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International audience; Hepatitis C virus (HCV) infection is associated with reduced patient survival following combined liver-kidney transplantation (LKT). The aim of this study was to assess the efficacy and safety of second-generation direct-acting antivirals (DAAs) in this difficult-to-treat population. The ANRS CO23 "Compassionate use of Protease Inhibitors in Viral C Liver Transplantation" (CUPILT) study is a prospective cohort including transplant recipients with recurrent HCV infection treated with DAAs. The present work focused on recipients with recurrent infection following LKT. The study population included 23 patients. All patients received at least one NS5B inhibitor (sofosbuvir) in their antiviral regimen an average of 90 months after LKT. Ninety-six percent of recipients achieved a sustained virological response (SVR) at week 12 (SVR12). In terms of tolerance, 39% of recipients presented with at least one serious adverse event. None of the patients experienced acute rejection during therapy and there were no deaths during follow-up. The glomerular filtration rate (GFR) decreased significantly from baseline to the end of therapy. However, this study did not show that the decline in GFR persisted over time or that it was directly related to DAAs. The DAA-based regimen is well tolerated with excellent results in terms of efficacy. It will become the gold standard for the treatment of recurrent HCV following LKT.

Resume Objectif Decrire la signification clinique des anticorps anti-SG2NA egalement appeles anti-pseudo-PCNA de type 1 ( proliferating cell nuclear antigen auto-antibodies ) qui sont des anticorps antinucleaires (ANA) rares detectes par immunofluorescence indirecte (IFI) sur cellules proliferatives HEp-2 en phase S/G2. Par analogie avec les anticorps anti-PCNA, ils sont associes au lupus erythemateux systemique (LES), aux cancers ou aux pathologies virales. Methodes Entre mai 2006 et fevrier 2013, 16 827 patients ont eu une recherche d’ANA positive au laboratoire d’immunologie de Strasbourg (France). Nous avons analyse de facon retrospective les donnees cliniques et biologiques des 126 patients ayant un aspect de fluorescence de type anti-pseudo-PCNA de type 1. Resultats La prevalence des anticorps anti-pseudo-PCNA de type 1 etait de 0,75 % parmi les patients ayant une recherche d’ANA positive. L’âge median etait de 56,9 ans (deviation standard [DS] 13,4 ans), avec un sex-ratio de 1,9 en faveur des femmes. En comparaison avec les patients porteurs d’anticorps antinucleaires, significativement plus de patients etaient hospitalises dans le service d’oncologie et hematologie de l’hopital (23 % vs 6,3 %, p + ( p −6 ). Finalement, la presence de l’anticorps anti-pseudo-PCNA de type 1 etait associee dans 30 cas sur 126 avec d’autres auto-anticorps (en particulier diriges contre les proteines du cycle cellulaire), suggerant un mecanisme plus general de rupture de tolerance lymphocytaire B envers les auto-antigenes. Conclusion A la lumiere de nos resultats, l’exploration des tumeurs devrait etre recommandee pour les patients ayant des Ac anti-pseudo-PCNA de type 1. Aucune association de ces auto-anticorps avec le lupus n’a pu etre montree.

Cirrhotic patients may present loculated ascites. We report a case of a 49-years old patient with cirrhosis and loculated infected ascites. Conventional and ultrasound (US)-guided paracentesis were ineffective. Moreover, US-guided drainages with 10 F drains could drain only small quantities of ascites localized in the largest loculated areas. Despite an adapted and long antibiotic therapy, the infection persisted. Intraabdominal fibrinolysis allowed the destruction of the fibrin septa, a better drainage and the sterilization of the ascites fluid. This is the first case report of effective intraabdominal fibrinolysis with urokinase in difficult to treat loculated infected ascites. case reports 2020 Jul 09 2020 07 09 imported

Long-term use of tenofovir disoproxil fumarate (TDF) reduces bone mineral density (BMD). Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has shown non-inferior efficacy to TDF in patients with chronic hepatitis B virus (HBV) infection, with improved bone effects at 48 weeks. We performed a randomized trial to evaluate the bone safety of TAF compared with TDF over 2 years, assessing baseline risk factors for bone loss, were evaluated after 2 years of treatment.In a double-blind study, hepatitis B e antigen (HBeAg)-positive patients (n = 873) and HBeAg-negative patients (n = 425) were randomly assigned (2:1) to groups given TAF (25 mg; n = 866) or TDF (300 mg; n = 432) once daily. We assessed bone safety, including hip and spine BMD, using dual-energy X-ray absorptiometry and measured changes in serum markers of bone turnover over 96 weeks.At baseline, treatment groups were well matched. At week 96, patients receiving TAF had significantly smaller decreases in hip BMD (mean reduction of 0.33%) than patients receiving TDF (mean reduction of 2.51%) (P.001) and spine BMD (reduction of 0.75% in patients receiving patients receiving TAF vs reduction of 2.57% in patients receiving TDF) (P.001). For hip BMD, the magnitude of difference in bone loss between the TAF and TDF groups increased at week 96 compared to week 48 (P.001). The TAF group had minimal changes in markers of bone turnover by 12 weeks of treatment, but the TDF group had significant changes, compared to baseline. Risk factors for bone loss had fewer effects in patients receiving TAF than TDF at week 96.In double-blind randomized trials, we found that after 2 years of treatment, patients receiving TAF had continued improvements in bone safety compared with patients receiving TDF. Clinicaltrial.gov ID NCT01940471 and NCT01940341.

Background: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma (HCC). We evaluated the intravenous perfusion of doxorubicin-loaded nanoparticles (DT) in HCC patients with prior failure of sorafenib therapy. Methods: We conducted a randomized, open label, 3 parallel groups, phase-3 trial at 70 sites in 11 countries. Patients with HCC with prior one or more systemic therapies including sorafenib were randomised 1:1:1 for DT-30 mg/m2 (DT-30), DT-20 mg/m2 (DT-20) or best standard of care (BSC); stratified by performance status, Child-Pugh score, DT dosage, macrovascular invasion, extrahepatic spread, alpha-fetoprotein level, number of prior systemic lines, reason of sorafenib discontinuation, and aetiology of HCC. The primary endpoint was overall survival. This trial is registered at ClinicalTrials.gov, number NCT01655693. Findings: Between June 2012 and January 2017, 541 patients were screened, 397 randomized (DT-30=133; DT-20=130; BSC=134; population for efficacy analysis), and 376 initiated treatments (DT-30=120; DT-20=122; BSC=134; population for safety analysis). After pooling the DT-30 and DT-20 arms in the analysis, pooled DT (pDT) did not improve overall survival with a hazard ratio of 1.00 (95% CI 0.78-1.28; p=0.99); median overall survival (95%CI) was 9.1 months (8.1-10.4) for pDT versus 9.0 months (7.1-11·8) for BSC. The hazard ratio for progression-free survival was 0.95 (95% CI 0.74-1.22; p=0.70) and for time to progression 0.96 (95%CI 0.74-1.23; p=0.74). Adverse events were reported in 94% (247/263) of pDT and 75% (100/134) of BSC. The most common grade 3 or 4 treatment-emergent adverse events included (pDT; BSC) neutropenia (8% [20/242]; 5% [6/134]), asthenia (3% [6/242]; 3% [4/134]), and thrombocytopenia (1% [3/242]; 7% [9/134]). Rates of drug-related death per investigators were 1% (3/242; pDT) and 1% (2/193; BSC). Interpretation: DT doesn't show benefit on survival in HCC patients with failure on prior sorafenib treatment, but it has a comforting safety profile. Trial Registration Number: ClinicalTrials.gov, number NCT01655693 Funding: ONXEO Conflict of Interest: PM has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, BMS, and MSD. JFB has received consultancy and advisory fees from Onxeo, Bayer, Lilly, Ipsen, and BMS. JPB has received consultancy and advisory fees from Onxeo, and Bayer. GP has received consultancy and advisory fees from Bayer, AbbVie, Novartis, and Gilead. AA has received consultancy and advisory fees from AbbVie, MSD, and Gilead. IW has received consultancy and advisory fees from Janssen, AbbVie, MSD, Marcyrl, Pharco, and Gilead. NY has received consultancy and advisory fees from Halozyme, Boston Biomedical Inc., Pharmacyclics, EMD Serono, Merck, Onxeo, Regeneron, and Momenta. Ethical Approval: The trial was approved by each centre’s ethics committee or institutional review board and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable local laws.

Etat de la question Le role de l’endotoxemie liee a la translocation bacterienne sur l’aggravation de la cirrhose fait l’objet de nombreuses etudes, mais son impact sur la mortalite au cours de la cirrhose est mal connu. Le but de ce travail etait d’etudier l’impact de la concentration sanguine de 3-hydroxymyristate (3-HM) total (composant specifique des lipopolysaccharides, endotoxine), sur le risque de deces et de complications des malades cirrhotiques. Materiel et methodes Au total, 593 patients atteints de cirrhose alcoolique ou virale, sans carcinome hepatocellulaire ont ete inclus entre 2008 et 2012 dans six centres hospitalo-universitaires francais. Le dosage de 3-HM total, libre et lie aux lipoproteines a ete realise en l’absence de complication aigue de la cirrhose par une methode innovante et brevetee de dosage massique des LPS. Le suivi annuel pendant cinq ans a permis de relever la survenue de complications ou du deces. L’analyse de survie a ete realisee par un modele de Cox multivarie avec stratification sur le centre et la severite de la cirrhose. Resultats Les patients avec une concentration de 3-HM elevee avait une cirrhose plus severe que les autres selon les scores de Child-Pugh et de Meld (p Conclusion Une concentration elevee de 3-HM, marqueur specifique de l’endotoxemie, est associee a un sur-risque de deces a cinq ans chez les patients avec cirrhose alcoolique ou virale compensee (Child Pugh A) suggerant un role majeur de la translocation bacterienne dans l’aggravation de la cirrhose.

Summary Hepatopulmonary syndrome (HPS) is of prognostic value in patients awaiting for orthotopic liver transplantation (OLT), but little is known about the effect of cirrhotic cardiomyopathy (CCM). The aim of the present study was to estimate the prevalence and possible relation between respiratory and cardiac abnormalities in a same series of patients awaiting OLT. Special attention was paid to the prognostic value of CCM in comparison to HPS. Eighty-three patients were included (19 females, 64 males; 52.1 ± 10.0 yrs). All had lung function testing with arterial blood gases and echocardiographic evaluation at rest with a contrast echocardiography in case of arterial oxygenation defect. To estimate the presence of CCM, patients underwent a complete left and right echocardiography and Doppler examination. Complete echocardiographic assessment could be obtained in 64 of the 83 patients of the study. HPS was observed in 16.9% (14/83) and CCM in 23.4% (15/64) of patients. There was a tendency of more serious adverse events before and after OLT in patients with HPS in comparison to others but CCM was not of prognostic value. HPS and CCM were frequent in these patients awaiting OLT but both abnormalities were not found in the same patients. CCM was neither related to death before OLT nor to death or serious adverse events after OLT.

The ability of hepatitis C virus (HCV) to infect leukocytes could favour HCV pathogenesis. Although viral infection of these immunocompetent cells is poorly (or not) productive, the impact on their immunomodulatory functions could be important. Viral envelope glycoproteins E1 and E2, because of their crucial role in the recognition of viral receptors on permissive cells, could contribute to viral leukocytic tropism and, as a consequence, to the pathophysiology of HCV chronic infection.

Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodies for control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.

Background & Aims TG4040 is a modified vaccinia Ankara (MVA) virus that expresses the hepatitis C virus (HCV) proteins NS3, NS4, and NS5B. We performed a phase II open-label study to determine the efficacy, safety, and immunotherapeutic properties of TG4040 in combination with pegylated interferon α-2a and ribavirin (PEG-IFNα/RBV) in patients with chronic HCV infection. Methods Treatment-naive patients with HCV genotype 1 infection were assigned randomly to 1 of the following groups: PEG-IFNα/RBV for 48 weeks (group A, n = 31), PEG-IFNα/RBV for 4 weeks followed by PEG-IFNα/RBV for 44 weeks with 6 injections of TG4040 (group B, n = 63), or TG4040 for 12 weeks (7 injections) followed by PEG-IFNα/RBV for 48 weeks with 6 injections of TG4040 (group C, n = 59). The primary end point was complete early virologic response (cEVR), defined as HCV-RNA level less than 10 IU/mL after 12 weeks of PEG-IFNα/RBV treatment. Results In group C, 64.2% of evaluable patients achieved cEVR, compared with 30.0% in group A and 45.9% in group B ( P = .0003 for group C vs A). A higher percentage of patients achieved a sustained virologic response 24 weeks after therapy ended in group C (58.2%) than in groups A (48.4%) or B (50.8%). HCV- and MVA-specific T-cell responses were observed predominantly in group C. As expected, most patients given injections of TG4040 developed anti-MVA antibodies. The combination of TG4040 and PEG-IFNα/RBV was reasonably well tolerated. However, PEG-IFNα–associated thrombocytopenia developed in 3 patients who carried the class II HLA allele DRB01*04. Conclusions A higher percentage of patients with chronic HCV infection who received immunotherapy with TG4040 followed by TG4040 and PEG-IFNα/RBV achieved a cEVR compared with patients who received only PEG-IFNα/RBV therapy. These findings show that immunotherapies that activate T cells are effective in patients with chronic HCV infection. ClinicalTrials.gov number, NCT01055821.

1194 SYNERGISTIC COMBINATIONS OF ENTRY INHIBITORS WITH DACLATASVIR OR SOFOSBUVIR FOR PREVENTION AND TREATMENT OF CHRONIC HEPATITIS C I. Fofana, F. Xiao, C. Thumann, R. Alles, F. Habersetzer, M. Doffoel, P. Leyssen, J. Neyts, M.B. Zeisel, T.F. Baumert. Inserm U 748, Universite de Strasbourg, Hopitaux Universitaires de Strasbourg, Strasbourg, France; Katholieke Universiteit Leuven, Leuven, Belgium E-mail: isabel.fofana@unistra.fr

1421 HIGH SUSTAINED VIROLOGIC RESPONSE RATE IN TREATMENT-NAIVE HCV GENOTYPE 1A AND 1B PATIENTS TREATED FOR 12 WEEKS WITH AN INTERFERON-FREE ALL-ORAL QUAD REGIMEN: INTERIM RESULTS M. Sulkowski, M. Rodriguez-Torres, E. Lawitz, M. Shiffman, S. Pol, R. Herring, J. McHutchison, P. Pang, D. Brainard, D. Wyles, F. Habersetzer. Johns Hopkins University School of Medicine, Lutherville, MD, Fundacion de Investigacion de Diego, Santurce, PR, Alamo Medical Research, San Antonio, TX, Liver Institute of Virginia, Richmond, VA, USA; Hopital Necker, Paris, France; Nashville Gastrointestinal Specialists, Inc., Nashville, TN, Gilead Sciences, Inc., Foster City, University of California, San Diego, La Jolla, CA, USA; Hopitaux Universitaires de Strasbourg, Strasbourg, France E-mail: msulkowski@jhmi.edu

The influence of genetically determined oxidation polymorphism on drug hepatotoxicity has been poorly investigated and results are controversial. We studied drug oxidation capacity in 51 patients with hepatitis caused mainly by drugs undergoing oxidative metabolism, using dextromcthorphan. a test compound recently proposed as a substitute for debrisoquine. Phenotyping was performed using the metabolic ratio (MR) calculated as MR=0–10 h urinary output of dextromethorphan/0–10 h urinary output of dextrorphan (the main oxidative metabolite), after oral administration of 40 mg dextromethorphan hydrobromide. Dextromethorphan oxidation capacity was similar in patients and in 103 control subjects as judged by: (a) the prevalence of each phenotype (5.9% versus 3.9% for the poor metabolizer phenotype and 94.1% versus 96.1% for the extensive metabolizer phenotype; (b) the frequency distribution histograms of log metabolic ratio; (c) the mean values of dextromethorphan and dextrorphan urinary outputs and of log metabolic ratio for each phenotype. These results show that hepatotoxicity of several drugs, including amineptine, amodiaquine and Plethoryl ® , is related neither to an impairment in dextromethorphan oxidation capacity nor to an unusually high capacity to oxidize this drug.