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Saint-Joseph-de-Rivière, France

Ferenci P.,Medical University of Vienna | Asselah T.,University Paris Diderot | Foster G.R.,Queen Mary, University of London | Zeuzem S.,Goethe University Frankfurt | And 21 more authors.
Journal of Hepatology

Background & Aims The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. Methods Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Results SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p <0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. Conclusions Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg. © 2014 European Association for the Study of the Liver. Source

Foster G.R.,Queen Mary, University of London | Ferenci P.,Vienna University Hospital | Asselah T.,University Paris Diderot | Mantry P.,Liver Institute at Methodist Dallas Medical Center | And 13 more authors.
Journal of Viral Hepatitis

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥800 000 IU/mL (80% vs 58%) and a non-CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir. © 2015 John Wiley & Sons Ltd. Source

Mohamed S.,Laboratoire Alphabio | Mohamed S.,French Institute of Health and Medical Research | Raimondo A.,CDL Pharma | Penaranda G.,Laboratoire Alphabio | And 7 more authors.

Background & Aims:Dried blood spots (DBS) on filter paper have been successfully used to diagnose and monitor several infectious diseases. The aim was to investigate the performance of DBS in hepatitis B virus (HBV) diagnosis using commercial tests in comparison to standard methods.Methods:Paired DBS and plasma samples were collected from 200 patients: 100 patients with HBsAg negative status and 100 patients with HBsAg positive status. In the latter patient, HBeAg reactivity was tested. Ten samples of anti-HBs were collected from people vaccinated against HBV. We also studied 50 patients with positive HBV DNA viral load in plasma and 10 HBV DNA negative patients. HBV genotypes and gene polymerase mutations were determined in 10 randomly selected HBV-infected patients. The DBS sample consisted of 50 μL of whole blood, i.e. a 12-mm paper card.Results:The sensitivity thresholds of HBsAg and anti-HBs antibody were 0.30±0.08 IU/mL and 18.11±6.05 IU/mL, respectively, for DBS with 98% sensitivity and 100% specificity. Sensitivity was 98% and specificity 100% for the detection of HBV DNA on a blotter, considering an HBV DNA threshold of 914.1±157.8 IU/ml. Ten patients had an HBeAg positive status in plasma, all were detected positive using DBS. HBV genotyping and mutation detection were successfully performed on DBS, with full concordance between the 10 paired DBS and plasma samples.Conclusion:This study shows DBS is a reliable alternative to plasma specimens for quantifying and detecting HBsAg, anti-HBs, HBeAg and genotyping. DBS may increase the opportunities for HBV testing and treatment follow-up in hard-to-reach individuals. © 2013 Mohamed et al. Source

Halfon P.,Laboratoire Alphabio | Ouzan D.,Institute Arnault Tzanck | Khiri H.,Laboratoire Alphabio | Penaranda G.,Laboratoire Alphabio | And 8 more authors.

Background & Aims: Point mutations in the coding region of the interleukin 28 gene (rs12979860) have recently been identified for predicting the outcome of treatment of hepatitis C virus infection. This polymorphism detection was based on whole blood DNA extraction. Alternatively, DNA for genetic diagnosis has been derived from buccal epithelial cells (BEC), dried blood spots (DBS), and genomic DNA from serum. The aim of the study was to investigate the reliability and accuracy of alternative routes of testing for single nucleotide polymorphism allele rs12979860CC. Methods: Blood, plasma, and sera samples from 200 patients were extracted (400 μL). Buccal smears were tested using an FTA card. To simulate postal delay, we tested the influence of storage at ambient temperature on the different sources of DNA at five time points (baseline, 48 h, 6 days, 9 days, and 12 days) Results: There was 100% concordance between blood, plasma, sera, and BEC, validating the use of DNA extracted from BEC collected on cytology brushes for genetic testing. Genetic variations in HPTR1 gene were detected using smear technique in blood smear (3620 copies) as well as in buccal smears (5870 copies). These results are similar to those for whole blood diluted at 1/10. A minimum of 0.04 μL, 4 μL, and 40 μL was necessary to obtain exploitable results respectively for whole blood, sera, and plasma. No significant variation between each time point was observed for the different sources of DNA. IL28B SNPs analysis at these different time points showed the same results using the four sources of DNA. Conclusion: We demonstrated that genomic DNA extraction from buccal cells, small amounts of serum, and dried blood spots is an alternative to DNA extracted from peripheral blood cells and is helpful in retrospective and prospective studies for multiple genetic markers, specifically in hard-to-reach individuals. © 2012 Halfon et al. Source

Halfon P.,Laboratoire Alphabio | Bourliere M.,Departement dHepato gastroenterologie | Ouzan D.,Institute Arnault Tzanck | Maor Y.,Sheba Medical Center | And 10 more authors.
European Journal of Gastroenterology and Hepatology

BACKGROUND: Recent studies have suggested that host genetics may be useful for predicting drug response and have supported the recommendation that single polynucleotide polymorphisms (SNPs) of IL28B should be investigated when treating hepatitis C virus (HCV)-1 infected patients. The aim of this study was to determine whether a single IL-28B genotype SNP rs8099917 or rs12979860 determination is sufficient to predict treatment failure in patients with chronic HCV. METHODS: A total of 198 patients were included; mean (±standard deviation) age was 47 ±12 years and 140 (71%) were men. One hundred and fifty-six (79%) patients were infected with HCV genotype 1 and 42 (21%) with HCV genotypes 2 or 3. One hundred and eight (55%) patients had sustained virologic response (SVR). Two SNPs in the IL-28B were analyzed (rs8099917 and rs12979860). RESULTS: A total of 115 (58%) patients had rs8099917 TT genotype and 61 (31%) had rs12979860 CC genotype. Rs8099917 TT and rs12979860 CC genotypes were associated with SVR in HCV genotype 1 patients [odds ratio=2.60 (1.36-5.00), P=0.004 and odds ratio=3.30 (1.58-6.90), P=0.03 respectively]. No association was found between SNPs and SVR in HCV genotype 2 or 3 patients. CONCLUSION: This study confirms that SNPs rs8099917 and rs12979860 used alone may be useful for predicting the outcome of HCV treatment. In a rational and cost-effective approach, determination of only one of these two SNPs is sufficient for predicting SVR. Because of the highest predictive SVR associated with rs12979860 CC compared with the rs8099917 TT (respective positive predictive value: 72% vs. 63%, P=ns), rs12979860 determination alone is sufficient for predicting interferon response. © 2011 Wolters Kluwer Health | Lippincott Williams &Wilkins. Source

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