Low alcohol consumption influences outcomes in individuals with alcohol-related compensated cirrhosis in a French multicenter cohort.

BACKGROUND & AIMS: The harmful impact of heavy alcohol consumption and recurrence in patients with alcohol-related cirrhosis is long-established, although this is based on old studies. However, the drivers of long-term outcome still need to be clearly investigated. METHOD: All patients with biopsy-proven compensated alcohol-related cirrhosis included in the CIRRAL cohort (22 centers) were prospectively studied. Prognostic variables of survival and liver event-free survival were assessed using multivariable Cox models with stepwise selection. The prognostic impact of alcohol recurrence during follow-up (computed in glass-years in the same way as pack-years for tobacco) was assessed using a time-dependent covariable. RESULTS: From 2010 to 2016, 650 patients were included. The median age at baseline was 58.4 years, 67.4% were men and the median BMI was 27.8 kg/m2, 63.8% had a history of liver decompensation, and 70.2% had discontinued alcohol. At 5 years, recurrence occurred in 30.9% of abstinent patients and this risk was higher in patients with a history of drug abuse and in those with shorter alcohol discontinuation times. Median survival was 97 months. Age, alcohol consumption at baseline, platelet count and Child-Pugh score >5 were associated with overall and liver event-free survival on multivariate analysis. Alcohol consumption of more than 25 glass-years during follow-up was independently associated with lower survival and with a trend toward lower liver event-free survival, with the risk increasing from 1 glass-year, though not significantly. Simon & Makuch plots confirm the benefit of no alcohol consumption (<1 glass/week) on both outcomes and the dose-dependent impact of alcohol over time. CONCLUSION: This prospective study in patients with compensated alcohol-related cirrhosis identifies factors predictive of alcohol recurrence during follow-up and shows that moderate alcohol consumption during follow-up negatively impacts outcomes. Patients with alcohol-related cirrhosis should be advised to completely stop drinking alcohol. REGISTRATION: CIRRAL (NCT01213927) cohort was registered at ClinicalTrials.gov and the full protocol is available at the following link: https://clinicaltrials.gov/ct2/show/NCT01213927. IMPACT AND IMPLICATIONS: In patients with alcohol-related cirrhosis, data are lacking about the impact of the amount of alcohol consumed on both survival and liver-related events. The present study based on the CIRRAL cohort demonstrates that alcohol recurrence occurs in more than 30% of patients with compensated cirrhosis and that even a moderate recurrence strongly influences outcomes. Patients with compensated alcohol-related cirrhosis should be advised to completely discontinue alcohol consumption, even in small amounts, as the present study shows that no alcohol consumption can be regarded as safe when cirrhosis has developed.

Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis.

BACKGROUND: In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. METHODS: We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. RESULTS: 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7-51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24-0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08-0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15-0.54, p < 0.0001), liver-related mortality (HR 0.40, 95% CI 0.17-0.96, p = 0.04), non-liver-related mortality (HR 0.17, 95% CI 0.06-0.49, p = 0.001), liver transplantation (HR 0.17, 95% CI 0.05-0.54, p = 0.003), and hepatocellular carcinoma (HR 0.52, 95% CI 0.29-0.93, p = 0.03). CONCLUSION: Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. TRIAL REGISTRATION:  ClinicalTrials.gov registry number: NCT01953458.

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis.

BACKGROUND & AIMS: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-soluble liver antigen (SLA) autoantibodies is associated with reduced overall survival, but the associated autoreactive CD4 T cells have not yet been characterised. Herein, we isolated and deeply characterised SLA-specific CD4 T cells in patients with AIH. METHODS: We used brief ex vivo restimulation with overlapping SLA peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterise their transcriptome and T-cell receptor (TCR) repertoire. Autoreactive TCRs were cloned and used to identify dominant SLA-derived epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing to identify their phenotypic niche. We further characterised disease-associated peripheral blood T cells by high-content flow cytometry in 42 patients with AIH and 17 controls with non-alcoholic steatohepatitis. RESULTS: Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1+CXCR5-CCR6-CD27+ phenotype. ScRNA-seq revealed their pro-inflammatory/B-helper profile. SLA81-100 and SLA177-204 contain dominant T-cell epitopes. Autoreactive TCR clonotypes were predominantly found in the memory PD-1+CXCR5-CD4 T cells, which were significantly increased in the blood of patients with AIH and supported B-cell differentiation through IL-21. Finally, we identified specific T-cell phenotypes linked to disease activity and IgG level during AIH. CONCLUSIONS: We provide a deep characterisation of rare circulating autoreactive CD4 T cells and identify their peripheral reservoir in AIH. We also propose a specific phenotype of autoreactive T cells related to AIH disease activity, which will be essential to track, delineate, and potentially target these pathogenic cells. LAY SUMMARY: One principal characteristic of autoimmune hepatitis (AIH), like for many other autoimmune diseases, is the accumulation of autoantibodies produced by B lymphocytes following their interaction with autoreactive CD4 T lymphocytes. In this study, we identified and characterised with high resolution these CD4 T cells. This will be essential to track, delineate, and potentially target them during AIH.

Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta.

BACKGROUND & AIMS: HDV infection causes severe chronic liver disease in individuals infected with HBV. However, the factors associated with poor prognosis are largely unknown. Thus, we aimed to identify prognostic factors in patients with HDV infection. METHODS: The French National Reference Centre for HDV performed a nationwide retrospective study on 1,112 HDV-infected patients, collecting epidemiological, clinical, virological and histological data from the initial referral to the last recorded follow-up. RESULTS: The median age of our cohort was 36.5 (29.9-43.2) years and 68.6% of our cohort were male. Most patients whose birthplace was known were immigrants from sub-Saharan Africa (52.5%), southern and eastern Europe (21.3%), northern Africa and the Middle East (6.2%), Asia (5.9%) and South America (0.3%). Only 150 patients (13.8%) were French native. HDV load was positive in 659 of 748 tested patients (88.1%). HDV-1 was predominant (75.9%), followed by sub-Saharan genotypes: HDV-5 (17.6%), HDV-7 (2.9%), HDV-6 (1.8%) and HDV-8 (1.6%). At referral, 312 patients (28.2%) had cirrhosis, half having experienced at least 1 episode of hepatic decompensation. Cirrhosis was significantly less frequent in African than in European patients regardless of HDV genotype. At the end of follow-up (median 3.0 [0.8-7.2] years), 48.8% of the patients had developed cirrhosis, 24.2% had ≥1 episode(s) of decompensation and 9.2% had hepatocellular carcinoma. European HDV-1 and African HDV-5 patients were more at risk of developing cirrhosis. Persistent replicative HDV infection was associated with decompensation, hepatocellular carcinoma and death. African patients displayed better response to interferon therapy than non-African patients (46.4% vs. 29.1%, p <0.001). HDV viral load at baseline was significantly lower in responders than in non-responders. CONCLUSION: Place of birth, HDV genotype and persistent viremia constitute the main determinants of liver involvement and response to treatment in chronic HDV-infected patients. LAY SUMMARY: Chronic liver infection by hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. Despite the fact that at least 15-20 million people are chronically infected by HDV worldwide, factors determining the severity of liver involvement are largely unknown. By investigating a large cohort of 1,112 HDV-infected patients followed-up in France, but coming from different areas of the world, we were able to determine that HDV genotype, place of birth (reflecting both viral and host-related factors) and persistent viremia constitute the main determinants of liver involvement and response to treatment.

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

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.

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.

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.

Gemcitabine plus platinum-based chemotherapy for first-line treatment of hepatocholangiocarcinoma: an AGEO French multicentre retrospective study.

BACKGROUND: Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line. METHODS: Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model. RESULTS: Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin ⩾30 µmol l-1 (P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS. CONCLUSIONS: Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC.

Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients.

BACKGROUND & AIMS: We report the first real-life results of the sofosbuvir+daclatasvir combination in hepatitis C virus (HCV) genotype 1 infected patients. METHODS: The France REcherche Nord&Sud Sida-hiv Hépatites (ANRS) CO22 HEPATHER "Therapeutic options for hepatitis B and C: A French cohort" is a multicentre observational cohort which aims to include 15,000 HCV- and 10,000 HBV-infected patients. We selected all participants (n=768) with a HCV genotype 1 who initiated sofosbuvir (400mg/day) and daclatasvir (60mg/day) before October 1st 2014, with or without ribavirin (1-1.2g/day) for a duration of 12weeks or 24weeks. The main endpoint criterion was sustained virological response at 12weeks (SVR12), defined by the absence of detectable HCV-RNA 12weeks after the last treatment intake. Missing SVR12 measurements were imputed using SVR24 measurements (n=45), otherwise considered as virological failure (n=18). RESULTS: A SVR12 was obtained in 729/768 (95%) patients, ranging from 92% (12-week sofosbuvir+daclatasvir) to 99% (24-week sofosbuvir+daclatasvir+ribavirin). The SVR12 rates did not significantly differ between the 24-week (550/574 (96%)) and the 12-week (179/194 (92%); p=0.0688) durations or between regimens with (165/169 (98%)) or without ribavirin (564/599 (94%); p=0.0850). The SVR12 rate was greater than 97% in non-cirrhotic patients irrespective of the treatment duration or the addition of ribavirin. Among cirrhotic patients, the SVR12 rate was higher with 24 than 12-week regimen (423/444 (95%) vs. 105/119 (88%); p=0.0054). CONCLUSION: The sofosbuvir+daclatasvir combination is associated with a high rate of SVR12 in patients infected by genotype 1, with an optimal duration of 12weeks in non-cirrhotic and 24weeks in cirrhotic patients. The number of patients receiving ribavirin was too low to adequately assess its impact. LAY SUMMARY: The sofosbuvir+daclatasvir combination of antiviral drugs is associated with a high rate (95%) of viral eradication in patients infected by HCV genotype 1. The best duration of a ribavirin-free sofosbuvir+daclatasvir combination seems to be 12weeks in non-cirrhotic patients and 24weeks for those with cirrhosis. Clinical trial number: NCT01953458.

Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.

Risk factors for hepatocellular carcinoma in Caucasian patients with non-viral cirrhosis: the importance of prior obesity.

BACKGROUND & AIMS: In patients with cirrhosis, the risk of hepatocellular carcinoma (HCC) depends upon age, gender and the etiology of liver disease. Few studies are available in Caucasian patients with alcoholic or metabolic cirrhosis without viral hepatitis. METHODS: Cross-sectional clinical data from 905 HCV- and HBV-negative Caucasian patients with alcoholic or metabolic cirrhosis were prospectively collected in four French centres. The risk factors for HCC were identified by logistic regression analysis in the whole population and in a nested case-control study. RESULTS: The etiology of cirrhosis was alcoholic (48%), metabolic (7%) or mixed (45%). Patients were predominantly male (80%), mean age 62 years old and 31% had HCC. Mean body mass index (BMI) was 27 ± 5 and 30% were obese at inclusion. The maximum BMI reached throughout life was 31 ± 6 and 63% had been obese. Ninety percent of the population had daily alcohol consumption, 73% were smokers. Hepatocellular carcinoma was independently related to male gender (P < 0.0001), older age (P < 0.0001), past obesity (P = 0.007), diabetes (P = 0.037), abnormal levels of transaminases (P < 0.0001) and tobacco consumption (P = 0.007). The case-control study (200 HCC cases matched with 400 non-HCC cases for gender, age and Child-Pugh score) confirmed past obesity, tobacco and abnormal levels of transaminases. CONCLUSIONS: Beside diabetes, male gender and age, a past history of obesity, but not an existing overweight, as well as exposure to tobacco and elevated transaminases were three risk factors which could improve the strategy for HCC screening in Caucasian cirrhotic patients without hepatitis B or C.

Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial.

BACKGROUND & AIMS: The first studies comparing covered stents (CS) and bare stents (BS) to achieve Transjugular Intrahepatic Portosystemic Shunt (TIPS) were in favor of CS, but only one randomized study has been performed. Our aim was to compare the primary patency of TIPS performed with CS and BS. METHODS: The study was planned as a multicenter, pragmatic (with centers different in size and experience), randomized, single-blinded (with blinding of patients only), parallel group trial. The primary endpoint was TIPS dysfunction defined as either a portocaval gradient ⩾12mmHg, or a stent lumen stenosis ⩾50%. A transjugular angiography with portosystemic pressure gradient measurement was scheduled every 6months after TIPS insertion. RESULTS: 137 patients were randomized: 66 to receive CS, and 71 BS. Patients who were found to have a hepato-cellular carcinoma, or whose procedure was cancelled were excluded, giving a sample of 129 patients (62 vs. 67). Median follow-up for CS and BS were 23.6 and 21.8months, respectively. Compared to BS, the risk of TIPS dysfunction with CS was 0.60 95% CI [0.38-0.96], (p=0.032). The 2-year rate of shunt dysfunction was 44.0% for CS vs. 63.6% for BS. Early post TIPS complications (22.4% vs. 34.9%), risk of hepatic encephalopathy (0.89 [0.53-1.49]) and 2-year survival (70% vs. 67.5%) did not differ in the two groups. The 2-year cost/patient was 20k€ [15.9-27.5] for CS vs. 23.4k€ [18-37] for BS (p=0.52). CONCLUSIONS: CS provided a significant 39% reduction in dysfunction compared to BS. We did not observe any significant difference with regard to hepatic encephalopathy or death.

Obliteration of liver sinusoids through platelet aggregates associated to extramedullary haematopoiesis in myeloid neoplasms.

Herein is reported a series of five patients with myeloid neoplasms presenting hepatic complications in whose liver biopsy revealed obstruction of sinusoids by platelet aggregates associated to liver extramedullary haematopoiesis. Indication of liver biopsies was jaundice, unexplained hepatomegaly or portal hypertension. Haematological disorders were classified according to the World Health Organisation. Molecular profile was established in all cases as well as grade of liver extramedullary haematopoiesis and myelofibrosis. The patients were four men and one woman aged from 50 to 82 years. Two patients had myeloproliferative neoplasm (triple negative primary myelofibrosis and JAK2-mutated essential thrombocytopenia), two patients had unclassifiable myelodysplastic/myeloproliferative neoplasm and one patient had chronic myelomonocytic leukaemia type 1. Liver biopsies revealed platelet aggregates occluding sinusoids in association with extramedullary haematopoiesis grade 1 in one patient, grade 2 in two patients and grade 3 in two patients. Two of these patients presented co-existing liver fibrosis due to chronic alcoholic consumption and ischemic heart failure. These five patients died from 2 to 23 months after liver biopsy due to acute myeloblastic leukaemia (three patients), portal hypertension (one patient) or other causes (acute heart failure). Intrahepatic sinusoidal microthromboses through platelet aggregates might cause portal hypertension or liver deficiency in patients with myeloid neoplasms, independently of JAK2 mutational status and grade of extramedullary haematopoiesis.

TACE and conformal radiotherapy vs. TACE alone for hepatocellular carcinoma: A randomised controlled trial.

Background & Aims: Transcatheter arterial chemoembolisation (TACE) is recommended for patients with hepatocellular carcinoma devoid of macrovascular invasion or extrahepatic spread but not eligible for curative therapies. We compared the efficacy and safety of the combination of a single TACE and external conformal radiotherapy (CRT) vs. classical TACE. Methods: TACERTE was an open-labelled, randomised controlled trial with a 1:1 allocation rate to two or three TACE (arm A) or one TACE + CRT (arm B). Participants had a mean age of 70 years, and 86% were male. The aetiology was alcohol in 85%. The primary endpoint was liver progression-free survival (PFS) in the intention-to-treat population. The typical CRT schedule was 54 Gy in 18 sessions of 3 Gy. Results: Of the 120 participants randomised, 64 were in arm A and 56 in arm B; 100 participants underwent the planned schedule and defined the 'per-protocol' group. In intention-to-treat participants, the liver PFS at 12 and 18 months were 59% and 19% in arm A and 61% and 36% in arm B (hazard ratio [HR] 0.69; 95% CI 0.40-1.18; p = 0.17), respectively. In the per-protocol population, treated liver PFS tended to be better in arm B (HR 0.61; 95% CI 0.34-1.06; p = 0.081) than in arm A. Liver-related grade III-IV adverse events were more frequent in arm B than in arm A. Median overall survival reached 30 months (95% CI 23-35) in arm A and 22 months (95% CI 15.7-26.2) in arm B. Conclusions: Although TACE + CRT tended to improve local control, this first Western randomised controlled trial showed that the combined strategy failed to increase PFS or overall survival and led more frequently to liver-related adverse effects. Impact and implications: Hepatocellular carcinoma is frequently treated by arterial embolisation of the tumour and more recently by external radiotherapy. We tried to determine whether combination of the two treatments (irradiation after embolisation) might produce interesting results. Our results in this prospective randomised study were not able to demonstrate a beneficial effect of combining embolisation and irradiation in these patients. On the contrary, we observed more adverse effects with the combined treatment. Clinical Trials Registration: NCT01300143.

Non-invasive diagnosis and follow-up of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a liver disease characterised by necrotico-inflammatory lesions of hepatocytes, the presence of specific autoantibodies and response to corticosteroid treatment. AIH must be considered in any patient with acute or chronic liver disease. As there is no pathognomonic sign of AIH, the diagnosis is based on a combination of clinical, biological, immunological and histological findings, after excluding other causes of liver disease. The clinical and biological presentation of AIH is variable and AIH can be associated with an autoimmune biliary disease, primary biliary cholangitis or primary sclerosing cholangitis in an overlap syndrome. For these reasons, diagnosis of AIH can be challenging. Even if liver histology remains essential in the diagnosis of AIH, non-invasive tests can be used at different steps of the management of AIH: diagnosis of AIH, notably diagnosis of an overlap syndrome, assessment of severity of AIH, searching for extra-hepatic disease frequently associated to AIH, evaluation of response to therapy, decision of treatment withdrawal. This review aims to provide practical guidelines for the use of non-invasive tests for the diagnosis and the follow-up of AIH.

Non-invasive diagnosis and follow-up of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare and chronic cholestatic liver disease of unknown cause commonly associated with inflammatory bowel disease (IBD) and characterized by progressive obliterative fibro-inflammation of the biliary tree. Although the natural course is highly variable, PSC is often progressive, leading to biliary cirrhosis and its complications. In addition, PSC is a condition harbouring broad neoplastic potential with increased susceptibility for the development of both biliary and colon cancer. As in other chronic liver diseases, non-invasive methods play a major role in the diagnosis and monitoring of PSC. MR cholangiography is the key exam for the diagnosis and has replaced diagnostic endoscopic retrograde cholangiopancreatography (ERCP). A strict and standardised protocol for carrying out MR cholangiography is recommended. Liver stiffness measured by FibroScan® correlates with the degree of liver fibrosis, has a prognostic value and should be repeated during follow-up. Invasive methods still play an important role, especially ERCP which is indicated for therapeutic purposes or for endo-biliary sample collection in suspected cholangiocarcinoma (following discussion in a multidisciplinary team meeting) and total colonoscopy which is recommended at the initial diagnosis of any PSC and annually in patients with IBD.

Infected pancreatic necrosis complicating severe acute pancreatitis in critically ill patients: predicting catheter drainage failure and need for necrosectomy.

BACKGROUND: Recent guidelines advocate a step-up approach for managing suspected infected pancreatic necrosis (IPN) during acute pancreatitis. Nearly half the patients require secondary necrosectomy after catheter drainage. Our primary objective was to assess the external validity of a previously reported nomogram for catheter drainage, based on four predictors of failure. Our secondary objectives were to identify other potential predictors of catheter-drainage failure. We retrospectively studied consecutive patients admitted to the intensive care units (ICUs) of three university hospitals in France between 2012 and 2016, for severe acute pancreatitis with suspected IPN requiring catheter drainage. We assessed drainage success and failure rates in 72 patients, with success defined as survival without subsequent necrosectomy and failure as death and/or subsequent necrosectomy required by inadequate improvement. We plotted the receiver operating characteristics (ROC) curve for the nomogram and computed the area under the curve (AUROC). RESULTS: Catheter drainage alone was successful in 32 (44.4%) patients. The nomogram predicted catheter-drainage failure with an AUROC of 0.71. By multivariate analysis, catheter-drainage failure was independently associated with a higher body mass index [odds ratio (OR), 1.12; 95% confidence interval (95% CI), 1.00-1.24; P = 0.048], heterogeneous collection (OR, 16.7; 95% CI, 1.83-152.46; P = 0.01), and respiratory failure onset within 24 h before catheter drainage (OR, 18.34; 95% CI, 2.18-154.3; P = 0.007). CONCLUSION: Over half the patients required necrosectomy after failed catheter drainage. Newly identified predictors of catheter-drainage failure were heterogeneous collection and respiratory failure. Adding these predictors to the nomogram might help to identify patients at high risk of catheter-drainage failure. CLINICALTRIALS: gov number: NCT03234166.

Prediction of hepatocellular carcinoma in Hepatitis C patients with advanced fibrosis after sustained virologic response.

BACKGROUND & AIMS: Prediction of hepatocellular carcinoma (HCC) occurrence in patients with chronic hepatitis C (HCV) who achieved a sustained virological response (SVR) after direct acting antivirals (DAAs) remains challenging. METHODS: Among HCC-free HCV patients with advanced fibrosis enrolled in the ANRS CO22 HEPATHER cohort who achieved SVR 12 weeks after treatment with DAAs, HCC predictive models were developed using Cox multivariable regression. The derived score was externally validated in a large Egyptian cohort. Our main outcome was the HCC-free survival. RESULTS: During follow-up (median 3.05 years), 153 out of 3531 patients developed a HCC. Main variables associated with HCC occurrence were: male gender, HCV genotype 3, esophageal varices, albumin < 40 g/L, total bilirubin >11 µmol/L and hypercholesterolemia before DAA initiation, together with age > 58 years, FIB-4 index ≥3.25 evaluated at SVR. A score was established allowing the stratification of patients by high (score ≥ 12/22), intermediate (7 ≤ score <12) and low risk of HCC (score < 7/22) with 3-yrs HCC incidence of 18.96%, 5.50% and 1.65%, respectively. The integrated time-dependent area under the ROC curve (i-AUC) was 0.76 in our patients and 0.61 in the validation cohort. CONCLUSION: The externally validated HEPATHER HCC score has good short-term predictive performance in HCV- patients who achieved SVR12 after DAAs allowing to identify high-risk patients in whom HCC screening may be cost-effective and low-risk patients in whom HCC screening may be superfluous in the first 3 years after SVR.

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.

BACKGROUND: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. METHODS: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. FINDINGS: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]). INTERPRETATION: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. FUNDING: The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.

Takayasu arteritis associated with hepatic sinusoidal dilatation.

Hepatic sinusoidal dilatation (HSD) is pathological entity that is characterized by peliosis hepatis (PH) like lesions, with vascular lesions that consist of multiple cyst-like, blood-filled cavities within the liver. To the best of our knowledge, neither PH nor HSD have been associated with systemic vasculitis. We describe herein two cases of idiopathic HSD associated with Takayasu arteritis (TA), diagnosed at an early stage of vasculitis. The same endothelial target in HSD and TA, and the favorable outcome of HSD with treatment of TA, suggest a pathogenic link between the two diseases.

Predictive Factors of Chemotherapy Initiation after Biliary Drainage for Advanced Biliary Tract Cancer: A Retrospective Multicenter Study.

BACKGROUND AND AIMS: In unresectable biliary tract cancers, the management of biliary obstruction is often the first step before introduction of chemotherapy. Our aim was to study the predictive factors of chemotherapy initiation after biliary drainage in a series of patients presenting with advanced biliary tract cancer and obstructive jaundice. METHODS: Data of all patients treated for unresectable biliary tract cancer with initial biliary obstruction requiring a drainage in six institutions, from January 2009 to January 2019, were retrospectively collected. RESULTS: Among 82 patients included in this study (median age 68 years, men 61%), 48 (59%) received chemotherapy. Median overall survival was 4.9 months (0.2-38.7) in the group of patients who did not receive chemotherapy and 12.2 months (1.9-61.0) in chemotherapy group (HR=2.93; 95%CI: 1.6-5.3; p<0.0001). In univariate analysis, younger age, male gender, Eastern Cooperative Oncology Group (ECOG) score ≤2, high albumin level, low C-reactive protein level, and endoscopic drainage were significantly associated with introduction of chemotherapy. In multivariate analysis, only ECOG score ≤2 at diagnosis (HR=70.4; 95%CI: 4.6-1097.6; p=0.002) and male gender (HR=5; 95%CI: 1.5-16.5; p=0.009), were significant independent predictive factors of chemotherapy introduction. Age and bilirubin level at diagnosis were not significant factors in multivariate analysis. CONCLUSIONS: ECOG score ≤ 2 and male gender were the only independent predictive factors of chemotherapy introduction in unresectable biliary tract cancers. Age or initial bilirubin level were not predictors for chemotherapy introduction. These results might help defining the initial therapeutic strategy.