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International audience; BACKGROUND:Choice of calcineurin inhibitor may influence response to antiviral therapy in liver transplant patients with hepatitis C virus (HCV) infection.MATERIAL AND METHODS:In a randomized, multicenter, 80-week trial, liver transplant recipients (>6 months and £10 years post-transplant) with recurrent HCV infection received cyclosporine (n=50) or tacrolimus (n=42) with a 48-week course of pegylated interferon (peg-IFNα2a) and ribavirin. Twenty-three patients in each group completed the trial on study medication. The primary endpoint was sustained virological response (SVR) 24 weeks after the end of antiviral therapy, for which 43 patients were eligible for analysis.RESULTS:The rate of SVR was 60.0% (12/20) with cyclosporine and 43.5% (10/23) with tacrolimus (adjusted odds ratio 1.85; 95% CI 0.53-6.43; p=0.331). There were no significant intergroup differences for rapid or early virological response, relapse, HCV RNA viral load, or fibrosis progression. One cyclosporine-treated patient experienced acute rejection. One patient died in each group. Adverse events, treatment-related adverse events, and serious adverse events were similar between groups.CONCLUSIONS:Since fewer patients were recruited than planned (92 versus 355), the study was underpowered and robust conclusions cannot be drawn regarding the effect of cyclosporine and tacrolimus on virological responses to antiviral treatment for recurrent HCV after liver transplantation. However, as reported in other trials, SVR was higher in cyclosporine-treated patients.

The intestinal microbiome (IM) is altered in patients with cirrhosis, and emerging literature suggests that this impacts on the development of complications. The PubMed database was searched from January 2000 to May 2015 for studies and review articles on the composition, pathophysiologic effects and therapeutic modulation of the IM in cirrhosis. The following combination of relevant text words and MeSH terms were used, namely intestinal microbiome, microbiota, or dysbiosis, and cirrhosis, encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal bleeding, hepatopulmonary syndrome, portopulmonary hypertension and hepatocellular carcinoma. The search results were evaluated for pertinence to the subject of IM and cirrhosis, as well as for quality of study design. The IM in cirrhosis is characterized by a decreased proportion of Bacteroides and Lactobacilli, and an increased proportion of Enterobacteriaceae compared to healthy controls. Except for alcoholic cirrhosis, the composition of the IM in cirrhosis is not affected by the etiology of the liver disease. The percentage of Enterobacteriaceae increases with worsening liver disease severity and decompensation and is associated with bacteremia, spontaneous bacterial peritonitis and hepatic encephalopathy. Lactulose, rifaximin and Lactobacillus-containing probiotics have been shown to partially reverse the cirrhosis associated enteric dysbiosis, in conjunction with improvement in encephalopathy. The IM is altered in cirrhosis, and this may contribute to the development of complications associated with end-stage liver disease. Therapies such as lactulose, rifaximin and probiotics may, at least partially, reverse the cirrhosis-associated changes in the IM. This, in turn, may prevent or alleviate the severity of complications.

Objective: To compare the outcome of adult live donor liver transplantation (LDLT) with grafts from older versus younger donors. Introduction: Using older donor grafts for adult LDLT may help expand the donor pool. However, the risks of LDLT with older donors remain controversial, and many centers are reluctant to use live donors aged 45 years or older for adult LDLT. Methods: Outcomes of patients receiving a LDLT graft from donors aged 50 years or older (n = 91) were compared with those receiving a live donor graft from donors younger than 50 years (n = 378). Results: Incidences of biliary (LDLT

• Ziel: Verhinderung des Voranschreitens zur Zirrhose, resp. der Entwicklung eines hepatozellularen Karzinoms. • Aktuelle medizinische Behandlung: Interferon-alfa. • Wirksamkeit: Suppression der viralen Replikation bei 40% der Patienten, die wahrend vier Monaten behandelt wurden. • Erfolgskontrolle: Serologische Konversion (Verschwinden des HBe-Ag und Auftreten von HBe-Ak) sowie Verschwinden der viralen DNS im Blut. • Studien mit Kombinationen mehrerer antiviraler Medikamente sind zur Zeit im Gange.

• But: empecher l'evolution de l'hepatite chronique vers la cirrhose et le carcinome hepatocellulaire. • Traitement medicamenteux actuel: interferon alpha. • Efficacite: suppression de la replication virale chez 40% des sujets traites pendant 4 mois. • Controle de l'efficacite: conversion serologique (disparition AgHBe et apparition anti-HBe) et negativation de l'ADN viral dans le sang. • Des protocoles de traitement associant plusieurs medicaments antiviraux sont a l'etude.

Because of a persistent discrepancy between the demand for liver transplantation (LT) and the supply of deceased donor organs, there is an interest in increasing living donation rates at centers trained in this method of transplantation. We examined a large socioeconomically heterogeneous cohort of patients listed for LT to identify recipient factors associated with living donation. We retrospectively reviewed 491 consecutive patients who were listed for LT at our center over a 24-month period. Demographic, medical, and socioeconomic data were extracted from electronic records and compared between those who had a potential living donor (LD) volunteer for assessment and those who did not; 245 patients (50%) had at least 1 potential LD volunteer for assessment. Multivariate logistic regression analysis identified that patients with a LD were more likely to have Child-Pugh C disease (odds ratio [OR], 2.44; P = 0.02), and less likely to be older (OR, 0.96; P = 0.002), single (OR, 0.34; P = 0.006), divorced (OR, 0.53; P = 0.03), immigrants (OR, 0.38; P = 0.049), or from the lowest income quintile (OR, 0.44; P = 0.02). In conclusion, this analysis has identified several factors associated with access to living donation. More research is warranted to define and overcome barriers to living donor liver transplantation through targeted interventions in underrepresented populations. Liver Transpl 21:897-903, 2015. © 2015 AASLD.

Long-term survival after paediatric liver transplantation is now the rule rather than the exception. Improving long-term outcomes after transplantation must consider not only the quantity but also the quality of life years restored.To characterize health-related quality of life (HRQOL) of LT recipients ≥15 years after paediatric LT.Recipients of a paediatric LT performed before December 1996 in a single institution with continuous follow-up at either the paediatric or adult partner centre were identified. Patients with severe developmental or neurological impairment were excluded. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0, the Medical Outcomes Study Short Form-36 version 2 and the Pediatric Liver Transplant Quality of Life Tool.A total of 27 (67% male) subjects (mean age 24.3±6.7 years [median 23.2 years; range 16.6 to 40.3 years]) participated. The median age at transplant was 1.7 years (range 0.5 to 17.0 years). Seven (26%) participants underwent retransplantation. Seventeen (63%) participants were engaged in full-time work/study. Mean Short Form-36 version 2 scores included physical (49.6±11.1) and mental (45.3±12.5) subscale scores. The mean score for the disease-specific quality of life tool for paediatric liver transplant recipients (the Pediatric Liver Transplant Quality of Life Tool) was 64.70±15.2. The physical health of the young adults strongly correlated with level of involvement in work/study (r=0.803; P0.05).The self-reported HRQOL of participants18 years of age was comparable with a standardized healthy population. In contrast, participants between 18 and 25 years of age had HRQOL scores that were more similar to a group with chronic illness. Participants engaged in full-time work/study experienced enhanced physical health.La survie à long terme après une transplantation du foie (TF) en pédiatrie est maintenant la règle plutôt que l’exception. Il faut tenir compte à la fois de la quantité et de la qualité des années de vie récupérées dans l’amélioration des résultats après la TF.Caractériser la qualité de vie liée à la santé (QdVLS) des greffés du foie de 15 ans et plus après une TF en pédiatrie.Les chercheurs ont dépisté des greffés du foie opérés avant décembre 1996 dans un seul établissement et recevant un suivi continu au centre pédiatrique ou au centre partenaire pour adultes. Les patients ayant une grave atteinte développementale et neurologique étaient exclus. La QdVLS était évaluée au moyen de l’inventaire de la qualité de vie en pédiatrie 4.0, de la version 2 du formulaire court sur les résultats médicaux en 36 questions et de l’outil sur la qualité de vie des greffés du foie en pédiatrie.Au total, 27 sujets (67 % d’hommes, âge moyen de 24,3±6,7 ans [médiane de 23,2 ans; plage de 16,6 à 40,3 ans]) ont participé. Ils avaient un âge médian de 1,7 an au moment de la transplantation (plage de 0,5 à 17,0 ans). Sept participants (26 %) ont dû subir une autre transplantation. Dix-sept participants (63 %) travaillaient ou étudiaient à temps plein. La version 2 du formulaire court en 36 questions incluait des scores de sous-échelle physique (49,6±11,1) et mentale (45,3±12,5). Le score moyen pour l’outil de qualité de vie propre à la maladie (outil de qualité de vie des greffés du foie en pédiatrie) était de 64,70±15,2. La santé physique des jeunes adultes était fortement corrélée avec le taux d’investissement dans le travail ou l’étude (r=0,803, P0,05).La QdVLS autodéclarée des participants de moins de 18 ans était comparable à celle d’une population en santé standardisée. En revanche, les participants de 18 à 25 ans avaient un score de QdVLS qui ressemblait davantage à celui d’un groupe ayant une maladie chronique. Les participants qui s’investissaient dans un emploi ou des études à temps plein présentaient une meilleure santé physique.

Data regarding transplantation outcomes in ventilated intensive care unit (ICU)–dependent patients with end-stage liver disease (ESLD) are conflicting. This single-center cohort study investigated the outcomes of patients with ESLD who were intubated with mechanical support before liver transplantation (LT). The ICU plus intubation group consisted of 42 patients with decompensated cirrhosis and mechanical ventilation before transplantation. LT was considered for intubated ICU patients if the fraction of inspired oxygen was ≤40% with a positive end-expiratory pressure ≤ 10, low pressor requirements, and the absence of an active infection. Intubated ICU patients were compared to 80 patients requiring ICU admission before transplantation without intubation and to 126 matched non–ICU-bound patients. Patients requiring ICU care with intubation and ICU care alone had more severe postoperative complications than non–ICU-bound patients. Intubation before transplantation was associated with more postoperative pneumonias (15% in intubated ICU transplant candidates, 5% in ICU-bound but not intubated patients, and 3% in control group patients; P = 0.02). Parameters of reperfusion injury and renal function on postoperative day (POD) 2 and POD 7 were similar in all groups. Bilirubin levels were higher in the ICU plus intubation group at POD 2 and POD 7 after transplantation but were normalized in all groups within 3 months. The ICU plus intubation group versus the ICU-only group and the non-ICU group had decreased 1-, 3-, and 5-year graft survival (81% versus 84% versus 92%, 76% versus 78% versus 87%, and 71% versus 77% versus 84%, respectively; P = 0.19), but statistical significance was not reached. A Glasgow coma scale score of 7 before transplantation was associated with high postoperative mortality in ICU-bound patients requiring intubation (38% versus 23%; P = 0.01). In conclusion, ICU admission and mechanical ventilation should not be considered contraindications for LT. With careful patient selection, acceptable long-term outcomes can be achieved despite increased postoperative complications. Liver Transpl 21:761–767, 2015. © 2015 AASLD.

Long-term biliary complications after living donor liver transplantation (LDLT) are not well described in the literature. This study was undertaken to determine the long-term impact of biliary complications after adult right-lobe LDLT.This retrospective review analyzed an 11-yr experience of 344 consecutive right-lobe LDLTs with at least two yr of follow-up.Biliary leaks occurred in 50 patients (14.5%), and strictures occurred in 67 patients (19.5%). Cumulative biliary complication rates at 1, 2, 5, and 10 yr were 29%, 32%, 36%, and 37%, respectively. Most early biliary leaks were treated with surgical drainage (N = 29, 62%). Most biliary strictures were treated first with endoscopic retrograde cholangiography (42%). There was no association between biliary strictures and the number of ducts (hazard ratio [HR] 1.017 [0.65-1.592], p = 0.94), but freedom from biliary stricture was associated with a more recent era (2006-2010) (HR 0.457 [0.247-0.845], p = 0.01). Long-term graft survival did not differ between those who had or did not have biliary complications (66% vs. 67% at 10 yr).Biliary strictures are common after LDLT but may decline with a center's experience. With careful follow-up, they can be successfully treated, with excellent long-term graft survival rates.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide.(1) Radiofrequency ablation (RFA) is the current recommended curative treatment option for non-surgical patients with early stage disease.(2) A recent report by Cancer Care Ontario shows the expected number of HCC cases requiring RFA will grow at a greater rate than RFA capacity estimates.(3) Currently, no recommended wait times exist for HCC. AIMS: In this study, we look at wait times for patients with HCC undergoing RFA and the development of adverse events. We also aimed to identify system gaps where quality improvement measures can be implemented. METHODS: This was a retrospective study conducted at the University Health Network looking at all patients diagnosed with HCC and referred for RFA between January 2010 until December 2013. Data on demographics and co-morbidities were obtained along with biochemistry, hematology and virology values. The time from diagnosis of HCC to presentation at Tumor Board rounds and the time from Tumor Board rounds to treatment were documented. Outcomes defined a priori were all-cause death and all-cause liver transplantation. Statistical analysis was performed with a help of a statistician. The study was approved by the UHN Research Ethics Board. RESULTS: 225 patients were included in the study. 72.4% percent were male and the median age was 63 years (SD+/-10.4). Median tumor size at diagnosis was 22 mm (SD +/-8.3), mean MELD was 8.7 (Range=7.2–11.3) and 55.6% had Barcelona stage 0. The cause of liver disease was viral hepatitis in 73% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 97 days (IQR 75–139). In multivariable analysis wait times per 30 days was associated with an increased risk of death (HR=1.16; 95% CI 1.08–1.25; p=

Hepatorenal syndrome type 1 (HRS1) is acute renal failure in the setting of advanced cirrhosis, and it results from hemodynamic derangements, which should be fully reversible after liver transplantation. However, the rate of hepatorenal syndrome (HRS) reversal and factors predicting renal outcomes after transplantation have not been fully elucidated. The aim of this study was to assess outcomes of HRS1 patients after liver transplantation and factors predicting HRS reversal. A chart review of all liver transplant patients with HRS1 (according to International Ascites Club criteria) at Toronto General Hospital from 2001 to 2010 was conducted. Patient demographic data, pretransplant and posttransplant laboratory data, and the presence of and time to posttransplant HRS reversal (serum creatinine

BACKGROUND: The literature regarding post-transplant lymphoproliferative disorder (PTLD) in liver transplant recipients (LTRs) is limited.OBJECTIVES: To study the incidence, predictors and outcomes of PTLD after liver transplantation in a single, large-volume centre.METHODS: The charts of all LTRs (n=1372) in the authors’ centre between January 2000 and June 2012 were retrospectively reviewed and those who developed PTLD were identified. Demographic, clinical and treatment data were prospectively collected. Responses to treatment, including complete response, no response, relapse and survival, were recorded.RESULTS: The incidence of PTLD in LTRs was 32 in 1372 (2.3%). Overall, median survival was 37 months (range 0.5 to 195 months), with one-, three- and five-year survival rates of 81%, 74% and 60%, respectively. Epstein-Barr virus (EBV)-negative patients had a better mean (± SD) survival (95±79 months) than EBV-positive patients (41±42 months) (P=0.02). For stage I/II PTLD, one-, three- and five-year actuarial survival was 87%, 87% and 75%, compared with 50%, 30% and 0% for stage III/IV PTLD, respectively (P=0.001). In patients with complete response, median survival was 58 months (range 10 to 195 months); and one-, three- and five-year actuarial survival was 100%, 94% and 76%, respectively, after diagnosis of PTLD. Changing immunosuppression (IS) from calcineurin inhibitor to sirolimus at the time of diagnosis may have improved survival (seven of seven survivors) compared with only decreasing or stopping IS (14 of 25 survivors) (P=0.07).CONCLUSIONS: This series from a single large-volume centre showed excellent short and long-term survival after PTLD in adult LTRs who were EBV negative, had early disease and showed complete response. Consistent with the known in vitro antiproliferative effect of sirolimus, switching IS from calcineurin inhibitor to sirolimus may improve survival.

BACKGROUND Reactivation of human herpesvirus (HHV)-6 and HHV-7 has been linked to various posttransplant adverse events through immunomodulatory effects. The potential utility of monitoring for HHV-6 and HHV-7 viremia remains unclear. METHODS In this clinical trial, 129 liver transplant recipients were randomized to be monitored in real-time for HHV-6 and HHV-7 viremia by polymerase chain reaction at regular intervals from 0 to 12 weeks after transplantation ("monitoring" group) or to undergo usual care ("no-monitoring" group). Therapeutic intervention for a positive polymerase chain reaction result included reduction in immunosuppression and preemptive antiviral therapy, at the discretion of the attending team. The primary outcome was a composite of adverse events indirectly attributable to viral reactivation (including opportunistic infection, graft rejection and severe hepatitis C virus recurrence). RESULTS In the "monitoring" group, HHV-6 and HHV-7 viremia occurred in 23 of 64 patients (35.9%) and 21 of 64 patients (32.8%) patients, respectively. We found no cases of symptomatic HHV-6 and HHV-7 disease. Some therapeutic interventions were performed in 59.1% of viremic episodes. There were no differences in cumulative incidence of the primary outcome between the "monitoring" and "no-monitoring" groups at 1 year (58.7% vs. 52.3%; odds ratio, 0.77; 95% confidence interval, 0.38-1.55) or at 5 years after transplantation (79.0% vs. 70.3%; odds ratio, 0.63; 95% confidence interval, 0.28-1.42). However, we found a trend toward a lower incidence of graft rejection at year 1 in the "monitoring" group (30.2% vs. 44.6%; P=0.091). CONCLUSION In this first trial, no benefit could be demonstrated from routine monitoring of HHV-6 and HHV-7 viremia in graft or patient outcome after liver transplantation.

Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy-seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol-related liver disease (ALD) was the underlying etiology in the majority (n = 47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end-stage liver disease (MELD) score

Introduction. Hepatitis C (HCV) continues to be the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for recurrent HCV in Genotype 1 (G1) LT recipients have been disappointing (30-40%). Experience with triple therapy using protease inhibitors (PI) boceprevir (BOC), telaprevir (TVR) in these patients has been limited. Material and methods. This national multicenter retrospective study included 76 patients (64 male, mean age 57 ± 6 years), treated for G1 HCV recurrence with either BOC (n = 41) or TVR (n = 35), who were non-responders or relapsers (n = 54), treatment naive (n = 22) or had fibrosing cholestatic HCV (n = 3). 53 patients were on cyclosporine, 22 on tacrolimus and one patient on prednisone alone. Results. On treatment virologic response was observed in 84% (64/76), 83% in BOC and 85% in TVR group. A higher week 4 response after starting triple therapy (RVR) was noted in TVR group 25/35 (81%) as compared to BOC group 26/41 (63%); p value = 0.02. The end of treatment response was 78% and 75% in BOC and TVR group, respectively. SVR 12 weeks after treatment discontinuation was observed in 59.5% (22/37); 58.3% in the BOC group and 61.5% in TVR group. Treatment was discontinued early in 23 patients (serious adverse effects n = 19, treatment failure n = 4). Infections occurred in 5 patients with 2 deaths (all in BOC). Anemia was the most common side effect (n = 55, 72%) requiring erythropoietin and RBV dose reduction. In the BOC group, cyclosporine dose reduction was 2.2 ± 1.0 fold and 8.6 ± 2.4 fold with tacrolimus. In TVR group, dose reduction was 3.0 ± 1.4 with cyclosporine and 12 ± 5.7 fold with tacrolimus. Conclusions. PI-based triple therapy appears more effective in producing HCV-RNA clearance than dual therapy. Tolerability is a serious issue and drug-drug interactions are manageable with close monitoring.

Drug induced pancreatitis (DIP) is a serious adverse effect of many commonly used drugs. Pegylated interferon (peg-IFN) and ribavirin used for treatment of chronic hepatitis C (CHC) infection and various protease inhibitors (PIs) such as indinavir, nelfinavir, ritonavir and saquinavir used for HIV infection have been reported to cause DIP; although the mechanism of pancreatitis is not well known. Recently, telaprevir and boceprevir are introduced for treatment of HCV genotype 1 infection along with peg-IFN and ribavirin. There are no reports of acute pancreatitis due to telaprevir and boceprevir in liver transplant setting. We managed two such cases; both were male with HCV genotype 1 infection, had living donor liver transplantation for hepatocellular cancer few years ago and stable on cyclosporine. Both developed AP a month after adding one of PI to their combination therapy. First patient had past history of partial response with peg-IFN and ribavirin and retreated with addition of telaprevir to combination therapy. Second patient received peg-IFN and ribavirin for 4 months and then boceprevir was added. Patients were managed conservatively, the culprit PI was stopped and they recovered. We used the Naranjo Probability Scale for Adverse Drug Events to estimate the probability that a drug was the cause of the acute pancreatitis. A score of 7 was calculated in both patients, indicating a probable adverse drug reaction. The algorithm devised by Trivedi et al to diagnose drug-induced pancreatitis was also used and confirmed that this was likely to be a drug reaction. There is adequate circumstantial evidence pointing to telaprevir and boceprevir as the cause of their acute pancreatitis. Further evidence is needed but in the meantime we would recommend routine monitoring of amylase levels for all patients on triple therapy and advise patients of potential symptoms for which they should seek medical advice.

Liver transplantation (LT) for hepatitis C virus (HCV)-related end-stage liver disease is impaired by universal disease recurrence and suboptimal response to antiviral therapy. Inhibition of angiotensin-II signalling by angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin-II receptor blockers (ARB) decreases hepatic stellate cell activation in vitro and hepatic fibrogenesis in animal models. A single-center retrospective analysis suggested that angiotensin blockade (AB) inhibits fibrosis progression in recurrent HCV post-LT. This study assessed the effect of AB on fibrosis progression in an independent patient cohort.Chart review of all patients who underwent transplantation in our institution for HCV-related ESLD between January 2000 and February 2008 revealed 109 patients with ≥2 protocol liver biopsies and free of antiviral therapy post-LT up to the last biopsy analyzed; 27 of 109 patients were treated with ACE-I/ARB for ≥12 months, 82 were not. Fibrosis was staged using METAVIR.Live-donor LT was more frequent in controls than in the AB group (25% vs 11%; P .05). However, parameters known to affect outcome of recurrent HCV, including donor age, prevalence of diabetes, acute cellular rejection, and immunosuppression, were similar in both groups. Time between first and last biopsy (median, 23 months), stage of fibrosis, fibrosis progression rates (median 0.47 vs 0.45 unit/y; P = .46), and time to develop fibrosis stage ≥2 did not differ between groups. Results held true if deceased-donor LT were analyzed separately.Our study does not support the contention of a previous report that use of AB reduces fibrosis progression in recurrent HCV post-LT.

Background In parallel with the obesity epidemic, liver transplantation for nonalcoholic steatohepatitis (NASH) is increasing dramatically in North America. Although survival outcomes are similar to other etiologies, liver transplantation in the NASH population has been associated with significantly increased resource utilization. We sought to compare outcomes between live donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) at a high volume North American transplant center, with a particular focus on resource utilization. Methods The study population consists of primary liver transplants performed for NASH at Toronto General Hospital from 2000 to 2014. Recipient characteristics, perioperative outcomes, graft and patient survivals, and resource utilization were compared for LDLT versus DDLT. Results A total of 176 patients were included in the study (48 LDLT vs 128 DDLT). LDLT recipients had a lower model for end-stage liver disease score and were less frequently hospitalized prior to transplant. Estimated blood loss and early markers of graft injury were lower for LDLT. LDLT recipients had a significantly shorter hospitalization (intensive care unit, postoperative, and total hospitalization). Conclusions LDLT for NASH facilitates transplantation of patients at a less severe stage of disease, which appears to promote a faster postoperative recovery with less resource utilization.