Publications by authors named "Armand Abergel"

103 Publications

Predictive Factors for Hepatocellular Carcinoma in Chronic Hepatitis B Using Structural Equation Modeling: A Prospective Cohort Study.

Clin Res Hepatol Gastroenterol 2021 Apr 27:101713. Epub 2021 Apr 27.

Digestive Center, Centre Hospitalier Universitaire de Nice, INSERM U1065-8, Nice, France.

Background & Aims: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort.

Methods: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified.

Results: Among the 4,489 patients included, 33 patients reported incident HCC. The median follow-up was 45.2 months. Age (β = 0.18 by decade, 95% CI 0.14-0.23), male gender (β = 0.23, 95% CI 0.18-0.29), metabolic syndrome (β = 0.28, 95% CI 0.22-0.33), alcohol consumption (β = 0.09, 95% CI 0.05-0.14) and HBV DNA (β = 0.25, 95% CI 0.17-0.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (β = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC.

Conclusions: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.
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http://dx.doi.org/10.1016/j.clinre.2021.101713DOI Listing
April 2021

Letter: is the AHHS score really useful in clinically severe alcoholic hepatitis?

Aliment Pharmacol Ther 2021 May;53(10):1160-1161

Department of Digestive and Hepatobiliary Medecine, CHU Clermont-Ferrand, Clermont-Ferrand, France.

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http://dx.doi.org/10.1111/apt.16307DOI Listing
May 2021

Large-scale screening of lipase acid deficiency in at risk population.

Clin Chim Acta 2021 Apr 20;519:64-69. Epub 2021 Apr 20.

Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France; University Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale UMR 938, Paris, France.

Background: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD).

Methods: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots.

Results: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel.

Conclusion: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.
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http://dx.doi.org/10.1016/j.cca.2021.04.005DOI Listing
April 2021

Risk factors of de novo malignancies after liver transplantation: a French national study on 11004 adult patients.

Clin Res Hepatol Gastroenterol 2021 Mar 11;45(4):101514. Epub 2021 Mar 11.

Hôpital Jean Minjoz, Service d'Hépatologie et Soins Intensifs Digestifs, Besançon, France.

Background: After liver transplantation (LT),de novo malignancies are one of the leading causes of late mortality. The aim of the present retrospective study was to identify the risk factors of de novo malignancies in a large cohort of LT recipients in France, using Fine and Gray competing risks regression analysis.

Methods: The study population consisted in 11004 adults transplanted between 2000 and 2013, who had no history of pre-transplant malignancy, except primary liver tumor. A Cox model adapted to the identification of prognostic factors (competitive risks) was used.

Results: From the entire cohort, one (or more)de novo malignancy was reported in 1480 L T recipients (13.45%). The probability to develop a de novo malignancy after LT was 2.07% at 1 year, 13.30% at 5 years, and 28.01% at 10 years. Of the known reported malignancies, the most common malignancies were hematological malignancy (22.36%), non-melanoma skin cancer (19.53%) and lung cancer (12.36%). According to Fine and Gray competing risks regression multivariate analysis, were significant risk factors for post-LT de novo malignancy: recipient age (Subdistribution Hazard Ratio (SHR) = 1.03 95%CI 1.03-1.04), male gender (SHR = 1.45 95%CI 1.27-1.67), non-living donor (SHR = 1.67 95%CI 1.14-2.38), a first LT (SHR = 1.35 95%CI 1.09-1.69) and the type of initial liver disease (alcohol-related liver disease (SHR = 1.63 95%CI 1.22-2.17), primary sclerosing cholangitis (SHR = 1.98 95%CI 1.34-2.91), and primary liver tumor (SHR = 1.88 95%CI 1.41-2.54)). Initial immunosuppressive regimen had no significant impact.

Conclusion: The present study confirms that LT recipient characteristics are associated with the risk ofde novo malignancy and this underlines the need for personalized screening in order to improve survival.
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http://dx.doi.org/10.1016/j.clinre.2020.07.019DOI 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

Department of Hepato-Gastroenterology, Claude Huriez University Hospital, Lille 59037, 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

Thrombin Generation and Cirrhosis: State of the Art and Perspectives.

Semin Thromb Hemost 2020 Sep 20;46(6):693-703. Epub 2020 Aug 20.

Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Epidemiological and laboratory studies performed in the last decades have changed our understanding of coagulopathy in cirrhosis, from a condition at increased risk of hemorrhagic events to one at higher thrombotic risk. However, it is not clear whether the decrease in factors that promote (except factor [F] VIII) versus inhibit coagulation in patients with cirrhosis results in a rebalanced state or in a hypercoagulable phenotype. This issue can be partially addressed using thrombin generation assays (TGA), which unlike routine clotting tests (prothrombin time or activated partial thromboplastin time) are sensitive to both procoagulant factors and coagulation inhibitors. However, many preanalytical issues and variable analytical methodologies used in TGAs complicate data analysis and interlaboratory comparisons. The introduction of TGAs in which activators of the protein C pathway (particularly soluble forms of thrombomodulin [TM]) are added has allowed detection of a reduced anticoagulant effect of TM or even a hypercoagulable phenotype as judged by endogenous thrombin potential. However, inter- and intra-assay variability may be greater with this TGA variant compared with "standard" TGAs. TGAs also allowed identifying main determinants of the hypercoagulability phenotype in the presence of TM: acquired antithrombin and protein C deficiencies, and elevated FVIII levels. The aim of this narrative review is to summarize the preanalytical and methodological variables of TGAs and also the findings of the main studies that have evaluated TGAs in patients with cirrhosis. The review also provides some propositions for future studies and outlines some perspectives on the potential implementation of this promising tool in clinical practice for the study of coagulation in patients with cirrhosis.
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http://dx.doi.org/10.1055/s-0040-1715102DOI Listing
September 2020

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

J Hepatol 2020 12 29;73(6):1434-1445. Epub 2020 Jun 29.

AP-HP, Groupe Hospitalier de La Pitié-Salpêtrière, Service d'Hépatologie, Paris.

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

Hypercoagulability (thrombin generation) in patients with cirrhosis is detected with ST-Genesia.

J Thromb Haemost 2020 09 23;18(9):2177-2190. Epub 2020 Jul 23.

Service d'hématologie biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Background: Thrombin generation assays (TGAs) performed with calibrated automated thrombography (CAT) in the presence of thrombomodulin (TM) indicate plasma hypercoagulability in cirrhosis.

Objective: To evaluate, in the presence of TM, the new ST-Genesia automated device developed for improving TGA vs the previously used CAT method, with plasma samples of patients with cirrhosis.

Patients/methods: Platelet-poor plasma samples were prepared from citrated blood samples of 52 healthy controls and 85 patients with cirrhosis (severity evaluated using the Child-Pugh score [CP]). TGAs were performed using CAT with PPP-Reagent and ST-Genesia with the STG-ThromboScreen reagent, in the presence of TM. Endogenous thrombin potential (ETP) was chosen as the main parameter.

Results: Whatever the method, ETP values were higher in patients than in healthy controls. All patients identified as hypercoagulable with ST-Genesia and STG-ThromboScreen were found hypercoagulable with CAT and PPP-Reagent. Conversely, eight and ten patients in the CP-A and CP-B classes respectively were identified as hypercoagulable only with CAT. The use of ST-Genesia with the STG-ThromboScreen reagent with TM led to a bias, with higher ETP values for healthy controls and lower for patients compared with CAT. Crossover analysis (CAT with the STG-ThromboScreen reagent) evidenced a substantial effect of the STG-ThromboScreen reagent; the analyzer (including calibration and data analysis) plays a lesser role.

Conclusion: ST-Genesia evidences hypercoagulability in patients with cirrhosis when TG is studied in the presence of TM, but the results are not interchangeable with those obtained with CAT.
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http://dx.doi.org/10.1111/jth.14963DOI Listing
September 2020

Efficacy and safety of glecaprevir/pibrentasvir in patients with HCV genotype 5/6: An integrated analysis of phase 2/3 studies.

Liver Int 2020 10 11;40(10):2385-2393. Epub 2020 Jun 11.

Department of Hepatology, Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France.

Background & Aims: Hepatitis C virus (HCV) has high genetic diversity with six major genotypes (GT) GT1-6 and global distribution. HCV GT5 and 6 are rare with < 10 million people infected worldwide. Data on direct-acting antiviral use in these rare HCV genotypes are limited. The study aimed to evaluate the efficacy and safety of glecaprevir/pibrentasvir (G/P) in a pooled analysis of phase 2/3 trials in HCV GT5 or 6-infected patients without cirrhosis or with compensated cirrhosis.

Methods: Patients with chronic HCV GT5 or 6 infection received oral G/P (300 mg/120 mg) once daily for 8 or 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12) in the intention-to-treat population.

Results: One hundred eighty-one patients were evaluated; 56 with HCV GT5 and 125 with HCV GT6. The majority were treatment-naïve (88%) and non-cirrhotic (85%). Overall SVR12 rate with 8- or 12-week G/P treatment was 98% (178/181). Eight-week treatment with G/P yielded SVR12 rates of 95% (21/22) in HCV GT5- and 99% (69/70) in HCV GT6-infected non-cirrhotic patients. Eight- and 12-week treatment of patients with compensated cirrhosis achieved SVR12 rates of 100% (10/10) and 94% (17/18) respectively. The G/P regimen was well-tolerated; 3% (6/181) Grade 3 or higher adverse events, and no serious adverse events were attributed to G/P or led to study drug discontinuation.

Conclusions: This integrated dataset demonstrates a high SVR12 rate following 8-week G/P treatment in patients with HCV GT5 (96%) or GT6 (99%) infection without cirrhosis or with compensated cirrhosis.
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http://dx.doi.org/10.1111/liv.14535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539968PMC
October 2020

Phase 3, Multicenter Open-Label study to investigate the efficacy of elbasvir and grazoprevir fixed-dose combination for 8 weeks in treatment-naïve, HCV GT1b-infected patients, with non-severe fibrosis.

Liver Int 2020 08 1;40(8):1853-1859. Epub 2020 Jun 1.

Service de médecine digestive et hépato-biliaire CHU Estaing, Clermont-Ferrand, France.

Background: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of 8 weeks fixed-dose combination of grazoprevir-elbasvir in treatment-naïve patients, with non-severe fibrosis.

Methods: HCV mono-infected and treatment naïve patients with non-severe fibrosis (Fibroscan <9.5 kPa and Fibrotest  < 0.59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non-1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12).

Findings: Mean age was 54 ± 13 years, 31% were men and viral load was higher than 800.000 IU/mL in 70 of 112 patients (63%). Using Fibroscan , 100 had F0-1 fibrosis score. FIB-4 lower than 1.45 and APRI less than 1 was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance-associated substitution). Then, modified intention-to-treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow-up week 24.

Interpretation: Naïve patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for 8 weeks.
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http://dx.doi.org/10.1111/liv.14502DOI Listing
August 2020

Extrahepatic portal vein obstruction (EHPVO) in cirrhosis.

Clin Res Hepatol Gastroenterol 2020 09 17;44(4):497-502. Epub 2020 Apr 17.

Department of Hepatology, DHU Unity, Beaujon Hospital, AP-HP, 100, boulevard du Général-Leclerc, 92118 Clichy, France.

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http://dx.doi.org/10.1016/j.clinre.2020.03.014DOI Listing
September 2020

Stress management in obesity during a thermal spa residential programme (ObesiStress): protocol for a randomised controlled trial study.

BMJ Open 2019 12 23;9(12):e027058. Epub 2019 Dec 23.

Université Clermont Auvergne, INRA, CRNH, University Hospital of Clermont-Ferrand, CHU Clermont-Ferrand, Unit of Human Nutrition, Clermont-Ferrand, France.

Introduction: Stress and obesity are two public health issues. The relationship between obesity and stress is biological through the actions of stress on the major hormones that regulate appetite (leptin and ghrelin). Many spa resorts in France specialise in the treatment of obesity, but no thermal spa currently proposes a specific programme to manage stress in obesity. The ObesiStress protocol has been designed to offer a new residential stress management programme. This thermal spa treatment of obesity implements stress management strategies as suggested by international recommendations.

Methods And Analysis: 140 overweight or obese participants with a Body Mass Index of >25 kg/m and aged over 18 years will be recruited. Participants will be randomised into two groups: a control group of usual practice (restrictive diet, physical activity and thermal spa treatment) and an intervention group with stress management in addition to the usual practice. In the present protocol, parameters will be measured on five occasions (at inclusion, at the beginning of the spa (day 0), at the end of the spa (day 21), and at 6 and 12 months). The study will assess the participants' heart rate variability, cardiac remodelling and function, electrodermal activity, blood markers, anthropometric profile, body composition, psychology and quality of life via the use of questionnaires and bone parameters.

Ethics And Dissemination: The ObesiStress protocol complies with the ethics guidelines for Clinical Research and has been approved by the ethics committee (CPP Sud-Est VI, Clermont-Ferrand - ANSM: 2016-A01774-47). This study aimed to highlight the efficacy of a 21-day thermal spa residential programme of stress management in obesity through objective measurements of well-being and cardiovascular morbidity. Results will be disseminated during several research conferences and articles published in peer-reviewed journals.

Trial Registration Number: NCT03578757.
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http://dx.doi.org/10.1136/bmjopen-2018-027058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008425PMC
December 2019

Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial.

J Hepatol 2020 03 2;72(3):441-449. Epub 2019 Nov 2.

Private Practice, Bakersfield, CA, USA.

Background & Aims: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis.

Methods: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed.

Results: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent.

Conclusions: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis.

Trial Registration: ClinicalTrials.gov, NCT03089944.

Lay Summary: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.
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http://dx.doi.org/10.1016/j.jhep.2019.10.020DOI Listing
March 2020

Quantification of steatosis in alcoholic and nonalcoholic fatty liver disease: Evaluation of four MR techniques versus biopsy.

Eur J Radiol 2019 Sep 19;118:169-174. Epub 2019 Jul 19.

CHU Estaing, Service de radiologie, Clermont-Ferrand, France.

Purpose: Given the growing prevalence of obesity and metabolic syndrome, the management of hepatic steatosis, especially its quantification, is a major issue. We assessed the quantification of liver steatosis using four different MR methods, in order to determine the one that is best correlated with the reference method which consists of histological measurement by liver biopsy.

Method: Seventy-one successive patients requiring liver biopsy for acute or chronic liver disease were enrolled prospectively between March 2017 and March 2018, 11 were excluded and 60 were reported. Liver MR (1.5 T) was organised in order to be performed the same day, using four different steatosis quantification techniques (3-echo MRI, 6-echo MRI, 11-echo MRI and MR Spectroscopy). Quantitative histological and imaging data were compared. In a secondary analysis, we studied the possible influence of alcohol drinking, hepatic iron overload, and the presence of liver fibrosis.

Results: All four MR techniques were found to have excellent correlations with the histological measurements: 3-echo MRI (r = 0.852, p < 0.001), 6-echo MRI (r = 0.819, p < 0.001), 11-echo MRI (r = 0.818, p < 0.001) and MR Spectroscopy (r = 0,812, p < 0,001). Interestingly, we also found that the presence of alcohol consumption, iron overload and fibrosis did not interfere with measurements, whichever technique was used.

Conclusion: In the evaluation of hepatic steatosis, our study showed very good correlations of all four MR techniques with the histological standard. There was no confounding factor in a representative group of patients with associated liver conditions such as alcohol consumption, fibrosis and iron overload, for each technique. All four MR techniques may be used in daily practice.
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http://dx.doi.org/10.1016/j.ejrad.2019.07.025DOI Listing
September 2019

A robust multi-variability model based liver segmentation algorithm for CT-scan and MRI modalities.

Comput Med Imaging Graph 2019 09 28;76:101635. Epub 2019 May 28.

Université Clermont Auvergne, CHU Clermont-Ferrand, CNRS, SIGMA Clermont, Institut Pascal, F-63000 Clermont-Ferrand, France.

Developing methods to segment the liver in medical images, study and analyze it remains a significant challenge. The shape of the liver can vary considerably from one patient to another, and adjacent organs are visualized in medical images with similar intensities, making the boundaries of the liver ambiguous. Consequently, automatic or semi-automatic segmentation of liver is a difficult task. Moreover, scanning systems and magnetic resonance imaging have different settings and parameters. Thus the images obtained differ from one machine to another. In this article, we propose an automatic model-based segmentation that allows building a faithful 3-D representation of the liver, with a mean Dice value equal to 90.3% on CT and MRI datasets. We compare our algorithm with a semi-automatic method and with other approaches according to the state of the art. Our method works with different data sources, we use a large quantity of CT and MRI images from machines in various hospitals and multiple DICOM images available from public challenges. Finally, for evaluation of liver segmentation approaches in state of the art, robustness is not adequacy addressed with a precise definition. Another originality of this article is the introduction of a novel measure of robustness, which takes into account the liver variability at different scales.
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http://dx.doi.org/10.1016/j.compmedimag.2019.05.003DOI Listing
September 2019

Automatic segmentation methods for liver and hepatic vessels from CT and MRI volumes, applied to the Couinaud scheme.

Comput Biol Med 2019 07 1;110:42-51. Epub 2019 May 1.

Université Clermont Auvergne, CHU Clermont-Ferrand, CNRS, SIGMA Clermont, Institut Pascal, F-63000, Clermont-Ferrand, France.

Background: Proper segmentation of the liver from medical images is critical for computer-assisted diagnosis, therapy and surgical planning. Knowledge of its vascular structure allows division of the liver into eight functionally independent segments, each with its own vascular inflow, known as the Couinaud scheme. Couinaud's description is the most widely used classification, since it is well-suited for surgery and accurate for the localization of lesions. However, automatic segmentation of the liver and its vascular structure to construct the Couinaud scheme remains a challenging task.

Methods: We present a complete framework to obtain Couinaud's classification in three main steps; first, we propose a model-based liver segmentation, then a vascular segmentation based on a skeleton process, and finally, the construction of the eight independent liver segments. Our algorithms are automatic and allow 3D visualizations.

Results: We validate these algorithms on various databases with different imaging modalities (Magnetic Resonance Imaging (MRI) and Computed Tomography (CT)). Experimental results are presented on diseased livers, which pose complex challenges because both the overall organ shape and the vessels can be severely deformed. A mean DICE score of 0.915 is obtained for the liver segmentation, and an average accuracy of 0.98 for the vascular network. Finally, we present an evaluation of our method for performing the Couinaud segmentation thanks to medical reports with promising results.

Conclusions: We were able to automatically reconstruct 3-D volumes of the liver and its vessels on MRI and CT scans. Our goal is to develop an improved method to help radiologists with tumor localization.
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http://dx.doi.org/10.1016/j.compbiomed.2019.04.014DOI Listing
July 2019

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.

Lancet Gastroenterol Hepatol 2019 06 4;4(6):454-465. Epub 2019 Apr 4.

Onxeo, Paris, France.

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed.

Methods: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m doxorubicin-loaded nanoparticles (30 mg/m group), 20 mg/m doxorubicin-loaded nanoparticles (20 mg/m group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693.

Findings: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m group; 130 to the 20 mg/m group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group.

Interpretation: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed.

Funding: Onxeo.
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http://dx.doi.org/10.1016/S2468-1253(19)30040-8DOI Listing
June 2019

Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification.

Open Forum Infect Dis 2019 Mar 22;6(3):ofz076. Epub 2019 Feb 22.

Gilead Sciences Inc, Foster City, California.

Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.

Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1-8 reference strains.

Results: A total of 14 653 patients with GT1-6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.

Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
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http://dx.doi.org/10.1093/ofid/ofz076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440686PMC
March 2019

Safety and efficacy of the combination simeprevir-sofosbuvir in HCV genotype 1- and 4-mono-infected patients from the French ANRS CO22 hepather cohort.

BMC Infect Dis 2019 Apr 2;19(1):300. Epub 2019 Apr 2.

Sorbonne Université, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique, F75012, Paris, France.

Background: Although real-life results of sofosbuvir/simeprevir have been extensively reported from the United States, data from other geographical areas are limited. In the French observational cohort, ANRS CO22 HEPATHER, 9432 patients were given the new oral antivirals from December 2013 to June 30, 2018. We report the results of sofosbuvir/simeprevir in genotypes 1- and 4-infected patients.

Methods: Demographics and history of liver disease were collected at entry in the cohort. Clinical, adverse events, and virological data were collected throughout treatment and post-treatment follow-up. The choice of treatment duration or addition of ribavirin was left up to the physician.

Results: Five hundred ninety-nine HCV (467 genotype 1 and 132 genotype 4) mono-infected, naïve for all oral-DAAs regimen patients were given sofosbuvir/simeprevir with (n = 63) or without ribavirin (n = 536) for 12 or 24 weeks; 56% had cirrhosis (4% decompensated) and 71% had prior treatment failure to interferon-based regimen. 7 patients (1.16%) were lost to follow-up. The overall SVR12 rate was 92.6%. The SVR12 was 90% in GT1a, 94.2% in GT1b and 91.6% in GT4 with no significant difference for genotype, treatment duration or ribavirin addition. Severity of liver disease was not associated with a lower SVR12 rate on multivariate analysis but was associated with a higher rate of severe side effects. Early treatment discontinuations were rare; no new safety signals were reported.

Conclusion: In this real life, observational, prospective cohort study, the 12-week sofosbuvir/simeprevir+/-ribavirin combination appears to be efficient and safe.

Trial Registration: Trial registration with ClinicalTrials.gov NCT01953458 .
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http://dx.doi.org/10.1186/s12879-019-3923-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446259PMC
April 2019

Editorial: direct-acting antivirals decrease the frequency of diabetes complications in patients with chronic hepatitis C.

Aliment Pharmacol Ther 2019 04;49(8):1094-1095

Service de médecine digestive et hépatobiliaire, CHU Clermont Ferrand, Clermont Ferrand, France.

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http://dx.doi.org/10.1111/apt.15152DOI Listing
April 2019

Validation of Baveno VI Criteria for Screening and Surveillance of Esophageal Varices in Patients With Compensated Cirrhosis and a Sustained Response to Antiviral Therapy.

Gastroenterology 2019 03 13;156(4):997-1009.e5. Epub 2019 Feb 13.

Hôpital Trousseau, Unité d'Hépatologie, CHRU de Tours.

Background & Aims: Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy.

Methods: We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (<50 IU/mL) 12 weeks after the end of treatment (SVR) or an undetectable level of HBV DNA. The primary aims were to validate the Baveno VI guidelines for screening and surveillance of EV in patients with compensated cirrhosis and to study the effects of an SVR on the progression of PHT.

Results: A total of 200 patients achieved an SVR (22.4%) (94 patients with HCV infection, 98 patients with HBV infection, and 8 patients with both); 80 of these patients had favorable Baveno VI status and none had VNT. Progression of PHT was studied in 548 patients; during a follow-up period of 61.2 months (interquartile range, 39.5-80.6 months), 105 of these patients (19.1%) had progression of PHT. Lack of an SVR and grade 1 EV were independently associated with progression of PHT. At the time of PHT progression, all patients had unfavorable Baveno VI status. Achieving favorable Baveno VI status after an SVR was associated with the absence of PHT progression. Favorable Baveno VI status and SVR were independently associated with survival.

Conclusions: In an analysis of data from a large cohort of patients with HBV- or HCV-associated cirrhosis in France, we validated the Baveno VI guidelines on screening and surveillance of PHT, even for patients who achieved a sustained response to antiviral therapy.
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http://dx.doi.org/10.1053/j.gastro.2018.11.053DOI Listing
March 2019

Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.

Lancet 2019 Apr 11;393(10179):1453-1464. Epub 2019 Feb 11.

Unit of Hepatology, Hépatogastroentérologie, CHU Trousseau, Tours, France.

Background: Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.

Methods: We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458.

Findings: Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27).

Interpretation: Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection.

Funding: INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
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http://dx.doi.org/10.1016/S0140-6736(18)32111-1DOI Listing
April 2019

Prospective evaluation of a dynamic insulin infusion algorithm for non critically-ill diabetic patients: A before-after study.

PLoS One 2019 28;14(1):e0211425. Epub 2019 Jan 28.

CHU Clermont-Ferrand, Service d'endocrinologie, diabétologie et maladies métaboliques, Clermont-Ferrand, France.

Introduction: Insulin infusion is recommended during management of diabetic patients in critical care units to rapidly achieve glycaemic stability and reduce the mortality. The application of an easy-to-use standardized protocol, compatible with the workload is preferred. Glycaemic target must quickly be reached, therefore static algorithms should be replaced by dynamic ones. The dynamic algorithm seems closer to the physiological situation and appreciates insulin sensitivity. However, the protocol must meet both safety and efficiency requirements. Indeed, apprehension from hypoglycaemia is the main deadlock with the dynamic algorithms, thus their application remains limited. In contrary to the critical care units, to date, no prospective study evaluated a dynamic algorithm of insulin infusion in non-critically ill patients.

Aim: This study primarily aimed to evaluate the efficacy of a dynamic algorithm of intravenous insulin therapy in non-critically-ill patients, and addressed its safety and feasibility in different departments of our university hospital.

Methods: A "before-after" study was conducted in five hospital departments (endocrinology and four "non-expert" units) comparing a dynamic algorithm (during the "after" period-P2) to the static protocol (the "before" period-P1). Static protocol is based on determining insulin infusion according to an instant blood glycaemia (BG) level at a given time. In the dynamic algorithm, insulin infusion rate is determined according to the rate of change of the BG (the previous and actual BG under a specific insulin infusion rate). Additionally, two distinct glycaemic targets were defined according to the patients' profile: 100-180 mg/dl (5.5-10 mmol/l) for vigorous patients and 140-220 mg/dl (7.8-12.2 mmol/l) for frail ones. Different BG measurements for each patient were collected and recorded in a specific database (e-CRF) in order to analyse the rates of hypo- and hyperglycaemia. A satisfaction survey was also performed. A study approval was obtained from the institutional revision board before starting the study.

Results: Over 8 months, 72 and 66 patients during P1 and P2 were respectively included. The dynamic algorithm was more efficient, with reduced time to control hyperglycaemia (P1 vs P2:8.3 vs 5.3 hours; HR: 2.02 [1.27; 3.21]; p<0.01), increased the number of in-target BG measurements (P1 vs P2: 37.0% vs 41.8%; p<0.05), and reduced the glycaemic variability related to each patient (P1 vs P2, %CV: 40.9 vs 38.2;p<0.05, Index Correlation Class:0.30 vs 0.14; p<0.05). In patients after the first event of hypoglycemia after having started the infusion, new events were lower (P1 vs P2: 19.4 vs 11.4; p<0.001) thanks to an earlier reaction to hypoglycaemia (8.3% during P1 vs 44.3% during P2; p = 0.004). With the dynamic algorithm, the percentage of recurrence of mild hypoglycaemia was significantly lower in frail patients (20.5% vs 10.2%; p<0.001), and in patients managed in the non-expert units (18 vs 7.1%, p<0.001). The %CV was significantly improved in frail patients (36.9%). Mean BG measurements for each patient/day were 5.5±1.1 during P1 and 6.0±1.6 during P2 (p = 0.6). The threat from hypoglycaemia and the difficulty in using dynamic algorithm are barriers for nurses' adherence.

Conclusions: This dynamic algorithm for non-critically-ill patients is more efficient and safe than the static protocol, and adapted for frail patients and non-expert units.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211425PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349328PMC
November 2019

Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus genotype 5 or 6 infection (ENDURANCE-5,6): an open-label, multicentre, phase 3b trial.

Lancet Gastroenterol Hepatol 2019 Jan 2;4(1):45-51. Epub 2018 Nov 2.

National Hospital for Tropical Diseases, Hanoi, Vietnam.

Background: The pangenotypic direct-acting antiviral regimen of glecaprevir coformulated with pibrentasvir is approved to treat chronic hepatitis C virus (HCV) genotype 1-6 infection in adults. In registrational studies, 84 (99%) of 85 patients with HCV genotype 5 or 6 infection achieved a sustained virological response (SVR) with glecaprevir/pibrentasvir, with no virological failures. To increase the body of data for these less prevalent genotypes, ENDURANCE-5,6 evaluated the efficacy and safety of glecaprevir/pibrentasvir exclusively in patients infected with HCV genotype 5 or 6.

Methods: ENDURANCE-5,6 was a phase 3b, single-arm, open-label, multicentre trial done in 24 hospitals or clinics in Europe, Oceania, North America, South Africa, and southeast Asia. Adults with chronic HCV genotype 5 or 6 infection who were previously untreated or treatment-experienced were eligible to be enrolled. Glecaprevir/pibrentasvir (300 mg/120 mg) was given orally once daily for 8 weeks (for patients without cirrhosis) or 12 weeks (for patients with compensated cirrhosis). The primary efficacy endpoint was SVR12 (ie, HCV RNA <15 IU/mL at 12 weeks post-treatment), assessed within each HCV genotype, and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02966795.

Findings: Between Feb 9, 2017, and Aug 28, 2018, 84 patients were enrolled: 23 with genotype 5 infection and 61 with genotype 6 infection. Overall, 82 (97·6%, 95% CI 94·4-100·0) of the 84 patients achieved SVR12. 22 (95·7%, 95% CI 87·3-100·0) of 23 patients with genotype 5 infection achieved SVR12, as did 60 (98·4%, CI 95·2-100·0) of 61 with genotype 6 infection. One patient with an HCV genotype 6f infection and cirrhosis had on-treatment virological failure at treatment week 12, and one patient with HCV genotype 5a without cirrhosis who had achieved SVR at post-treatment week 4 relapsed at post-treatment week 12. Five (6%) patients had serious adverse events, none of which were deemed related to glecaprevir/pibrentsavir or led to discontinuation. Fatigue (11 [13%] patients) and headache (11 [13%]) were the only adverse events that occurred in 10% or more of patients. No post-baseline grade 3 or higher increases in aminotransferase concentrations were reported.

Interpretation: Glecaprevir/pibrentasvir achieved high SVR12 rates, comparable with data reported in registrational studies, and was well tolerated in patients with HCV genotype 5 or 6 infection with compensated liver disease.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S2468-1253(18)30341-8DOI Listing
January 2019

Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs.

Gastroenterology 2018 11 19;155(5):1436-1450.e6. Epub 2018 Jul 19.

Hôpital de la Côte de Nacre, Service d'Hépatologie, Caen, France.

Background & Aims: Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN).

Methods: Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC.

Results: Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73).

Conclusions: Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.
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http://dx.doi.org/10.1053/j.gastro.2018.07.015DOI Listing
November 2018

Longterm Risk of Solid Organ De Novo Malignancies After Liver Transplantation: A French National Study on 11,226 Patients.

Liver Transpl 2018 10;24(10):1425-1436

Département d'Hépatologie et Transplantation Hépatique, Centre Hospitalier Universitaire Saint Eloi, Montpellier, France.

De novo malignancies are one of the major late complications and causes of death after liver transplantation (LT). Using extensive data from the French national Agence de la Biomédecine database, the present study aimed to quantify the risk of solid organ de novo malignancies (excluding nonmelanoma skin cancers) after LT. The incidence of de novo malignancies among all LT patients between 1993 and 2012 was compared with that of the French population, standardized on age, sex, and calendar period (standardized incidence ratio; SIR). Among the 11,226 LT patients included in the study, 1200 de novo malignancies were diagnosed (10.7%). The risk of death was approximately 2 times higher in patients with de novo malignancy (48.8% versus 24.3%). The SIR for all de novo solid organ malignancies was 2.20 (95% confidence interval [CI], 2.08-2.33). The risk was higher in men (SIR = 2.23; 95% CI, 2.09-2.38) and in patients transplanted for alcoholic liver disease (ALD; SIR = 2.89; 95% CI, 2.68-3.11). The cancers with the highest excess risk were laryngeal (SIR = 7.57; 95% CI, 5.97-9.48), esophageal (SIR = 4.76; 95% CI, 3.56-6.24), lung (SIR = 2.56; 95% CI, 2.21-2.95), and lip-mouth-pharynx (SIR = 2.20; 95% CI, 1.72-2.77). In conclusion, LT recipients have an increased risk of de novo solid organ malignancies, and this is strongly related to ALD as a primary indication for LT.
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http://dx.doi.org/10.1002/lt.25310DOI Listing
October 2018

A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

N Engl J Med 2018 Jun;378(23):2171-2181

From the Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department, Saint-Antoine University Hospital, Assistance Publique-Hôpitaux de Paris (APHP) (C.C., O.C., S.L., F.G., R.P.), INSERM Unité Mixte de Recherche (UMR) S938 (C.C., O.C., S.L., R.P.) and the Biochemistry Laboratory (L.H., D.R.), Saint-Antoine University Hospital, APHP, INSERM Unité 1157/UMR 7203, Sorbonne University, the Biochemistry Laboratory, Tenon University Hospital, APHP (G.L.), and the Immunology Laboratory, INSERM UMR S996, Bichat University Hospital, APHP (L.C., S.C.-M.), Paris-Sud University, the Department of Clinical Pharmacology and Clinical Research Platform of the East of Paris, APHP (A.R., F.-H.A., T.S.), and Sorbonne University (T.S.), Paris, the Hepatology and Gastroenterology Department, Rouen University Hospital, Rouen (O.G.), the Hepatology and Gastroenterology Department, Pontchaillou University Hospital, Rennes (A.L.G.), the Hepatology and Gastroenterology Department, University Hospitals of Strasbourg, Institute of Viral and Liver Diseases, INSERM Unité 1110, Laboratory of Excellence HepSYS, University of Strasbourg, Strasbourg (F.H.), the Hepatology and Gastroenterology Department, Claude Huriez University Hospital, Lille (P.M.), the Hepatology and Gastroenterology Department, Orleans Hospital, Orleans (P.P.), the Hepatology and Gastroenterology Department, Dijon Bourgogne University Hospital, Dijon (A.M.), the Hepatology and Gastroenterology Department, University Hospital of Poitiers, Poitiers (C.S.), the Hepatology and Gastroenterology Department, Estaing University Hospital, Clermont-Ferrand (A.A.), the Hepatology and Gastroenterology Department, University Hospital of Limoges, Limoges (M.D.-G.), the Hepatology and Gastroenterology Department, Saint-Eloi University Hospital, Montpellier (D.L.), the Hepatology Department, Beaujon University Hospital, Clichy (O.R.), the Hepatology and Gastroenterology Department, Brabois University Hospital, Nancy (J.-P.B.), the Hepatology and Gastroenterology Department, University Hospital of Angers, Hemodynamics, Interaction, Fibrosis, and Tumor Invasiveness in Hepatic and Digestive Organs Laboratory, Unité Propre de Recherche de l'Enseignement Supérieur 3859, Structures Fédératives de Recherche 4208, Bretagne Loire University, Angers (J.B.), the Hepatology and Gastroenterology Department, Haut-Lévêque University Hospital, Pessac (V.L.), the Hepatology and Gastroenterology Department, Robert Debré University Hospital, Reims (A.H.-B.), the Hepatology and Gastroenterology Department, University Hospital of Amiens, Amiens (E.N.-K.), the Hepatology and Gastroenterology Department, Croix-Rousse University Hospital, Lyon (F.Z.), the Hepatology and Gastroenterology Department, University Hospital of Caen, Caen (I.O.-H.), the Hepatology and Gastroenterology Department, Michallon University Hospital, Grenoble (J.-P.Z.), and the Hepatology and Gastroenterology Department, Jean Verdier University Hospital, Bondy (G.N.) - all in France.

Background: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition.

Methods: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months.

Results: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group.

Conclusions: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).
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http://dx.doi.org/10.1056/NEJMoa1714519DOI Listing
June 2018

The epidemiology of Budd-Chiari syndrome in France.

Dig Liver Dis 2018 Sep 12;50(9):931-937. Epub 2018 Apr 12.

Service d'Hépato-gastroentérologie, Centre Hospitalier Régional, Orléans, France.

Introduction: Epidemiological data is lacking on primary Budd-Chiari syndrome (BCS) in France.

Methods: Two approaches were used: (1) A nationwide survey in specialized liver units for French adults. (2) A query of the French database of discharge diagnoses screening to identify incident cases in adults. BCS associated with cancer, alcoholic/viral cirrhosis, or occurring after liver transplantation were classified as secondary.

Results: Approach (1) 178 primary BCS were identified (prevalence 4.04 per million inhabitants (pmi)), of which 30 were incident (incidence 0.68 pmi). Mean age was 40 ± 14 yrs. Risk factors included myeloproliferative neoplasms (MPN) (48%), oral contraceptives (35%) and factor V Leiden (16%). None were identified in 21% of patients, ≥2 risk factors in 25%. BMI was higher in the group without any risk factor (25.7 kg/m vs 23.7 kg/m, p < 0.001). Approach (2) 110 incident primary BCS were admitted to French hospitals (incidence 2.17 pmi). MPN was less common (30%) and inflammatory local factors predominated (39%).

Conclusion: The entity of primary BCS as recorded in French liver units is 3 times less common than the entity recorded as nonmalignant hepatic vein obstruction in the hospital discharge database. The former entity is mostly related to MPN whereas the latter with abdominal inflammatory diseases.
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http://dx.doi.org/10.1016/j.dld.2018.04.004DOI Listing
September 2018

Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study.

Gastroenterology 2018 08 3;155(2):431-442.e10. Epub 2018 May 3.

Hôpital de la Côte de Nacre, Service d'Hépatologie, Caen, France.

Background & Aims: Semi-annual surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. We aimed to determine how compliance with HCC surveillance guidelines affects survival times of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis who developed HCC.

Methods: We collected data from the prospective ANRS CO12 CirVir study, from March 2006 through June 2012, on 1671 patients with biopsy-proven viral cirrhosis and no previous liver complications who were undergoing surveillance for HCC at 35 centers in France. Only 216 patients who developed HCC during the follow-up period were included in the analysis. Patients were considered to be compliant with surveillance guidelines if the time between their last surveillance image evaluation and diagnosis of HCC were fewer than 7 months and noncompliant if this time was 7 months or longer.

Results: HCC was detected in 216 patients, at a median follow-up time of 59.7 months. Of these patients, 140 (80.5%) were Barcelona Clinic Liver Cancer stage 0/A, 135 (69.9%) received first-line curative treatment (15 underwent transplantation, 29 underwent resection, 89 received percutaneous ablation, and 2 received resection and percutaneous ablation), and 129 (60.0%) were compliant with surveillance guidelines. Seventy-nine of the patients with HCC died; 49 deaths were associated with tumor progression. After lead-time adjustment, overall survival (OS) time was longer in patients compliant with surveillance guidelines (median OS time, 53.2 months) than noncompliant patients (median OS time, 25.4 months) (P = .0107); this difference remained significant even when we changed lead time assumptions. In multivariate analysis adjusted for a propensity score, compliance with HCC surveillance guidelines was associated with low tumor burden, allocation of curative treatment, and increased OS time compared with noncompliance (hazard ratio for OS, 2.19; 95% confidence interval, 1.16-4.14; P = .0150).

Conclusions: In an analysis of data from the ANRS CO12 CirVir cohort, we associated compliance with HCC surveillance guidelines (fewer than 7 months between image evaluations) with early diagnosis, allocation of curative treatment, and longer adjusted OS of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis and a diagnosis of HCC.
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http://dx.doi.org/10.1053/j.gastro.2018.04.027DOI Listing
August 2018