multicenter, international study collected data on long-term effectiveness, safety, patient satisfaction (Treatment Satisfaction Questionnaire for Medication, TSQM-11), and quality of life (EQ-5D questionnaire) in routine practice over a 2-year treatment period. Data analysis was based on 195 adults (82.1% male) transplanted for HBV-related liver diseases and treated with s.c. HBIg with/without NUC(s). RESULTS HBV recurrence (seropositivity of HBV surface antigen and/or HBV DNA) was observed in 7/195 (3.6%) patients (annual rate: 2.01%). Hepatocellular carcinoma (HCC) recurred in 4/83 (4.8%) patients transplanted for HBV-HCC (annual rate: 2.88%). Twenty-nine adverse drug reactions occurred in 16/195 (8.2%) patients. Convenience and overall satisfaction scores of the TSQM-11 were significantly (P<0.05) improved under treatment at the 3-month, 2-year, and last follow-up visits. Quality of life remained constant over the entire observation period (EQ-5D index [P≥0.075]). S.c. HBIg was mainly self-administered (6458/9021 administrations, 71.6%) at home (8514/9021 administrations, 94.4%). CONCLUSIONS The results indicate long-term effectiveness and safety of s.c. HBIg in combination with NUC therapy in preventing post-transplant HBV reinfection under real-life conditions. The convenience of the therapy contributed to the high overall treatment satisfaction and acceptance by the patients.

Background & Aims: The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate., Methods: We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe COVID-19 among hospitalised patients were analysed using multivariate Cox regression., Results: A total of 111 liver transplant patients were diagnosed with COVID-19 (SIR = 191.2 [95% CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between the liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2-96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 3.94; 95% CI 1.59-9.74; p = 0.003), particularly at doses higher than 1,000 mg/day (p = 0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit., Conclusions: Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring COVID-19 but their mortality rates are lower than the matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe COVID-19. However, complete immunosuppression withdrawal should be discouraged., Lay Summary: In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalised patients., Competing Interests: Conflicts of interest JC has received lecture fees from Chiesi, Astellas, and Novartis and is an advisory to Chiesi. MR-P has received lecture fees from Astellas, Novartis, and Intercept Pharma. MS has received lecture fees from Astellas, Novartis, and Chiesi and is an advisory to Jazz and Novartis. MG has received speaker fees from and/or acted as advisor for Astellas, Novartis, Chiesi, Baxter, and Medtronic. MN has received lecture fees from Astellas Pharma. MI has received lecture fees from BMS. CV has received lecture fees from Novartis, Abbie, and Gilead. AC has received lecture fees from Astellas Pharma. GB-F has received lecture fees from Bayer and Astellas. JLM has received lecture fees from Bayer and Gilead. JP has received lecture fees by Astellas, Chiesi, and Gilead. AA-M, AM-S, JG, JN, JB-S, AC, LL, AC, AF-Y, CL, IF, CF, LC, SP, PR, MG-D, RG-G, LH, FN, AO, JA, EF, FG-P, ST and GDR have no conflict of interest to disclose regarding this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions., Competing Interests: Declaration of competing interest We declare that no public or private company has had any role in the study design, data collection, experimental work, data analysis, decision to publish, or preparation of the manuscript. Roche Diagnostics S.L. provided support in the form of a salary for one of the authors [Josep Gregori], but the company did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No other Competing Interests to declare. Thus, our adherence to Antiviral Research policies on sharing data and materials is not altered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Orthotopic liver transplantation (OLT) is successful therapy for patients with end-stage liver disease. Infection is currently a life-threatening complication for these patients. The aims of this study are to determine the incidence of various infections in patients with OLT, to study overall survival rates and survival as related to individual infections, and to investigate the risk factors associated with first episodes of bacterial (BI), fungal (FI), invasive fungal (IFI) and cytomegalovirus (CMV) infections., Methods: The study includes 165 OLTs performed in 152 recipients from May 1994 to May 1998. A descriptive analysis estimating the 95% confidence interval was performed with 100 variables stratified according to preoperative, operative and postoperative conditions. Cox regression analysis was used to identify the variables associated with infection. Survival studies were carried out with the Kaplan-Meier method., Results: Among the total, 66% of patients developed infection: 41.8% viral, 33.9% BI, 20.6% FI and 4.2% IFI. One-year and 4-year survival rates after transplantation were 90% and 75%, respectively. All the infections decreased survival. Multivariate analyses identified the following risk factors for the specific infections: BI - dialysis, mechanical ventilation, and time of organ ischemia during harvesting; FI - number of hours of surgery and pretransplantation plasma albumin concentrations; IFI - number of blood units transfused, pretransplantation plasma albumin and retransplantation. Cytomegalovirus infection was associated with FI and IFI in the univariate analysis, but the multivariate analysis identified no variables that independently increased the risk of developing this infection.