Publications by authors named "Victor de Ledinghen"

218 Publications

HCV eradication in primary or secondary prevention optimizes hepatocellular carcinoma curative management.

Cancer Prev Res (Phila) 2021 Feb 19. Epub 2021 Feb 19.

Public Health, APHP.

To assess the impact of HCV eradication on the outcomes of cirrhotic patients treated curatively for incidental hepatocellular carcinoma (HCC) detected during surveillance program. Data were collected on 1323 French patients with compensated biopsy-proven HCV cirrhosis recruited in 35 centers (ANRS CO12 CirVir cohort). Sustained virological responses (SVR) and the occurrence of HCC were recorded prospectively. During a median follow-up (FU) of 68.3 months, 218 patients developed HCC, 126 of whom underwent a curative procedure as first-line therapy (ablation=95, resection=31). The HCC BCLC stage was 0/A in 97.5% of patients; 74 (58.7%) never achieved SVR. During a median FU of 26.0 months after HCC treatment, 59 (46.8%) experienced HCC recurrence. SVR was not associated with a recurrence, whether considering final SVR status (HR=0.77 [0.43; 1.39]; P=0.39) or its time to achievement (prior to/after HCC occurrence; global P=0.28). During the same timeframe, 46 HCC patients (36.5%) died (liver failure: 41.9%, HCC progression: 37.2%, extrahepatic causes: 20.9%). Under multivariate analysis, SVR was associated with improved survival (HR=0.21 [0.08; 0.52]; P=0.001). Survival benefit was explained by a lower incidence of liver decompensation and higher rates of sequential HCC re-treatment. Direct antivirals intake was not associated with a higher risk of HCC recurrence but with improved survival (HR=0.23 [0.06; 0.83]; P=0.024). HCV eradication in primary or secondary prevention optimizes HCC management through preservation of liver function and improves survival, whatever the regimen.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0465DOI Listing
February 2021

Disease burden and economic impact of diagnosed non-alcoholic steatohepatitis (nash) in five european countries in 2018: A cost-of-illness analysis.

Liver Int 2021 Feb 15. Epub 2021 Feb 15.

Hôpital de la Pitié-Salpêtrière, Paris, France.

Background And Aims: Non-alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end-stage liver disease (ESLD). A large proportion of early-stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom (UK) in 2018.

Methods: The socioeconomic burden of diagnosed NASH was estimated using cost-of-illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on literature review, databases and consultation with clinical experts, economists and patient groups.

Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8% to 39.1% for advanced fibrosis (F3 to F4 compensated cirrhosis). Total economic costs were €8,548-19,546M. Of these, health system costs were €619-1,292M. Total wellbeing costs were €41,536-90,379M. The majority of the undiagnosed population (87.3% to 88.2% of total prevalence) was found to have early stage NASH which, left untreated, may progress to more resource consuming ESLD over time.

Conclusions: This study found the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs.
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http://dx.doi.org/10.1111/liv.14825DOI Listing
February 2021

The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial.

Ann Intern Med 2021 Feb 2. Epub 2021 Feb 2.

University Hospital of Toulouse and Toulouse III Paul Sabatier University, Toulouse, France (C.B., J.M.P., J.P.V.).

Background: The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established.

Objective: To determine whether rifaximin prevents overt HE after TIPS compared with placebo.

Design: Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196).

Participants: 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding.

Intervention: Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure.

Measurements: The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure.

Results: An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group ( = 93) and 53% (CI, 43% to 63%) in the placebo group ( = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups.

Limitations: The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated.

Conclusion: In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE.

Primary Funding Source: French Public Health Ministry.
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http://dx.doi.org/10.7326/M20-0202DOI Listing
February 2021

Early liver transplantation for corticosteroid non-responders in acute severe autoimmune hepatitis: the SURFASA score.

J Hepatol 2021 Jan 24. Epub 2021 Jan 24.

AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Inserm Unité 1193, Univ Paris-Sud, Université Paris-Saclay, FHU Hépatinov, Centre de Référence Maladies Inflammatoires des Voies Biliaires et Hépatites Auto-immunes, Villejuif, F-94800, France. Electronic address:

Background & Aims: In acute severe autoimmune hepatitis (AS-AIH), the optimal timing for liver transplantation (LT) remains controversial. The objectives of this study were to determine early predictive factors for a non-response to corticosteroids and to propose a score to identify patients in whom LT is urgently indicated.

Methods: This was a retrospective, multicenter study (2009-2016). A diagnosis of AS-AIH was based on: 1. Definite or probable simplified IAIHG score; 2. INR ≥1.5 and/or bilirubin >200 μmol/L; 3. No previous history of AIH; 4. Histologically-proven AIH. A treatment response was defined as LT-free survival at 90 days. The evolution of variables from corticosteroid initiation (day-D0) to D3 was estimated from: Δ%3=(D3 - D0)/D0.

Results: 128 patients were included, median age of 52 [39-62] years; 72% were female. Overall survival reached 88%. 115 patients (90%) received corticosteroids with a 66% LT-free survival rate at 90 days. Under multivariate analysis, D0-INR (odds ratio [OR] 6.85; 95%CI 2.23-21.06, p<0.001), Δ%3-INR≥0.1% (OR 6.97; 95%CI 1.59-30.46, p<0.01) and Δ%3-bilirubin≥-8% (OR 5.14; 95%CI 1.09-24.28, p<0.04) were predictive of a non-response. The SURFASA score -6.80+1.92*(D0-INR) +1.94*(Δ%3-INR)+ 1.64*(Δ%3-bilirubin), created by combining these variables, was highly predictive of LT or death (AUC=0.93) (88% specificity; 84% sensitivity) with a cut-off point of <-0.9. Below this cut-off, the chance of responding was 75%. With a score higher than 1.75, the risk of dying or being transplanted was between 85% and 100%.

Conclusion: In AS-AIH patients, INR at the introduction of corticosteroids and the evolution of INR and bilirubin are predictive of LT or death. Within 3 days of initiating corticosteroids, the SURFASA score can identify non-responders who require a referral for LT. This score needs to be validated in a prospective cohort.
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http://dx.doi.org/10.1016/j.jhep.2020.12.033DOI Listing
January 2021

Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease.

Gut 2021 Jan 21. Epub 2021 Jan 21.

Internal Medicine I, University of Bonn, Bonn, Germany.

Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.

Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.

Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.

Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
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http://dx.doi.org/10.1136/gutjnl-2020-323419DOI Listing
January 2021

Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis.

Lancet Gastroenterol Hepatol 2021 03 16;6(3):185-198. Epub 2021 Jan 16.

Division of Gastroenterology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany. Electronic address:

Background: Diagnostic tools for liver disease can now include estimation of the grade of hepatic steatosis (S0 to S3). Controlled attenuation parameter (CAP) is a non-invasive method for assessing hepatic steatosis that has become available for patients who are obese (FibroScan XL probe), but a consensus has not yet been reached regarding cutoffs and its diagnostic performance. We aimed to assess diagnostic properties and identify relevant covariates with use of an individual patient data meta-analysis.

Methods: We did an individual patient data meta-analysis, in which we searched PubMed and Web of Science for studies published from database inception until April 30, 2019. Studies reporting original biopsy-controlled data of CAP for non-invasive grading of steatosis were eligible. Probe recommendation was based on automated selection, manual assessment of skin-to-liver-capsule distance, and a body-mass index (BMI) criterion. Receiver operating characteristic methods and mixed models were used to assess diagnostic properties and covariates. Patients with non-alcoholic fatty liver disease (NAFLD) were analysed separately because they are the predominant patient group when using the XL probe. This study is registered with PROSPERO, CRD42018099284.

Findings: 16 studies reported histology-controlled CAP including the XL probe, and individual data from 13 papers and 2346 patients were included. Patients with a mean age of 46·5 years (SD 14·5) were recruited from 20 centres in nine countries. 2283 patients had data for BMI; 673 (29%) were normal weight (BMI <25 kg/m), 530 (23%) were overweight (BMI ≥25 to <30 kg/m), and 1080 (47%) were obese (BMI ≥30 kg/m). 1277 (54%) patients had NAFLD, 474 (20%) had viral hepatitis, 285 (12%) had alcohol-associated liver disease, and 310 (13%) had other liver disease aetiologies. The XL probe was recommended in 1050 patients, 930 (89%) of whom had NAFLD; among the patients with NAFLD, the areas under the curve were 0·819 (95% CI 0·769-0·869) for S0 versus S1 to S3 and 0·754 (0·720-0·787) for S0 to S1 versus S2 to S3. CAP values were independently affected by aetiology, diabetes, BMI, aspartate aminotransferase, and sex. Optimal cutoffs differed substantially across aetiologies. Risk of bias according to QUADAS-2 was low.

Interpretation: CAP cutoffs varied according to cause, and can effectively recognise significant steatosis in patients with viral hepatitis. CAP cannot grade steatosis in patients with NAFLD adequately, but its value in a NAFLD screening setting needs to be studied, ideally with methods beyond the traditional histological reference standard.

Funding: The German Federal Ministry of Education and Research and Echosens.
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http://dx.doi.org/10.1016/S2468-1253(20)30357-5DOI Listing
March 2021

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus.

World J Hepatol 2020 Dec;12(12):1326-1340

U1248 INSERM, Department of Hepatology and Gastroenterology, Univ. Limoges, CHU Limoges, Limoges F-87000, France.

Background: The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.

Aim: To determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated untreated hepatitis B virus (HBV)-monoinfected patients.

Methods: A prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher's exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.

Results: Of the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% 30.7%, 0.42 and 50.0% 30.7%, = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group the naïve group (hazard ratio: 2.283, = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.

Conclusion: The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.
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http://dx.doi.org/10.4254/wjh.v12.i12.1326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772739PMC
December 2020

Reliability Criteria of Two-Dimensional Shear Wave Elastography: Analysis of 4277 Measurements in 788 Patients.

Clin Gastroenterol Hepatol 2020 Dec 16. Epub 2020 Dec 16.

Laboratoire HIFIH, UPRES EA3859, SFR 4208, Université d'Angers, Angers, France; Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire d'Angers, Angers, France.

Background & Aims: Two-dimensional shear wave elastography (2D-SWE) is an accurate method for the non-invasive evaluation of liver fibrosis. We aimed to determine the reliability criteria and the number of necessary reliable measurements for 2D-SWE.

Methods: 788 patients with chronic liver disease underwent liver biopsy and 2D-SWE examination in three centers. The 4277 2D-SWE measurements performed were 2:1 randomly divided into derivation (n = 2851) and validation (n = 1426) sets. Reliability criteria for a 2D-SWE measurement were defined in the derivation set from the intrinsic characteristics given by the device (mean liver stiffness, standard deviation, diameter of the region of interest), with further evaluation in the validation set.

Results: In the whole population of 4277 measurements, AUROC for bridging fibrosis was 0.825 ± 0.006 and AUROC for cirrhosis was 0.880 ± 0.006. Mean stiffness and coefficient of variation (CV) were independent predictors of bridging fibrosis or cirrhosis. From these two parameters, new criteria were derived to define a reliable 2D-SWE measurement: stiffness <8.8 kPa, or stiffness between 8.8-11.9 kPa with CV <0.25, or stiffness ≥12.0 kPa with CV <0.10. In the validation set, AUROC for bridging fibrosis was 0.830 ± 0.013 in reliable measurements vs 0.667 ± 0.031 in unreliable measurements (p < 0.001). AUROC for cirrhosis was 0.918±0.014 vs 0.714 ± 0.027, respectively (p < 0.001). The best diagnostic accuracy for a 2D-SWE examination was achieved from three reliable measurements.

Conclusions: Reliability of a 2D-SWE measurement relies on the coefficient of variation and the liver stiffness level. A 2D-SWE examination should include three reliable measurements according to our new criteria.
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http://dx.doi.org/10.1016/j.cgh.2020.12.013DOI Listing
December 2020

Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease.

J Hepatol 2020 Dec 8. Epub 2020 Dec 8.

UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK. Electronic address:

Background: The Baveno VI consensus proposed a dual liver stiffness (LS) by transient elastography threshold of <10 and >15 kPa for excluding and diagnosing compensated advanced chronic liver disease (cACLD), in the absence of other clinical signs. We validated these criteria in a real-world multicentre study.

Methods: We included 5648 patients (mean age 51±13 years, 53% males) from ten European liver centres who had a liver biopsy and LS measurement within 6 months. We included patients with chronic hepatitis C (CHC, n=2913, 52%), non-alcoholic fatty liver disease (NAFLD, n=1073, 19%), alcohol-related liver disease (ALD, n=946, 17%) or chronic hepatitis B (CHB, n=716, 13%). cACLD was defined as fibrosis stage ≥F3.

Results: Overall, 3606 (66%) and 987 (18%) patients had LS <10 and >15 kPa, respectively, while cACLD was histologically confirmed in 1772 (31%) patients. The cut-offs of <10 and >15 kPa showed 75% sensitivity and 96% specificity to exclude and diagnose cACLD, respectively. Examining the ROC curve, a more optimal dual cut-off at <7 and >12 kPa, with 91% sensitivity and 92% specificity for excluding and diagnosing cACLD (AUC=0.87, 95%CI:0.86-0.88, P<0.001) was derived. Specifically for ALD and NAFLD, a low cut-off of 8 kPa can be used (sensitivity=93%). For the unclassified patients, we derived a risk model based on common patient characteristics with better discrimination than LS alone (AUC=0.74 vs. 0.69, P<0.001).

Conclusions: Instead of the Baveno VI proposed <10 and >15 kPa dual cut-offs, we found that the <8 kPa (or <7 kPa for viral hepatitis) and >12 kPa dual cut-offs have better diagnostic accuracy in cACLD.
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http://dx.doi.org/10.1016/j.jhep.2020.11.050DOI Listing
December 2020

Transient Versus 2-Dimensional Shear-Wave Elastography in a Multistep Strategy to Detect Advanced Fibrosis in NAFLD.

Hepatology 2020 Nov 24. Epub 2020 Nov 24.

Centre d'Investigation de la Fibrose Hépatique, Hôpital Haut-Lévêque, University Hospital of Bordeaux, Pessac, France.

The combination of laboratory and elastography tests allows the accurate diagnosis of advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). In this study, we compared the diagnostic performances of a two-step strategy (laboratory tests and vibration-controlled transient elastography [VCTE] or 2-dimensional shear-wave elastography with SuperSonic Imagine [2D-SWE-SSI]) and the added value of a three-step strategy (laboratory tests and two elastography methods). From a prospective registry, we retrospectively selected 577 consecutive patients with suspicion of NAFLD who underwent laboratory tests to calculate the Fibrosis-4 (FIB-4) score, liver stiffness evaluation by VCTE (M and XL probes) and 2D-SWE-SSI, and liver biopsy. The diagnostic performances and need for liver biopsy in unclassified patients for the diagnosis of advanced fibrosis (F ≥3) in multistep strategies were compared. The area under the curve of FIB-4, VCTE, and 2D-SWE-SSI was 0.74, 0.82, and 0.88, respectively. Using the same thresholds, the FIB-4/2D-SWE-SSI and FIB-4/VCTE diagnostic performances were comparable (sensitivity: 71.4% and 66%; specificity: 91.4% and 91.5%; and accuracy: 83.7% and 81.4%; all P = NS). Conversely, more patients required liver biopsy after 2D-SWE-SSI (24.6% vs. 15.3%; P < 0.001). Performing a second elastography technique in patients with unreliable or grey zone (between 8 and10 kPa) results greatly decreased the need for liver biopsy (42/577; 7.3%). The diagnostic performances (accuracy, sensitivity, and specificity) of FIB-4/2D-SWE-SSI/VCTE and FIB-4/VCTE/2D-SWE-SSI were comparable (81.1%, 71.5%, and 87.9% vs. 81.3%, 69.7%, and 89.5%, respectively [all P = NS]). Conclusion: Using the same cut-off values, 2D-SWE-SSI is as accurate as VCTE for advanced liver fibrosis diagnosis in NAFLD. The three-step strategy in selected patients strongly decreased the need for liver biopsy while maintaining excellent accuracy.
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http://dx.doi.org/10.1002/hep.31655DOI Listing
November 2020

French hepatitis C care cascade: substantial impact of direct-acting antivirals, but the road to elimination is still long.

BMC Infect Dis 2020 Oct 15;20(1):759. Epub 2020 Oct 15.

Paris-Saclay University, Versailles Saint-Quentin University, Inserm, CESP, Anti-infective evasion and pharmacoepidemiology, Villejuif, France.

Background: Hepatitis C virus (HCV) elimination by 2030, as targeted by the World Health Organization (WHO), requires that 90% of people with chronic infection be diagnosed and 80% treated. We estimated the cascade of care (CoC) for chronic HCV infection in mainland France in 2011 and 2016, before and after the introduction of direct-acting antivirals (DAAs).

Methods: The numbers of people (1) with chronic HCV infection, (2) aware of their infection, (3) receiving care for HCV and (4) on antiviral treatment, were estimated for 2011 and 2016. Estimates for 1) and 2) were based on modelling studies for 2011 and on a virological sub-study nested in a national cross-sectional survey among the general population for 2016. Estimates for 3) and 4) were made using the National Health Data System.

Results: Between 2011 and 2016, the number of people with chronic HCV infection decreased by 31%, from 192,700 (95% Credibility interval: 150,900-246,100) to 133,500 (95% Confidence interval: 56,900-312,600). The proportion of people aware of their infection rose from 57.7 to 80.6%. The number of people receiving care for HCV increased by 22.5% (representing 25.7% of those infected in 2016), while the number of people on treatment increased by 24.6% (representing 12.1% of those infected in 2016).

Conclusions: This study suggests that DAAs substantially impact CoC. However, access to care and treatment for infected people remained insufficient in 2016. Updating CoC estimates will help to assess the impact of new measures implemented since 2016 as part of the goal to eliminate HCV.
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http://dx.doi.org/10.1186/s12879-020-05478-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559725PMC
October 2020

Increased mortality in HIV/HCV-coinfected compared to HCV-monoinfected patients in the DAA era due to non-liver-related death.

J Hepatol 2021 Jan 14;74(1):37-47. Epub 2020 Aug 14.

ISPED, INSERM, Bordeaux Population Health Research Center, Team MORPH3EUS, UMR 1219, CIC-EC 1401, University of Bordeaux, Bordeaux, France; CHU de Bordeaux, Pôle de Santé Publique, Bordeaux, France. Electronic address:

Background & Aims: Direct-acting antivirals (DAA) lead to high sustained virological response (SVR) rates and decrease the risk of disease progression. We compared SVR rates and all-cause, liver- and non-liver-related deaths, liver-related events, and non-liver-related cancers in HIV/HCV-coinfected and HCV-monoinfected participants from 2 French cohort studies after initiation of DAA treatment.

Methods: Up to 4 HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to each HIV/HCV-coinfected patient from the ANRS CO13 HEPAVIH cohort; both are nationwide, prospective, multicentre, and observational. Participants were initiated on DAAs between March 2014 and December 2017. Cox proportional hazards models adjusted by age, sex, duration since HCV diagnosis, HCV transmission routes, HCV genotypes, cirrhosis, tobacco, alcohol consumption, and SVR (time dependent) were used.

Results: A total of 592 HIV/HCV-coinfected and 2,049 HCV-monoinfected participants were included; median age was 53.3 years (inter-quartile range: 49.6-56.9) and 52.9 years (49.6; 56.7), 1,498 (73.1%) and 436 (73.6%) were men, and 159 (28.8%) and 793 (41.2%) had cirrhosis, respectively. SVR was observed in 92.9% and 94.6%, respectively. HIV coinfection was associated with higher risk of all-cause death (hazard ratio [HR] 1.93; 95% CI 1.01-3.69), non-liver-related death (HR 2.84; 95% CI 1.27-6.36), and non-liver-related cancer (HR 3.26; 95% CI 1.50-7.08), but not with liver-related-death (HR 1.04; 95% CI 0.34-3.15) or liver-related events (HR 0.66; 95% CI 0.31-1.44).

Conclusions: After DAA treatment, HIV-coinfected individuals had similar SVR rates and risk of liver-related deaths and events compared with HCV-monoinfected individuals, but had a higher risk of all-cause and non-liver-related deaths and non-liver-related cancers.

Lay Summary: We compared the risk of several clinical events in participants infected by human immunodeficiency virus and hepatitis C virus with those infected with hepatitis C virus alone, matched on age and sex, after treatment with contemporary direct-acting antivirals. We found a higher risk of all-cause deaths, non-liver-related deaths, and non-liver-related cancers in participants coinfected with the human immunodeficiency virus and hepatitis C virus, and no differences for the risk of liver-related deaths or events.
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http://dx.doi.org/10.1016/j.jhep.2020.08.008DOI Listing
January 2021

Molecular profiling and risk classification of patients with myeloproliferative neoplasms and splanchnic vein thromboses.

Blood Adv 2020 08;4(15):3708-3715

Centre d'Investigations Cliniques (CIC) 1427, INSERM, Hôpital Saint-Louis, Université de Paris, Paris, France.

Myeloproliferative neoplasms (MPNs) are the most frequent underlying causes of splanchnic vein thromboses (SVTs). MPN patients with SVTs (MPN-SVT) often have a unique presentation including younger age, female predominance, and low Janus kinase 2 (JAK2) mutation allele burden. This study aimed at identifying risk factors for adverse hematologic outcomes in MPN-SVT patients. We performed a retrospective study of a fully characterized cohort of MPN-SVT patients. The primary outcome was the incidence of evolution to myelofibrosis, acute leukemia, or death. Eighty patients were included in the testing cohort. Median follow-up was 11 years. Most of the patients were women with a mean age of 42 years and a diagnosis of polycythemia vera. The primary outcome was met in 13% of the patients and was associated with a JAK2V617F allele burden ≥50% (odds ratio [OR], 14.7) and presence of additional mutations in genes affecting chromatin/spliceosome (OR, 9). We identified high-risk patients (29% of the cohort) as those harboring at least 1 molecular risk factor: JAK2-mutant allele burden ≥50%, presence of chromatin/spliceosome/TP53 mutation. High-risk patients had worse event-free survival (81% vs 100%; P = .001) and overall survival at 10 years (89% vs 100%; P = .01) than low-risk patients. These results were confirmed in an independent validation cohort of 30 MPN-SVT patients. In conclusion, molecular profiling identified MPN-SVT patients with dismal outcome. In this high-risk population, a disease-modifying therapy should be taken into consideration to minimize the probability of transformation.
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http://dx.doi.org/10.1182/bloodadvances.2020002414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422133PMC
August 2020

Eight Weeks of Treatment With Glecaprevir/Pibrentasvir Is Safe and Efficacious in an Integrated Analysis of Treatment-Naïve Patients With Hepatitis C Virus Infection.

Clin Gastroenterol Hepatol 2020 Oct 1;18(11):2544-2553.e6. Epub 2020 Jul 1.

Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom.

Background & Aims: The direct-acting antiviral combination glecaprevir/pibrentasvir has been approved by the Food and Drug Administration for 8 weeks of treatment in treatment-naïve patients with hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis. We performed an integrated analysis of data from trials to evaluate the overall efficacy and safety of 8 weeks of glecaprevir/pibrentasvir in treatment-naïve patients without cirrhosis or with compensated cirrhosis.

Methods: We pooled data from 8 phase 2 or phase 3 trials of treatment-naïve patients with HCV genotype 1 to 6 infections, without cirrhosis or with compensated cirrhosis, who received 8 weeks of glecaprevir/pibrentasvir.

Results: Of 1248 patients, 343 (27%) had cirrhosis. Most patients were white (80%) and had HCV genotype 1 infection (47%) or genotype 3 infection (22%); the median age was 54 years. Overall rates of sustained virologic response at post-treatment week 12 were 97.6% (1218 of 1248) in the intention to treat (ITT) and 99.3% (1218 of 1226) in the modified ITT populations. When we excluded patients with genotype 3 infections with compensated cirrhosis (consistent with the European label), rates of sustained virologic response at post-treatment week 12 were 97.6% in the ITT and 99.4% in the modified ITT populations. Eight virologic failures (7 in patients without cirrhosis and 1 in a patient with cirrhosis) occurred in the ITT population. Virologic failure was not associated with markers of advanced liver disease or populations of interest (current alcohol use, opioid substitution therapy, history of injection-drug use, and severe renal impairment). Treatment-emergent adverse events (AEs) occurred in 58% of patients. The most frequent AEs (>10%) were headache (12%) and fatigue (12%). Serious AEs and AEs that led to glecaprevir/pibrentasvir discontinuation were reported in 2% and less than 1% of patients, respectively.

Conclusions: In a pooled analysis of data from 8 trials, we found that 8 weeks of treatment with glecaprevir/pibrentasvir is efficacious and well tolerated in treatment-naïve patients with HCV genotype 1 to 6 infections, with or without cirrhosis.
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http://dx.doi.org/10.1016/j.cgh.2020.06.044DOI Listing
October 2020

Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease.

Clin Gastroenterol Hepatol 2020 Jul 2. Epub 2020 Jul 2.

Centre d'Investigation de la Fibrose Hépatique, INSERM U1053, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France.

Background & Aims: Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events.

Methods: We performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3-F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19-63 months).

Results: Based on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00-1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02-1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11-2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02).

Conclusions: In patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.
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http://dx.doi.org/10.1016/j.cgh.2020.06.045DOI Listing
July 2020

Personalized surveillance for hepatocellular carcinoma in cirrhosis - using machine learning adapted to HCV status.

J Hepatol 2020 Dec 29;73(6):1434-1445. Epub 2020 Jun 29.

AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy; Université Paris 13, Sorbonne Paris Cité, "Equipe labellisée Ligue Contre le Cancer", F-93206 Saint-Denis; Inserm, UMR-1162, "Génomique fonctionnelle des tumeur solides", F-75000, Paris, France. Electronic address:

Background & Aims: Refining hepatocellular carcinoma (HCC) surveillance programs requires improved individual risk prediction. Thus, we aimed to develop algorithms based on machine learning approaches to predict the risk of HCC more accurately in patients with HCV-related cirrhosis, according to their virological status.

Methods: Patients with compensated biopsy-proven HCV-related cirrhosis from the French ANRS CO12 CirVir cohort were included in a semi-annual HCC surveillance program. Three prognostic models for HCC occurrence were built, using (i) Fine-Gray regression as a benchmark, (ii) single decision tree (DT), and (iii) random survival forest for competing risks survival (RSF). Model performance was evaluated from C-indexes validated externally in the ANRS CO22 Hepather cohort (n = 668 enrolled between 08/2012-01/2014).

Results: Out of 836 patients analyzed, 156 (19%) developed HCC and 434 (52%) achieved sustained virological response (SVR) (median follow-up 63 months). Fine-Gray regression models identified 6 independent predictors of HCC occurrence in patients before SVR (past excessive alcohol intake, genotype 1, elevated AFP and GGT, low platelet count and albuminemia) and 3 in patients after SVR (elevated AST, low platelet count and shorter prothrombin time). DT analysis confirmed these associations but revealed more complex interactions, yielding 8 patient groups with varying cancer risks and predictors depending on SVR achievement. On RSF analysis, the most important predictors of HCC varied by SVR status (non-SVR: platelet count, GGT, AFP and albuminemia; SVR: prothrombin time, ALT, age and platelet count). Externally validated C-indexes before/after SVR were 0.64/0.64 [Fine-Gray], 0.60/62 [DT] and 0.71/0.70 [RSF].

Conclusions: Risk factors for hepatocarcinogenesis differ according to SVR status. Machine learning algorithms can refine HCC risk assessment by revealing complex interactions between cancer predictors. Such approaches could be used to develop more cost-effective tailored surveillance programs.

Lay Summary: Patients with HCV-related cirrhosis must be included in liver cancer surveillance programs, which rely on ultrasound examination every 6 months. Hepatocellular carcinoma (HCC) screening is hampered by sensitivity issues, leading to late cancer diagnoses in a substantial number of patients. Refining surveillance periodicity and modality using more sophisticated imaging techniques such as MRI may only be cost-effective in patients with the highest HCC incidence. Herein, we demonstrate how machine learning algorithms (i.e. data-driven mathematical models to make predictions or decisions), can refine individualized risk prediction.
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http://dx.doi.org/10.1016/j.jhep.2020.05.052DOI Listing
December 2020

Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis.

Liver Transpl 2020 11 22;26(11):1477-1491. Epub 2020 Oct 22.

Service d'Hépatologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), and its effect on the outcomes of liver transplantation (LT) for PSC is unclear. We retrospectively collected data from adults who underwent LT for PSC from 1989 to January 2018 in 4 French LT centers. We compared the rates of patient and graft survivals and of complications after LT. Among 87 patients, 52 (60%) had preexisting IBD. Excluding those who died within the first 3 months, the 10-year patient survival and graft survival rates were 92.6% (95% confidence interval [CI], 84.3%-100%) and 77.1% (53.8%-85.3%), respectively, in the PSC with IBD (PSC-IBD) group and 97.1% (91.4%-100%; P = 0.44) and 83.2% (69.6%-96.9%; P = 0.43) in the isolated PSC group, respectively. Exposure to azathioprine after LT was significantly associated with mortality (odds ratio [OR], 15.55; 1.31-184.0; P = 0.03), whereas exposure to mycophenolate mofetil was associated with improved survival (OR, 0.17; 95% CI, 0.04-0.82; P = 0.03), possibly an era effect. The rate of recurrent PSC was 21% in the PSC-IBD group and 11% in the isolated PSC group (P = 0.24). Severe infections occurred in 125 per 1000 person-years in both groups. Exposure to mycophenolate mofetil was associated with a lower risk of infection (OR, 0.26; 95% CI, 0.08-0.85; P = 0.03). The presence of IBD was associated with cytomegalovirus (CMV) infection (OR, 3.24; 95% CI, 1.05-9.98; P = 0.04). IBD prior to LT for PSC may not affect patient or transplant survival but may increase the risk of CMV infection.
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http://dx.doi.org/10.1002/lt.25838DOI Listing
November 2020

Absence of impact of direct acting antivirals for hepatitis C virus on recurrent hepatocellular carcinoma tumor growth in the AFEF/ANRS CO22 Hepather cohort.

Clin Res Hepatol Gastroenterol 2021 Jan 25;45(1):101459. Epub 2020 Jun 25.

Hepatology Unit, Hôpital Cochin, AP-HP, 27, rue du Fg Saint-Jacques, 75014 Paris, France.

Background: Although it has now been excluded that direct-acting antivirals (DAA) are associated with a significant risk of hepatocellular carcinoma (HCC) in HCV-infected patients, a possible effect of DAA on tumor growth is still a subject of debate. We performed a blind comparison of the kinetics of HCC recurrence in patients after HCV treatment with or without DAA to evaluate the potential aggressiveness of HCC after DAA treatment.

Basic Procedures: Thirty-nine HCV-infected patients from the AFEF/ANRS CO22 Hepather cohort who experienced HCC recurrence after so-called curative treatment were evaluated. Contrast-enhanced CT and/or MR images were read blindly 6 months before HCC recurrence and during the follow-up period. Seventeen patients who received DAA (DAA+) before HCC recurrence were compared to the 22 who did not receive (DAA-), according to the LiRads and mRECIST criteria.

Main Findings: There were 28 men and 11 women, median age 62 years old, 37 (95%) with cirrhosis. DAA+ patients had a lower median MELD score (8±2 vs. 10±4, P=0.0286) than DAA- patients. The median time to HCC recurrence (time from the date of curative treatment to the diagnosis of recurrence) was not different (20 vs. 18 months) (P=0.73) between the two groups. There was no difference between the 2 groups in the overall survival and/or transplantation-free survival (P=0.71) and for the mRECIST time to progression (P=0.25).

Conclusion: This blinded analysis of HCC recurrence after HCC treatment does not support any negative impact of DAA therapy on the severity or progression of recurrent HCC.
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http://dx.doi.org/10.1016/j.clinre.2020.04.022DOI Listing
January 2021

Including Ratio of Platelets to Liver Stiffness Improves Accuracy of Screening for Esophageal Varices That Require Treatment.

Clin Gastroenterol Hepatol 2020 Jun 17. Epub 2020 Jun 17.

Hepato-Gastroenterology Department, University Hospital, Angers, France; HIFIH Laboratory, UPRES 3859, UNIV Angers, France; INSERM UMR 1162, Paris, France. Electronic address:

Background & Aims: Based on platelets and liver stiffness measurements, the Baveno VI criteria (B6C), the expanded B6C (EB6C), and the ANTICIPATE score can be used to rule out varices needing treatment (VNT) in patients with compensated chronic liver disease. We aimed to improve these tests by including data on the ratio of platelets to liver stiffness.

Methods: In a retrospective analysis of data from 10 study populations, collected from 2004 through 2018, we randomly assigned data from 2368 patients with chronic liver disease of different etiologies to a derivation population (n = 1579; 15.1% with VNT, 50.2% with viral hepatitis, 28.9% with nonalcoholic fatty liver disease, 28.9% with alcohol-associated liver disease, 20.8% with model for end-stage liver disease scores of 9.5 ± 3.0, and 93.0% with liver stiffness measurements ≥10 kPa) or a validation population (n = 789). Test results were compared with results from a sequential algorithm (VariScreen). VariScreen incorporated data on platelets or liver stiffness measurements and then the ratio of platelets to liver stiffness measurement, adjusted for etiology, patient sex, and international normalized ratio.

Results: In the derivation population, endoscopies were spared for 23.9% of patients using the B6C (VNT missed in 2.9%), 24.3% of patients using the ANTICIPATE score (VNT missed in 4.6%), 34.5% of patients using VariScreen (VNT missed in 2.9%), and 41.9% of patients using the EB6C (VNT missed in 10.9%). Differences in spared endoscopy rates were significant (P ≤ .001), except for B6C vs ANTICIPATE and in missed VNT only for EB6C vs the others (P ≤ .009). VariScreen was the only safe test regardless of sex or etiology (missed VNT, ≤5%). Moreover, VariScreen secured screening without missed VNT in patients with model for end-stage liver disease scores higher than 10. This overall strategy performed better than a selective strategy restricted to patients with compensated liver disease. Test performance and safety did not differ significantly among populations.

Conclusions: In a retrospective study of data from 2368 patients with chronic liver disease, we found that the B6C are safe whereas the EB6C are unsafe, based on missed VNT. The VariScreen algorithm performed well in patients with chronic liver disease of any etiology or severity-it is the only test that safely rules out VNT and can be used in clinical practice.
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http://dx.doi.org/10.1016/j.cgh.2020.06.022DOI Listing
June 2020

Sofosbuvir-Daclatasvir is suboptimal in patients with genotype 2 chronic hepatitis C infection: real-life experience from the HEPATHER ANRS CO22 cohort.

J Viral Hepat 2020 10 21;27(10):964-973. Epub 2020 May 21.

Hepatology Unit, APHP Cochin, Paris, France.

Sofosbuvir plus daclatasvir with or without ribavirin has demonstrated a high efficacy and an acceptable safety profile in clinical trials of patients infected with genotype 2 hepatitis Cvirus (HCV); however, there are currently no real-world data available for this regimen. To evaluate the real-life safety and efficacy of sofosbuvir/daclatasvir with or without ribavirin in genotype 2 HCV patients in the French cohort ANRS CO22 HEPATHER(NCT01953458). In this ongoing, national, multicentre, prospective, observational study, we observed patients with HCV genotype 2 infection who initiated treatment with sofosbuvir (400 mg/d) plus daclatasvir with or without ribavirin (1-1.2 g/d). Patients were divided into two treatment groups: sofosbuvir/daclatasvir with or without ribavirin (12 weeks/24 weeks). The primary end point was a sustained virological response at week 12 following the end of therapy. Overall, 88% and 91% of patients achieved a sustained virological response following 12 and 24 weeks of treatment with sofosbuvir/daclatasvir with or without ribavirin, respectively. The most common adverse events were asthenia (29%), headache (15%) and fatigue (20%), and ribavirin addition was associated with a higher rate of adverse events and treatment discontinuation. Sofosbuvir/daclatasvir with or without ribavirin was associated with lower rates of sustained virological response in the real-life setting compared with the clinical setting and demonstrated suboptimal efficacy for the treatment of patients with genotype 2 chronic HCV.
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http://dx.doi.org/10.1111/jvh.13321DOI Listing
October 2020

Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.

Neurology 2020 05 12;94(21):e2189-e2202. Epub 2020 May 12.

From the Neurology Department (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital; National Reference Centre for Wilson's Disease (A.P., P.C., J.-M.T., F.W.), AP-HP, Lariboisière University Hospital, Paris; Hepatobiliary Centre (R.S., D.C., D.S., J.-C.D.-V.), DHU Hepatinov, UMR-1193, AP-HP, Paul Brousse Hospital, Villejuif; Service de Neurologie (W.G.M.), CHU Bordeaux; Université de Bordeaux (W.G.M.), Institut des Maladies Neurodégénératives, CNRS UMR 5393, France; Department of Medicine (W.G.M.), University of Otago and New Zealand Brain Research Institute (W.G.M.), Christchurch; Hepatology, Gastroenterology and Nutrition Department (A.-S.B., A.L.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon; National Reference Centre for Wilson's Disease (A.-S.B., E.B., C.L., L.L.-F., O.G., A.L.), Hospices Civils de Lyon; Neurology Department (E.B., C.L.), Hôpital Neurologique Pierre-Wertheimer, Hospices Civils de Lyon; CNRS (E.B., C.L.), UMR 5229, Institut des Sciences Cognitives Marc-Jeannerod, Bron; Faculté de Médecine Lyon Sud Charles-Mérieux (E.B., C.L., A.L.), Université Claude-Bernard Lyon 1; Neurology and Paediatrics Department (L.L.-F.), Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron; Hepatogastroenterology Department (O.G.), Edouard Herriot Hospital, Hospices Civils de Lyon; Internal Medicine Department (F.M.), National Reference Centre for Inborn Errors of Metabolism, Université François Rabelais; Neurology Department (J.B.), CHRU Bretonneau, Tours; Surgery, Oncology and Liver Transplantation Department (E.S.), CHRU Tours; Hepatology and Gastroenterology Department (C.V.) and Surgery and Liver Transplantation Department (B.H.), CHU Besançon; Neurology and Paediatrics Department (C. Bellesme), AP-HP, Bicêtre University Hospital, Kremlin-Bicetre; Pediatric Hepatology and Pediatric Liver Transplantation Unit (U.H) and National Reference Centre for Rare Pediatric Liver Diseases (U.H), Bicêtre University Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, DHU Hepatinov, AP-HP, Le Kremlin Bicêtre; INSERM (D.H.), UMR-S1174, Hepatinov, University of Paris Sud 11, Orsay; Hepatology and Gastroenterology Department (C. Bureau) and Neurology Department (F.O.-M.), CHU Toulouse; Centre D'investigation de la Fibrose Hépatique (V.L.), Hôpital Haut-Lévêque, CHU Bordeaux; and INSERM U1053 (V.d.L.), Université de Bordeaux, France. A. Poujois is currently at Neurology Department, Rothschild Foundation Hospital, and National Reference Centre for Wilson's Disease, Rothschild Foundation Hospital, Paris.

Objective: To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods: French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results: Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved ( < 0.0001 and = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved ( = 0.0007). Severe sepsis ( = 0.011) and intensive care unit admission ( = 0.001) before LT were significantly associated with death.

Conclusions: LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

Classification Of Evidence: This study provides Class IV evidence that for patients with WD with severe neurologic worsening resistant to active pharmacologic therapy, LT might decrease neurologic impairment.
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http://dx.doi.org/10.1212/WNL.0000000000009474DOI Listing
May 2020

Agreement Between 2-Dimensional Shear Wave and Transient Elastography Values for Diagnosis of Advanced Chronic Liver Disease.

Clin Gastroenterol Hepatol 2020 Dec 26;18(13):2971-2979.e3. Epub 2020 Apr 26.

Centre d'investigation de la fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac, France.

Background & Aims: Inter-platform variation in liver stiffness evaluation (LSE) could hinder dissemination and clinical implementation of new ultrasound methods. We aimed to determine whether measurements of liver stiffness by bi-dimensional shear wave elastography (2D-SWE) with a Supersonic Imagine apparatus are comparable to those made by vibration-controlled transient elastography (VCTE).

Methods: We collected data from 1219 consecutive patients with chronic liver disease who underwent LSE by VCTE and 2D-SWE (performed by blinded operators), on the same day, at a single center in France from September 2011 through June 2019. We assessed the ability of liver stiffness value distributions and 2D-SWE performances to identify patients with compensated advanced chronic liver disease (cACLD) according to the Baveno VI criteria, based on VCTE cut-off values.

Results: VCTE and 2D-SWE values correlated (Pearson's correlation coefficient, 0.882; P < .0001; Lin concordance coefficient, 0.846; P < .0001). The median stiffness values were 6.7 kPa with VCTE (interquartile range, 4.8-11.6 kPa) and 7.1 kPa with 2D-SWE (interquartile range, 5.4-11.1 kPa) (P = .736). 2D-SWE values were slightly higher in the low percentiles and lower in the high percentiles; the best match with VCTE values were at approximately 7-9 kPa. The area under the curve of 2D-SWE for identifying of VCTE values below 10 was 0.964 (95% CI, 0.952-0.976) and for VCTE values above 15 kPa was 0.976 (95% CI, 0.963-0.988), with Youden index-associated cut-off values of 9.5 and 13kPa and best accuracy cut-off values of 10 kPa and 14 kPa, respectively. A 2D-SWE cut-off value of 10 kPa detected VCTE values below 10k Pa with 92% sensitivity, 87% specificity, and 91% accuracy.

Conclusions: Measurement of liver stiffness by VCTE or 2D-SWE produces comparable results. 2D-SWE accurately identifies patients with cACLD according to the Baveno VI criteria based on VCTE cut-off values. A 10 kPa 2D-SWE cut-off value can be used to rule out cACLD.
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http://dx.doi.org/10.1016/j.cgh.2020.04.034DOI Listing
December 2020

Sinusoidal obstruction syndrome.

Clin Res Hepatol Gastroenterol 2020 09 3;44(4):480-485. Epub 2020 Apr 3.

Department of Hepatology, DHU Unity, Beaujon Hospital, AP-HP, 100, boulevard du Général-Leclerc, 92118 Clichy, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France; Reference center of vascular liver diseases, European Reference Network (ERN) 'Rare-Liver', France.

Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is characterized by concentric and non-thrombotic obstruction of the sinusoid and central vein lumen with no identified primitive or thrombotic hepatic vein lesions. The initial lesion is a result of endothelial denudation, corresponding to the migration of damaged sinusoidal cells to the central veins of the hepatic lobules, leading to sinusoidal and veno-occlusive congestive obstruction. SOS may be associated with other lesions such as centrilobular perisinusoidal fibrosis, peliosis, or nodular regenerative hyperplasia. The first cases of SOS were documented in 1920 in South Africa, after ingestion of food sources contaminated by pyrrolizidine alkaloids. SOS is a well-known complication of hematopoietic stem cell transplantation (HSCT). Numerous toxins and drugs have been associated with SOS, mainly chemotherapies and immunosuppressive therapies, as well as total body or liver irradiation and ABO mismatch platelet transfusion. The pathogenesis of this entity remains unknown.
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http://dx.doi.org/10.1016/j.clinre.2020.03.019DOI Listing
September 2020

Prediction of Esophageal Varices by Liver Stiffness and Platelets in Persons With Human Immunodeficiency Virus Infection and Compensated Advanced Chronic Liver Disease.

Clin Infect Dis 2020 Dec;71(11):2810-2817

McGill University Health Centre, Montreal, Quebec, Canada.

Background: People living with human immunodeficiency virus (PLWH) are at increased risk of cirrhosis and esophageal varices. Baveno VI criteria, based on liver stiffness measurement (LSM) and platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for esophageal varices needing treatment (EVNT). This approach has not been validated in PLWH.

Methods: PLWH from 8 prospective cohorts were included if they fulfilled the following criteria: (1) compensated advanced chronic liver disease (LSM >10 kPa); (2) availability of EGD within 6 months of reliable LSM. Baveno VI (LSM <20 kPa and platelets >150 000/μL), expanded Baveno VI (LSM <25 kPa and platelets >110 000/μL), and Estudio de las Hepatitis Víricas (HEPAVIR) criteria (LSM <21 kPa) were applied to identify patients not requiring EGD screening. Criteria optimization was based on the percentage of EGDs spared, while keeping the risk of missing EVNT <5%.

Results: Five hundred seven PLWH were divided into a training (n = 318) and a validation set (n = 189). EVNT were found in 7.5%. In the training set, Baveno VI, expanded Baveno VI, and HEPAVIR criteria spared 10.1%, 25.5%, and 28% of EGDs, while missing 0%, 1.2%, and 2.2% of EVNT, respectively. The best thresholds to rule out EVNT were platelets >110 000/μL and LSM <30 kPa (HIV cirrhosis criteria), with 34.6% of EGDs spared and 0% EVNT missed. In the validation set, HEPAVIR and HIV cirrhosis criteria spared 54% and 48.7% of EGDs, while missing 4.9% and 2.2% EVNT, respectively.

Conclusions: Baveno VI criteria can be extended to HEPAVIR and HIV cirrhosis criteria while sparing a significant number of EGDs, thus improving resource utilization for PLWH with compensated advanced chronic liver disease.
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http://dx.doi.org/10.1093/cid/ciz1181DOI Listing
December 2020

Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease.

Liver Int 2020 03 8;40(3):581-589. Epub 2019 Dec 8.

Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépatologie, Bordeaux, France.

Background And Aims: In non-alcoholic fatty liver disease (NAFLD), fibrosis is the strongest prognostic factor and can be assessed by non-invasive methods. We evaluated the ability of liver stiffness measurement (LSM) to predict overall survival and liver, cardiovascular and oncologic complications.

Methods: We prospectively collected data on 2251 consecutive NAFLD patients (mean age 59 years, male 53%, mean body mass index 28 kg/m ) in two centres. At inclusion, all patients had LSM, clinical and biological evaluation. During follow-up, we recorded cardiovascular events, cancers, liver complications, liver transplantation and death. The primary endpoint was overall survival. Survival curves according to LSM were first performed using Kaplan-Meier method for the primary endpoint, and Aalen-Johansen method for secondary outcomes to take into account competitive risks. In a second step, a Cox proportional hazard model analysis was done to identify independent predictors of overall survival.

Results: Median follow-up was 27 months [IQR: 25-38]. Fifty-five patients died and three patients had liver transplantation. Overall survival significantly decreased as baseline LSM increased. Twenty-one patients (0.9%) had a liver event, 142 (6.3%) developed cancer (excluding HCC) and 151 (6.7%) had a cardiovascular event during follow-up. By multivariable analysis, independent predictors of overall survival were as follows: baseline LSM (adjusted HR (aHR) = 2.85 [1.65-4.92], P = .0002), age (aHR = 1.11 [1.08-1.13], P < .0001) and male sex (aHR = 2.05 [1.17-3.57], P = .012). Patients with elevated LSM were also more likely to develop cardiovascular, and liver events but not other cancers.

Conclusion: LSM can be used to predict survival, cardiovascular and liver complications in NAFLD patients.
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http://dx.doi.org/10.1111/liv.14301DOI Listing
March 2020

Performance of Simple Fibrosis Scores in Nonobese Patients With Nonalcoholic Fatty Liver Disease.

Clin Gastroenterol Hepatol 2020 Nov 28;18(12):2843-2845.e2. Epub 2019 Sep 28.

Centre d'Investigation de la Fibrose Hépatique, Bordeaux University Hospital, Pessac, France; INSERM U1053, Bordeaux University, Bordeaux, France. Electronic address:

Because only a minority of patients with nonalcoholic fatty liver disease (NAFLD) have advanced fibrosis and would eventually develop liver-related complications, current guidelines recommend initial assessment with noninvasive tests of fibrosis. Most previous studies focused on overweight and obese patients. Despite a strong association between obesity and NAFLD, 3%-30% of people with relatively normal body mass index (BMI) may still have NAFLD. Hence, this study aims to evaluate the performance of the common noninvasive tests in non-obese (BMI <25 kg/m) and obese (BMI ≥25 kg/m) NAFLD patients.
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http://dx.doi.org/10.1016/j.cgh.2019.09.027DOI Listing
November 2020

A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices.

Liver Int 2020 01 11;40(1):175-185. Epub 2019 Sep 11.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Background & Aims: Several non-invasive tests (NITs) have been developed to diagnose oesophageal varices (EV), including the recent Baveno VI criteria to rule out high-risk varices (HRV). Spleen stiffness measurement (SSM) with the standard FibroScan® (SSM@50Hz) has been evaluated. However, the EV grading could be underestimated because of a ceiling threshold (75 kPa) of the SSM@50Hz. The aims were to evaluate SSM by a novel spleen-dedicated FibroScan® (SSM@100Hz) for EV diagnosis compared with SSM@50Hz, other validated NITs and Baveno VI criteria.

Methods: This prospective multicentre study consecutively enrolled patients with chronic liver disease; blood data, endoscopy, liver stiffness measurement (LSM), SSM@50Hz and SSM@100Hz were collected.

Results: Two hundred and sixty patients met inclusion criteria. SSM@100Hz success rate was significantly higher than that of SSM@50Hz (92.5% vs 76.0%, P < .001). SSM@100Hz accuracy for the presence of EV (AUC = 0.728) and HRV (AUC = 0.756) was higher than in other NITs. SSM@100Hz AUC for large EV (0.782) was higher than SSM@50Hz (0.720, P = .027). AUC for HRV with SSM@100Hz (0.780) was higher than with LSM (0.615, P < .001). The spared endoscopy rate of Baveno VI criteria (8.1%) was significantly increased by the combination to SSM@50Hz (26.5%) or SSM@100Hz (38.9%, P < .001 vs others). The missed HRV rate was, respectively, 0% and 4.7% for combinations.

Conclusions: SSM@100Hz is a new performant non-invasive marker for EV and HRV providing a higher accuracy than SSM@50Hz and other NITs. The combination of Baveno VI criteria and SSM@100Hz significantly increased the spared endoscopy rate compared to Baveno VI criteria alone or combined with SSM@50Hz. Clinical trial number: NCT02180113.
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http://dx.doi.org/10.1111/liv.14228DOI Listing
January 2020

Comparison of the effect of direct-acting antiviral with and without ribavirin on cyclosporine and tacrolimus clearance values: results from the ANRS CO23 CUPILT cohort.

Eur J Clin Pharmacol 2019 Nov 5;75(11):1555-1563. Epub 2019 Aug 5.

AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, France.

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: NCT01944527.
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http://dx.doi.org/10.1007/s00228-019-02725-xDOI Listing
November 2019

Impact of Obesity and Alanine Aminotransferase Levels on the Diagnostic Accuracy for Advanced Liver Fibrosis of Noninvasive Tools in Patients With Nonalcoholic Fatty Liver Disease.

Am J Gastroenterol 2019 06;114(6):916-928

Centre d'Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Bordeaux University Hospital, Pessac, France.

Introduction: Some evidence suggests an interference of obesity and alanine aminotransferase (ALT) levels on the diagnostic accuracy for advanced fibrosis of noninvasive tools such as liver stiffness measurement (LSM) by FibroScan, Fibrosis-4 (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). We assessed whether the diagnostic accuracy of LSM, Fibrosis-4 (FIB-4), and NFS and strategies based on the combination of these tools is affected by obesity and/or ALT levels.

Methods: We analyzed data from 968 patients with a histological diagnosis of nonalcoholic fatty liver disease. FIB-4, NFS, and LSM by FibroScan were measured.

Results: LSM was better than both FIB-4 and NFS for staging F3-F4 fibrosis area under the receiver operating characteristic curve test (AUC) 0.863, 0.777, and 0.765, respectively; P < 0.001 for both), showing higher accuracy and higher negative predictive value (NPV), but lower positive predictive value (PPV). LSM worked less well in high ALT (>100 IU) (AUC 0.811 vs 0.877, P = 0.04; PPV 57.5% vs 62.4%; NPV 90.7% vs 94%) or obese patients (AUC 0.786 vs 0.902, P < 0.001; PPV 58.7% vs 64.8%; NPV 88.3% vs 95.2%), the latter not being affected by the M or XL probe. Consistently, LSM worked better in terms of AUC and accuracy compared with both FIB-4 and NFS only in nonobese or high ALT patients, even with always keeping a slightly lower PPV. A serial combination of FIB-4 or NFS with LSM as the second test in patients in the gray area of the first test retained-in most scenarios-similar PPV and NPV compared with LSM alone. These strategies also increased the diagnostic accuracy of about 20% in all groups of patients, even if with a lower overall accuracy in obese patients (71.3% and 67.1% for FIB-4 and NFS as the first test, respectively) compared to nonobese patients (81.9% and 82.4% for FIB-4 and NFS as the first test, respectively).

Conclusions: All tested noninvasive tools have overall better NPV than PPV. LSM has a better diagnostic accuracy for advanced fibrosis than both FIB-4 and NFS only in nonobese and/or low ALT patients. Serial combination strategies are better than a single tool strategy, regardless of obesity and ALT levels, although the accuracy is lower in obese patients.
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http://dx.doi.org/10.14309/ajg.0000000000000153DOI Listing
June 2019