Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in ...the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up.
An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals.
A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child-Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed.
DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective.
Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with ...detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.
Body composition is sex dependent and associated with an increased mortality risk in patients with cirrhosis. We evaluated whether it was also associated with short-term mortality in patients ...critically ill with acute-on-chronic liver failure (ACLF).
We retrospectively included all patients with cirrhosis and ACLF hospitalised in the intensive care unit (ICU) of Lausanne University Hospital between 2010 and 2019 for whom an abdominal computed tomography (CT) scan performed ±7 days from admission was available. Patients from the ICU of Paul Brousse University Hospital admitted between 2017 and 2020 served as an external cohort. All body composition parameters at the third lumbar vertebral level (L3) were quantified using a deep learning-based method.
In total, 192 patients from Lausanne were included. Median age was 62 years and 28-day survival rate was 58.2%. In males, variables independently associated with 28-day mortality on days 1 and 3 were Chronic Liver Failure Consortium (CLIF-C) ACLF-lactate and sarcopenia. In females, CLIF-C ACLF-lactate on days 1 and 3 was the only predictor of 28-day survival. We derived two scores combining sarcopenia and the CLIF-C ACLF-lactate score on days 1 and 3, with area under the receiver operating characteristic outperforming the CLIF-C ACLF-lactate score alone in male but not in female patients. Comparable results were found in the external cohort of 58 patients and supported the sex specificity of the performance of the model. Patients with sarcopenia had increased risks of invasive fungal infection and renal replacement therapy.
Sarcopenia was associated with 28-day mortality in male but not in female patients critically ill with ACLF. Although screening for sarcopenia could impact the management of male patients, further studies are needed in female cohorts to investigate whether other body composition parameters are associated with outcomes.
Body composition, easily assessed by CT, is altered in patients with cirrhosis and associated with outcome; it has never been investigated in patients critically ill with ACLF. The results of the present study, underlining the benefit of sarcopenia evaluation to improve prognosis prediction in males critically ill with ACLF, are of importance for physicians managing such patients to optimise the decision-making process toward continued treatment, liver transplantation, or limitation of care. In a wider sense, besides the number and course of organ failures, the results recall the weight of the general condition of males with ACLF at admission to ICU. In females critically ill with ACLF, in analyses limited by the sample size, none of the body composition parameters was associated with short-term mortality independently of organ failures; this suggests that the number and course of organ failures are the main determinant of mortality in these patients.
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•Sarcopenia is independently associated with 28-day mortality in male but not in female patients critically ill with cirrhosis and ACLF.•Incorporation of sarcopenia into the CLIF-C ACLF-lactate score improves the prediction of prognosis in male patients.•Patients with sarcopenia have an increased risk of severe ACLF course and of fungal infection, as well as an increased risk of requiring renal replacement therapy.
First generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for ...3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft.
This cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety.
The SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011).
The use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.
Abstract
Background
In patients with end stage liver disease (ESLD) scheduled for liver transplantation (LT), an intraoperative incidental finding of elevated mean pulmonary arterial pressure (mPAP) ...may be observed. Its association with patient outcome has not been evaluated. We aimed to estimate the effects of an incidental finding of a mPAP > 20 mmHg during LT on the incidence of pulmonary complications.
Methods
We examined all patients who underwent a LT at Paul-Brousse hospital between January 1,2015 and December 31,2020. Those who received: a LT due to acute liver failure, a combined transplantation, or a retransplantation were excluded, as well as patients for whom known porto-pulmonary hypertension was treated before the LT or patients who underwent a LT for other etiologies than ESLD. Using right sided pulmonary artery catheterization measurements made following anesthesia induction, the study cohort was divided into two groups using a mPAP cutoff of 20 mmHg. The primary outcome was a composite of pulmonary complications. Univariate and multivariable logistic regression analyses were performed to identify variables associated with the primary outcome. Sensitivity analyses of multivariable models were also conducted with other mPAP cutoffs (mPAP ≥ 25 mmHg and ≥ 35 mmHg) and even with mPAP as a continuous variable.
Results
Of 942 patients who underwent a LT, 659 met our inclusion criteria. Among them, 446 patients (67.7%) presented with an elevated mPAP (mPAP of 26.4 ± 5.9 mmHg). When adjusted for confounding factors, an elevated mPAP was not associated with a higher risk of pulmonary complications (adjusted OR: 1.16; 95%CI 0.8–1.7), nor with 90 days-mortality or any other complications. In our sensitivity analyses, we observed a lower prevalence of elevated mPAP when increasing thresholds (235 patients (35.7%) had an elevated mPAP when defined as ≥ 25 mmHg and 41 patients (6.2%) had an elevated mPAP when defined as ≥ 35 mmHg). We did not observe consistent association between a mPAP ≥ 25 mmHg or a mPAP ≥ 35 mmHg and our outcomes.
Conclusion
Incidental finding of elevated mPAP was highly prevalent during LT, but it was not associated with a higher risk of postoperative complications.
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.
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.
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.
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.
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.
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•We analyzed the rate of histological recurrence in 150 patients transplanted for NAFLD cirrhosis.•Median follow-up after liver transplantation was 4.7 years.•Recurrence of the initial disease is frequent and rapid after liver transplantation.•Grade ≥2 steatosis at 1 year is highly predictive of recurrence of NASH and advanced fibrosis.
Purpose
Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic ...data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse.
Methods
Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays.
Results
Sixty-seven mainly male patients (79%) were included, with a mean age of 57 years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4 weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30–2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (
p =
0.02) and lower haemoglobin during direct-acting antiviral treatment (
p =
0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range.
Conclusion
Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels.
Trial registration
NCT 01944527
Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study was to evaluate the selection ...process for LTx in patients with ACLF admitted to the intensive care unit (ICU) and to assess outcomes.
This prospective, non-interventional, single high-volume center study collected data on patients with ACLF admitted to the ICU between 2017-2020.
Among 200 patients (mean age: 55.0 ± 11.2 years and 74% male), 96 patients (48%) were considered potential candidates for LTx. Unfavourable addictology criteria (n = 76) was the main reason for LTx ineligibility. Overall, 69 patients were listed for LTx (34.5%) and 50 were transplanted (25% of the whole population). The 1-year survival in the LTx group was significantly higher than in the non-transplanted group (94% vs. 15%, p <0.0001). Among patients eligible for LTx, mechanical ventilation during the first 7 days of ICU stay and an increase in the number of organ failures at day 3 were associated with the absence of LTx or death (odds ratio 9.58; 95% CI 3.29–27.89; p <0.0001 for mechanical ventilation and odds ratio 1.87; 95% CI 1.08–3.24; p <0.027 for increasing organ failures). The probability of not being transplanted in patients with ACLF under mechanical ventilation is >85.4% in those experiencing an increase of 2 organ failures since admission or >91% if experiencing an increase >2 organ failures, at which point futility could be considered.
This prospective analysis of outcomes of patients with ACLF admitted to the ICU highlights the drastic nature of selection in this setting. Unfavourable addictology criteria, mechanical ventilation and increasing number of organ failures since admission were predictive of absence of LTx, futility and death.
Liver transplantation (LT) is the best therapeutic option in selected cirrhotic patients admitted to the ICU with acute on chronic liver failure. However, the selection criteria are poorly described and based on retrospective studies. This is the first prospective study that aimed to describe the selection process for LT in a transplant center. Patients with ACLF should be admitted to the ICU and evaluated within a short period of time for LT. In the context of organ shortage, eligibility for LT and either absence of LT, futility of care or death are better clarified in our study. These are mainly determined by prolonged respiratory failure and worsening of organ failures since ICU admission. Considering worldwide variations in the etiology and definition of ACLF, transplant availability and a narrow therapeutic window for transplant further prospective studies are awaited.
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•Among 200 patients with ACLF admitted to the ICU, half were considered eligible for LTx and a quarter were transplanted.•Reasons for LTx ineligibility were active alcohol consumption (73%), uncontrolled infections (12.5%) and severe malnutrition (12.5%).•In eligible patients, the main cause of death during evaluation or on the waitlist was sepsis (66%).•Mechanical ventilation within 7 days of ICU admission and additional organ failures between admission and day 3 predicted absence of LTx and death.•We established an equation to determine the probability of not being transplanted in eligible patients.
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