Dataset Information

SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon ?-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.

ABSTRACT: Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon ?-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).

SUBMITTER: Dieterich D

PROVIDER: S-EPMC4068493 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon α-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.

Dieterich Douglas D Asselah Tarik T Guyader Dominique D Berg Thomas T Schuchmann Marcus M Mauss Stefan S Ratziu Vlad V Ferenci Peter P Larrey Dominique D Maieron Andreas A Stern Jerry O JO Ozan Melek M Datsenko Yakov Y Böcher Wulf Otto WO Steinmann Gerhard G

Antimicrobial agents and chemotherapy 20140407 6

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 ...[more]

PMID: 24709256

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Project description:About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFN?) and ribavirin (RBV) have been shown to be superior to PegIFN??+?RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available.This was a historical comparison of study C212 (simeprevir?+?PegIFN?-2a?+?RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFN?-2a?+?RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFN?-2a?+?RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212.The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFN?-2a?+?RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24?=?72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir?+?PegIFN?-2a?+?RBV compared to PegIFN?-2a?+?RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies.This historical comparison provides first systematic evidence for the superiority of simeprevir?+?PegIFN?-2a?+?RBV compared to PegIFN?-2a?+?RBV in patients with HCV-1/HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1/HIV coinfection would be desirable.Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868.

Project description:BACKGROUND:Abnormal serum lipid profiles have been noted in patients with chronic hepatitis C virus (HCV) infection. Moreover, many reports suggest that serum lipoprotein profiles are more profoundly distorted in patients with HCV G1b infection who have an unfavorable response to pegylated interferon (peg-IFN) plus ribavirin (RBV) combination therapy. However, after the discovery of single nucleotide polymorphisms near the IL28B gene (rs8099917 and rs12979860) as potent predictive factors affecting the response to peg-IFN plus RBV, lipid factors are thought to be confounding factors. OBJECTIVES:To re-examine the significance of lipoprotein profiles on virological response to peg-IFN plus RBV combination therapy in patients with chronic HCV G1b infection, we examined cholesterol and triglyceride concentrations in each lipoprotein fraction separated by high performance liquid chromatography. PATIENTS AND METHODS:Lipoprotein profiles were examined using fasting sera from 108 patients infected with HCV G1b who had chronic hepatitis, as determined by liver biopsy. Results of lipoprotein profiles and clinical data, including IL28B genotype and amino acid substitution at aa70 of HCV G1b, were compared between patients with a sustained virological response (SVR) and non-SVR or a non-virological response (NVR) and virological responses other than NVR (non-NVR). In addition, significant predictive factors independently associated with virological response to peg-IFN?-2b plus RBV were determined by logistic regression analysis. RESULTS:An increased ratio of cholesterol/triglyceride in very low-density lipoprotein (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.01-9.44) along with a major genotype of rs8099917 (OR 9.09; 95% CI 2.94-33.33), were independent predictive factors for SVR. In contrast, lipid factors were not elucidated as independent predictive factors for NVR. CONCLUSIONS:Examination of the fasting lipid profile has clinical importance in predicting the efficacy of peg-IFN-?-2b plus RBV combination therapy for patients with HCV G1b even after the discovery of the IL28 genotype as a potent predictive factor.

Dataset Information

SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon ?-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.

Publications

SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon α-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.

Similar Datasets

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