Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis.: HCV variability and steatosis

International audienceMost clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses

Eloge du détour: l'anthropologie historique du droit

Cet ouvrage collectif, publié sous l'égide de l'Association des historiens des facultés de droit (AHFD), rassemble une trentaine de contributions relatives aux évolutions récentes de la recherche en histoire du droit. Cette discipline universitaire, devenue officiellement autonome par un arrêté de 1896, engage aujourd'hui en France environ cent-vingt professeurs et plus de cent-cinquante maîtres de conférences. Chaque contribution a été préparée en équipe. Toutes témoignent que de l'étude des droits antiques jusqu'à celle des droits contemporains, cette discipline a considérablement élargi ses objets, continuant d'affirmer sa spécificité et son utilité dans le champ des sciences juridiques comme dans celui des sciences de l'homme et de la société. (résumé directeurs d'ouvrage

A morphometric analysis of hepatitis B subviral particles shows no correlation of filament proportion and length with clinical stage and genotype

International audienceIt was recently suggested that the composition of circulating hepatitis B subviral particles (SVPs) could be used to differentiate the various stages in chronic hepatitis B virus (HBV) infection, with significantly lower proportions of L and M proteins in inactive carriers than in individuals with chronic hepatitis. L protein is abundant in virions and filamentous SVPs but almost absent from spherical SVPs. We, therefore, performed a morphometric analysis of SVPs in these two groups of patients, by conducting a retrospective analysis on sera from 15 inactive carriers and 11 patients with chronic hepatitis infected with various HBV genotypes. Subviral particles were concentrated by centrifugation on a sucrose cushion, with monitoring by transmission electron microscopy. The percentage of filamentous SVPs and filament length for 100 SVPs was determined with a digital camera. The L protein PreS1 promoter was sequenced from viral genomes by the Sanger method. No marked differences were found between patients, some of whom had only spherical SVPs, whereas others had variable percentages of filamentous SVPs (up to 28%), of highly variable length. High filament percentages were not associated with a particular sequence of the L protein promoter, HBV genotype or even disease stage. High levels of circulating filamentous SVPs are probably more strongly related to individual host factors than to viral strain characteristics or disease stage

Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection.

International audienceBACKGROUND & AIMS: We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection. METHODS: Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population. RESULTS: Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p<10(-3)) for a binary diagnosis of significant fibrosis. CONCLUSIONS: Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients

Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

International audienceTo investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon alpha-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia

Efficacy of Sofosbuvir and Daclatasvir in Patients with Fibrosing Cholestatic Hepatitis C After Liver Transplantation

International audienceBACKGROUND & AIMS: Fibrosing cholestatic hepatitis (FCH) is a life-threating disorder that develops in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation. Until recently, therapeutic options have been limited. We evaluated the efficacy and safety of sofosbuvir- and daclatasvir-based regimens. METHODS: We analyzed data from 23 patients with FCH who participated in a prospective cohort study in France and Belgium of the effects of anti-viral agents in patients with recurrence of HCV infection after liver transplantation, from October 2013 through April 2014. Most of the patients had genotype 1 infections that had not responded to previous treatment; 4 were also infected with HIV. Eight patients (37%) had ascites and 15 (65%) had bilirubin levels \textgreater100 mmol/L; their median serum level of HCV-RNA was 7 log IU/mL. The median time between transplantation and treatment initiation was 5 months. Subjects were given either sofosbuvir and daclatasvir (n=15) or sofosbuvir and ribavirin (n=8), for 24 weeks. The primary outcome was complete clinical response (survival without re-transplantation, bilirubin \textless 34 μmol/L, and no ascites or hepatic encephalopathy 36 weeks after treatment began). RESULTS: All patients survived, without re-transplantation, until week 36. Rapid and dramatic improvements in clinical status were observed. The patients' median bilirubin concentration decreased from 122 μmol/L at baseline to a normal value at week 12 of treatment. Twenty-two patients (96%) had a complete clinical response at week 36. Despite the low rate of rapid virologic response, 22 patients (96%) achieved a sustained virologic response at week 12 (SVR12). The only relapse of HCV infection occurred in a patient with HIV infection who received sofosbuvir and ribavirin. Tolerance was satisfactory, with no grade 3 or 4 adverse events related to sofosbuvir or daclatasvir and no significant interactions among drugs. CONCLUSION: Sofosbuvir therapy with daclatasvir or ribavirin leads complete clinical responses and high rates of SVR12 in most patients with recurrence of HCV infection and FCH following liver transplantation. ClinicalTrial.gov no: NCT0194452

Daclatasvir plus sofosbuvir with or without ribavirin in genotype 3 patients from a large French multicenter compassionate use program

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Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme

International audienceBACKGROUND & AIMS:Optimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real-world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization.METHODS:Patients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post-liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post-treatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting.RESULTS:The efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6-92.5%), 98% (43/44) without cirrhosis (95% CI 88.2-99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5-90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5-89.6%]). Among 516 GT3-infected patients with safety data, 5 discontinued for adverse events and 11 died.CONCLUSIONS:Daclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks

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

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