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Le Touquet – Paris-Plage, France

Moucari R.,French Institute of Health and Medical Research | Forestier N.,Goethe University Frankfurt | Larrey D.,Montpellier University Hospital Center | Guyader D.,Rennes University Hospital Center | And 8 more authors.
Gut | Year: 2010

Background/aim: Insulin resistance (IR) is a major predictor of treatment failure in patients with hepatitis C virus (HCV) infection treated with peginterferon/ribavirin. The aim of this study was to evaluate the short-term effect of an HCV protease inhibitor monotherapy on IR in parallel with an antiviral effect. Patients/methods: In a phase 1b placebo-controlled study, four cohorts of treatment-naïve patients with genotype 1 HCV received danoprevir (ITMN-191/RG7227), a protease inhibitor, or placebo (8/2 patients in each cohort respectively) in a gelatin capsule every 12 h (100, 200 mg) or 8 h (100, 200 mg) for 14 days. A fifth cohort including prior non-responders to peginterferon/ribavirin was similarly randomised to receive placebo or 300 mg danoprevir every 12 h. IR was assessed with the homeostasis model (HOMA-IR) at baseline and days 7, 14 and 15. Results: Serum HCV-RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p<0.0001). At baseline, mean±SD serum HCV-RNA level and mean±SD HOMA-IR score were 6.2±0.5 log10IU/ml and 3.8±1.9, respectively. At the end of 14 days of monotherapy the mean±SD decrease in viral load was 2.2±1.3 log10IU/ml (p<0.0001) in patients who received the active drug (n=40). In parallel, the mean±SD HOMA-IR score also decreased in these patients by 1.6±1.1 (p<0.0001), with a close correlation between the extent of HOMA-IR improvement and the decrease in viral load. By contrast, serum HCV-RNA and HOMA-IR remained unchanged in patients who received placebo (n=10; 6.3±0.5 log10IU/ml and 3.8±2.5, respectively). Conclusion: HCV protease inhibitor may restore insulin sensitivity in patients with genotype 1 HCV. The place of insulin sensitisers remains to be determined in the era of triple therapy. Source

Balak D.M.W.,Erasmus University Rotterdam | Ratziu V.,Service dHepato gastro enterologie | Ratziu V.,University Pierre and Marie Curie
Current Opinion in Lipidology | Year: 2013

Purpose of review: Mipomersen has been approved by the US Food and Drug Administration as an orphan drug for patients with homozygous familial hypercholesterolemia (HoFH). In contrast, the European Medicines Agency advised negatively on the use of mipomersen. In this review, we discuss the efficacy and safety considerations for this discrepancy. Recent findings: On the basis of the results of clinical trials with mipomersen, safety concerns have been raised regarding cardiovascular risk reduction and development of hepatic steatosis. In addition, (long-term) tolerability concerns have been raised predominantly regarding injection site reactions. A pooled analysis of cardiovascular events in phase III trials with mipomersen did not provide evidence for either a positive or negative effect on cardiovascular disease. Although long-term studies with mipomersen are eagerly awaited, hepatic fat content appears to stabilize after 6-12 months notwithstanding continued mipomersen administration. Summary: HoFH is a disease with an unmet medical need for new lipid-lowering therapies. On the basis of a mean 2.9 mmol/l LDL-cholesterol reduction, mipomersen is expected to reduce cardiovascular risk in HoFH. Available evidence suggests that the fat accumulation associated with this treatment differs from steatohepatitis, which is a progressive and damaging liver disease. No evidence is available suggesting that injection site reactions because of mipomersen treatment will result in safety issues. © 2013 Wolters Kluwer Health. Source

Bourliere M.,Hepato gastroenterologie | Bronowicki J.-P.,University of Lorraine | de Ledinghen V.,Bordeaux University Hospital Center | Hezode C.,French Institute of Health and Medical Research | And 23 more authors.
The Lancet Infectious Diseases | Year: 2015

Background: Patients with cirrhosis resulting from chronic hepatitis C virus (HCV) infection are at risk of life-threatening complications, but consistently achieve lower sustained virological response (SVR) than patients without cirrhosis, especially if treatment has previously failed. We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir, with and without ribavirin. Methods: In this multicentre, double-blind trial, between Oct 21, 2013, and Oct 30, 2014, we enrolled patients with HCV genotype 1 and compensated cirrhosis who had not achieved SVR after successive treatments with pegylated interferon and protease-inhibitor regimens at 20 sites in France. With a computer-generated randomisation sequence, patients were assigned in a 1:1 ratio to receive placebo matched in appearance to study drugs for 12 weeks followed by once daily combination fixed-dose tablets of 90 mg ledipasvir and 400 mg sofosbuvir plus weight-based ribavirin for 12 weeks, or ledipasvir-sofosbuvir plus placebo once daily for 24 weeks. The primary endpoint was SVR 12 weeks after the end of treatment (SVR12), for which 95% CIs were calculated with the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, number NCT01965535. Findings: Of 172 patients screened, 155 entered randomisation, 77 were assigned to receive ledipasvir-sofosbuvir plus ribavirin and 78 ledipasvir-sofosbuvir. 114 (74%) were men, 151 (97%), were white, 98 (63%) had HCV genotype 1a, and 145 (94%) had non-CC IL28B alleles. SVR12 rates were 96% (95% CI 89-99) for patients in the ledipasvir-sofosbuvir plus ribavirin group and 97% (91-100) in the ledipasvir-sofosbuvir group. One patient discontinued treatment because of adverse events while receiving only placebo. The most frequent adverse events were asthenia and headache, pruritus, and fatigue. Interpretation: Ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks provided similarly high SVR12 rates in previous non-responders with HCV genotype 1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat treatment-experienced patients with cirrhosis if longer-term treatment is not possible. Funding: Gilead Sciences. © 2015 Elsevier Ltd. Source

Gastric carcinogenesis is related to inflammatory reaction induced by Helicobacter pylori infection. Infection is involved in pathogenesis of both histological types of gastric cancer, intestinal or diffuse. In the first type, cancer is the last step of successive alterations of the gastric mucosa (atrophy, intestinal metaplasia, dysplasia). In the second type, cancer occurs faster due to chromosomic alterations related to oxidative stress. Inflammation and consequently cancer risk are modulated by bacterial virulence and by the immunological responsiveness of the host. Helicobacter pylori eradication should be proposed to high risk patients: first degree relatives of patients having gastric cancer, patients with preneoplastic lesions. Cancer prevention is more effective when eradication is performed before occurrence of preneoplastic lesions. When preneoplastic lesions are present, eradication decreases but not suppresses the risk of cancer. Therefore periodic follow-up with gastroscopy and biopsies should be planned in these patients. Source

Moal V.,Aix - Marseille University | Gerolami R.,Service dHepato gastro enterologie | Colson P.,Pole des Maladies Infectieuses et Tropicales Clinique et Biologique | Colson P.,French National Center for Scientific Research
Intervirology | Year: 2012

Hepatitis E virus (HEV), the main etiologic agent of enterically transmitted acute hepatitis in developing countries, is now recognized as an emerging agent of autochthonous disease and chronic hepatitis E in immunocompromised patients in Europe where HEV infection is probably zoonotically acquired. We describe the first human case of acute HEV infection with two genotype 3 viruses in a French kidney transplant recipient, probably acquired through consumption of uncooked pig liver sausage (figatellu). The patient presented two viral sequences nearly identical to sequences recovered from figatelli. Autochthonous co-infections with different genotype 3 HEV strains can occur in our geographical area. © 2012 S Karger AG Basel. Source

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