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Oliver Lenz - One of the best experts on this subject based on the ideXlab platform.
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a 3 year follow up study after treatment with Simeprevir in combination with pegylated interferon α and ribavirin for chronic hepatitis c virus infection
Virology Journal, 2018Co-Authors: Fabien Zoulim, Eric Lawitz, Christophe Moreno, Oliver Lenz, Bart Fevery, Andrzej Horban, P Buggisch, Samuel S Lee, Chris Corbett, Thierry VerbinnenAbstract:Simeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union. This 3-year follow-up study assessed the durability of sustained virologic response (SVR) (undetectable HCV RNA 12 or 24 weeks after treatment end), and evaluated the persistence of treatment-emergent NS3/4A protease inhibitor resistance in patients not achieving SVR following treatment with Simeprevir plus PR in the parent study. The maintenance of SVR after the last post-therapy follow-up visit of the parent study (LPVPS) was assessed using HCV RNA measurements. The persistence of treatment-emergent NS3 amino acid substitutions in patients with no SVR at LPVPS was assessed using population sequencing. No study medications were administered. Overall, 249 patients were enrolled (200 with SVR at LPVPS; 49 with no SVR at LPVPS); 40 patients discontinued prematurely (18 with SVR; 22 with no SVR). All 200 enrolled patients who achieved SVR in the parent study maintained SVR until the last available visit in this study (median follow-up time: 35.8 months). The treatment-emergent NS3 amino acid substitutions detected at time of failure in the parent study in 43/49 enrolled patients were no longer detected in 37/43 (86.0%) at the end of this study (median follow-up time: 179.9 weeks [41.3 months]). This 3-year follow-up study provides evidence for the long-term durability of SVR (100%) after successful treatment with Simeprevir plus PR. Treatment-emergent NS3 amino acid substitutions became undetectable in the majority of patients. NCT01349465; ClinicalTrials.gov .
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efficacy of a 12 week Simeprevir plus peginterferon ribavirin pr regimen in treatment naive patients with hepatitis c virus hcv genotype 4 gt4 infection and mild to moderate fibrosis displaying early on treatment virologic response
PLOS ONE, 2017Co-Authors: Tarik Asselah, Graham R. Foster, Christophe Moreno, A Craxi, C Sarrazin, M Gschwantler, P Buggisch, Faisal M Sanai, Ceyhun Bicer, Oliver LenzAbstract:Background: HCV GT4 accounts for up to 20% of HCV infections worldwide. Simeprevir, given for 12 weeks as part of a 24- or 48-week combination regimen with PR is approved for the treatment of chronic HCV GT4 infection. Primary study objectives were assessment of efficacy and safety of Simeprevir plus PR in treatment-naive patients with HCV GT4 treated for 12 weeks. Primary efficacy outcome was sustained virologic response 12 weeks post-treatment (SVR12). Additional objectives included investigation of potential associations of rapid virologic response and baseline factors with SVR12. Methods: This multicentre, open-label, single-arm study (NCT01846832) evaluated efficacy and safety of Simeprevir plus PR in 67 patients with HCV GT4 infection. Patients were treatment-naive, aged 18–70 years with METAVIR F0–F2 fibrosis. Patients with early virologic response (HCV RNA <25 IU/mL [detectable/undetectable in IL28B CC patients or undetectable in IL28B CT/TT patients] at Week 2 and undetectable at Weeks 4 and 8) were eligible to stop all treatment at the end of Week 12, otherwise PR therapy was continued to Week 24. Results: Of 67 patients treated, 34 (51%) qualified for 12-week treatment including all but one patient with IL28B CC genotype (14/15). All patients in the 12-week group had undetectable HCV RNA at end of treatment, and 97% (33/34) achieved SVR12. No new safety signals with Simeprevir plus PR were identified. The proportion of patients experiencing Grade 3–4 adverse events was lower in the 12-week group than in the 24-week group. Conclusions: Our findings on Simeprevir plus PR therapy shortened to 12 weeks in patients with HCV GT4 infection with favourable baseline characteristics and displaying early on-treatment virologic response are encouraging. No new safety signals were associated with Simeprevir plus PR in this study.
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in vitro activity of Simeprevir against hepatitis c virus genotype 1 clinical isolates and its correlation with ns3 sequence and site directed mutants
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Thierry Verbinnen, Leen Vijgen, Bart Fevery, T L Jacobs, Sandra De Meyer, Oliver LenzAbstract:Simeprevir (TMC435) is a once-daily, single-pill, oral hepatitis C virus (HCV) NS3 protease inhibitor approved for the treatment of chronic HCV infection. Phenotypic characterization of baseline isolates and isolates from HCV genotype 1-infected patients failing with a Simeprevir-based regimen was performed using chimeric replicons carrying patient-derived NS3 protease sequences. Cutoff values differentiating between full susceptibility to Simeprevir (≤ 2.0-fold reduction in Simeprevir activity) and low-level versus high-level resistance (≥ 50-fold reduction in Simeprevir activity) were determined. The median Simeprevir fold change in the 50% effective concentration (FC) of pretreatment genotype 1a isolates, with and without Q80K, and genotype 1b isolates was 11, 0.9, and 0.4, respectively. Naturally occurring NS3 polymorphisms that reduced Simeprevir activity, other than Q80K, were uncommon in the Simeprevir studies and generally conferred low-level resistance in vitro. Although the proportion of patients with failure differed by HCV geno/subtype and/or presence of baseline Q80K, the level of Simeprevir resistance observed at failure was similarly high irrespective of type of failure, HCV genotype 1 subtype, and presence or absence of baseline Q80K. At the end of the study, Simeprevir activity against isolates that lost the emerging amino acid substitution returned to pretreatment values. Activity of Simeprevir against clinical isolates and site-directed mutant replicons harboring the corresponding single or double amino acid substitutions correlated well, showing that Simeprevir resistance can be attributed to these substitutions. In conclusion, pretreatment NS3 isolates were generally fully susceptible (FC, ≤ 2.0) or conferred low-level resistance to Simeprevir in vitro (FC, >2.0 and <50). Treatment failure with a Simeprevir-based regimen was associated with emergence of high-level-resistance variants (FC, ≥ 50).
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virology analyses of hcv isolates from genotype 1 infected patients treated with Simeprevir plus peginterferon ribavirin in phase iib iii studies
Journal of Hepatology, 2015Co-Authors: Oliver Lenz, Maria Beumont, Leen Vijgen, M Peeters, Thierry Verbinnen, Bart Fevery, Lotke Tambuyzer, Annemie Buelens, Hugo Ceulemans, Gaston PicchioAbstract:Background & Aims Simeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of chronic HCV infection. Baseline NS3 polymorphisms in all patients and emerging mutations in patients who failed to achieve sustained virologic response (SVR) with Simeprevir plus peginterferon/ribavirin (PR) in Phase IIb/III studies are described. Methods Baseline sequencing data were available for 2007 genotype 1 (GT1)-infected patients. Post-baseline data were available for 197/245 Simeprevir-treated patients who did not achieve SVR. In vitro Simeprevir susceptibility was assessed in a transient replicon assay as site-directed mutants or in chimeric replicons with patient-derived NS3 protease sequences. Results Baseline NS3 polymorphisms at positions associated with reduced in vitro susceptibility to Simeprevir (43, 80, 122, 155, 156, and/or 168; EC 50 fold change >2.0) were uncommon (1.3% [26/2007]), with the exception of Q80K, which confers ∼10-fold reduction in Simeprevir activity in vitro (13.7% [274/2007]; GT1a 29.5% [269/911], GT1b 0.5% [5/1096]). Baseline Q80K had minor effect on initial response to Simeprevir/PR, but resulted in lower SVR rates. Overall, 91.4% of Simeprevir-treated patients [180/197] without SVR had emerging mutations at NS3 positions 80, 122, 155, and/or 168 at failure (mainly R155K in GT1a with and without Q80K, and D168V in GT1b), conferring high-level resistance in vitro (EC 50 fold change >50). Emerging mutations were no longer detectable by population sequencing at study end in 50% [90/180] of patients (median follow-up 28.4weeks). Conclusions Simeprevir treatment failure was usually associated with emerging high-level resistance mutations, which became undetectable over time in half of the patients.
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Simeprevir with peginterferon ribavirin for treatment of chronic hepatitis c virus genotype 1 infection pooled safety analysis from phase iib and iii studies
Journal of Viral Hepatitis, 2015Co-Authors: Michael P Manns, Michael W. Fried, Stefan Zeuzem, Ira M Jacobson, M Peeters, Oliver Lenz, Fred Poordad, Xavier Forns, Sivi Ouwerkerkmahadevan, W JessnerAbstract:Summary This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of Simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received Simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued Simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in ‘Photosensitivity’ were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the Simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for Simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for Simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in Simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for Simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for Simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.
Mark S. Sulkowski - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and safety of 6 or 8 weeks of Simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection.
Journal of Viral Hepatitis, 2018Co-Authors: Mark S. Sulkowski, Eric Lawitz, Jordan J. Feld, Franco Felizarta, A. Corregidor, O. Khalid, R. Ghalib, William B. Smith, V. Van Eygen, Donghan LuoAbstract:The phase 2, open-label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6- or 8-week regimen of Simeprevir, daclatasvir and sofosbuvir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early-stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early-stage fibrosis: Simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of Simeprevir, daclatasvir and sofosbuvir were investigated. Sixty-eight patients were treated (6-week group: n = 59; 8-week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early-stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6-week group was viral relapse (11.9%; 7/59). One patient had on-treatment failure due to an early withdrawal (lost to follow-up due to incarceration). One patient with SVR12 in the 6-week group had a late viral relapse at post-treatment week 24. No clinically significant drug-drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct-acting antiviral regimens of Simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment-naive, HCV GT1-infected patients with early-stage fibrosis or compensated cirrhosis.
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all oral direct acting antiviral therapy in hcv advanced liver disease is effective in real world practice observations through hcv target database
Alimentary Pharmacology & Therapeutics, 2017Co-Authors: K R Reddy, Joseph K Lim, Alexander Kuo, A M Di Bisceglie, Joseph S Galati, G Morelli, G T Everson, Paul Y Kwo, Robert S Brown, Mark S. SulkowskiAbstract:SummaryBackground Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. Aim To assess efficacy of all-oral HCV therapy in advanced liver disease. Methods Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. Results Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus Simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66–74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and Simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. Conclusions All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811
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effectiveness of Simeprevir plus sofosbuvir with or without ribavirin in real world patients with hcv genotype 1 infection
Gastroenterology, 2016Co-Authors: Mark S. Sulkowski, Jordan J. Feld, Robert S Brown, Rajender K Reddy, Hugo E Vargas, Adrian M Di Bisceglie, Giuseppe Morelli, Jama M Darling, Lynn M Frazier, Thomas G StewartAbstract:Background & Aims The interferon-free regimen of Simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. Methods We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET—a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with Simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment—a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. Results The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%–87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. Conclusions In a large prospective observational cohort study, a 12-week regimen of Simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.
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Simeprevir plus sofosbuvir with or without ribavirin to treat chronic infection with hepatitis c virus genotype 1 in non responders to pegylated interferon and ribavirin and treatment naive patients the cosmos randomised study
The Lancet, 2014Co-Authors: E Lawitz, Mark S. Sulkowski, A. Corregidor, Mordechai Rabinovitz, Edwin Dejesus, Reem Ghalib, Brian L Pearlman, Maribel Rodrigueztorres, Zobair M Younossi, Norman GitlinAbstract:Summary Background Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined Simeprevir and sofosbuvir. Methods We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg Simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0–F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3–F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. Findings 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81–96] in cohort 1 and n=82 [94%, 87–98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3–4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. Interpretation Combined Simeprevir and sofosbuvir was efficacious and well tolerated. Funding Janssen.
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cost effectiveness analysis of sofosbuvir plus peginterferon ribavirin in the treatment of chronic hepatitis c virus genotype 1 infection
Alimentary Pharmacology & Therapeutics, 2014Co-Authors: Sammy Saab, Mark S. Sulkowski, Stuart C Gordon, Haesuk Park, Ali Ahmed, Zobair M YounossiAbstract:SummaryBackground Sofosbuvir, an oral NS5B nucleotide polymerase inhibitor, is indicated for the treatment of patients infected with hepatitis C virus (HCV). Aim To evaluate the long-term health economic outcomes of sofosbuvir + pegylated interferon alfa/ribavirin (pegIFN/RBV) compared with current treatments in patients infected with HCV genotype 1 in the US. Methods A decision-analytic Markov model was developed to estimate health outcomes, number needed to treat and short-term and long-term economic outcomes, including incremental cost-effectiveness ratios and cost per sustained virological response (SVR), for several sofosbuvir–comparator regimen pairings for a cohort of 10 000 patients. It considered three patient cohorts: treatment-naive, treatment-experienced and treatment-naive human immunodeficiency virus (HIV) co-infected. Subgroup analyses were conducted for treatment-naive patients with and without cirrhosis. Results Reductions in the incidence of new cases of liver-disease complications with sofosbuvir + pegIFN/RBV compared with pegIFN/RBV, boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and Simeprevir + pegIFN/RBV were 64–82%, 50–68%, 43–58% and 33–56%, respectively. Sofosbuvir + pegIFN/RBV was typically associated with the lowest 1-year cost per SVR. When considering the lifetime incremental cost per quality-adjusted life-year gained, sofosbuvir + pegIFN/RBV was the most cost-effective treatment option assessed. Sofosbuvir + pegIFN/RBV generally dominated (less costly and more effective than) boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and Simeprevir + pegIFN/RBV. Conclusion Sofosbuvir + pegIFN/RBV yields more favourable future health and economic outcomes than current treatment regimens for patients across all levels of treatment experience and cirrhosis stage, as well as for individuals with or without HIV co-infection.
Hiromitsu Kumada - One of the best experts on this subject based on the ideXlab platform.
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Simeprevir tmc435 once daily with peginterferon α 2b and ribavirin in patients with genotype 1 hepatitis c virus infection the concerto 4 study
Hepatology Research, 2015Co-Authors: Hiromitsu Kumada, Norio Hayashi, Namiki Izumi, Takeshi Okanoue, Hirohito Tsubouchi, Hiroshi Yatsuhashi, Mai Kato, Yuji Komada, Ki Rito, Chiharu SetoAbstract:Aim The efficacy and safety of Simeprevir in combination with peginterferon-α-2b and ribavirin (PEG IFN-α-2b/RBV) were investigated in patients infected with hepatitis C virus (HCV) genotype 1 who were treatment-naive or had previously received interferon (IFN)-based therapy. Methods CONCERTO-4 (NCT01366638) was an open-label, non-comparative, multicenter study of once-daily Simeprevir (TMC435) 100 mg in combination with PEG IFN-α-2b/RBV in treatment-naive and -experienced patients (prior relapsers or non-responders to IFN-based therapy) with chronic HCV genotype 1 infection. Twelve-week combination treatment was followed by 24/48-week response-guided PEG IFN-α-2b/RBV therapy for treatment-naive patients and prior relapsers, and 48-week PEG IFN-α-2b/RBV therapy for prior non-responders. Patients were followed for 72 weeks after treatment initiation. The proportions of patients with sustained viral response (SVR; undetectable HCV RNA) at treatment end and 12 weeks after the last treatment (SVR12) were among the major efficacy end-points. Safety, including adverse events (AE), was monitored. Results Of the 79 patients treated, the proportion achieving SVR12 was highest among treatment-naive patients (91.7%) and prior relapsers (100%) versus 38.5% of prior non-responders. All treatment-naive patients and prior non-responders who achieved SVR12 also achieved SVR at treatment end and 24 weeks after last dose; 96.6% of prior relapsers achieved both end-points. Most AE were of grade 1 or 2 severity. Grade 3 AE occurred in 17 patients, most frequently neutropenia (6.3%). Conclusion Simeprevir combined with PEG IFN-α-2b/RBV was effective in patients infected with HCV genotype 1, both for initial treatment of naive patients and for retreatment of patients in whom previous IFN-based therapy had failed.
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Simeprevir with peginterferon ribavirin for treatment naive hepatitis c genotype 1 patients in japan concerto 1 a phase iii trial
Journal of Hepatology, 2014Co-Authors: Norio Hayashi, Namiki Izumi, Hiromitsu Kumada, Takeshi Okanoue, Hirohito Tsubouchi, Hiroshi Yatsuhashi, Mai Kato, Yuji Komada, Chiharu Seto, Shoichiro GotoAbstract:Background & Aims In a Japanese Phase II study, the hepatitis C virus NS3/4A protease inhibitor Simeprevir demonstrated potent antiviral activity and significantly improved sustained virologic response rates when added to peginterferon α-2a/ribavirin in treatment-naive patients infected with hepatitis C virus genotype 1. Methods CONCERTO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. Treatment-naive adults (⩽70years) with chronic hepatitis C virus genotype 1 infection (hepatitis C virus RNA ⩾5log 10 IU/ml) were randomized (2:1) to Simeprevir 100mg once-daily with peginterferon α-2a/ribavirin for 12weeks then response-guided therapy with peginterferon α-2a/ribavirin for 12 or 36weeks, or to placebo with peginterferon α-2a/ribavirin for 12weeks then peginterferon α-2a/ribavirin for 36weeks. Results Overall, 183 patients were treated. Sustained virologic response 12weeks after treatment end (primary efficacy endpoint) was achieved in 88.6% of Simeprevir- and 61.7% of placebo-treated patients ( p Conclusions Simeprevir once daily with peginterferon α-2a/ribavirin significantly improved sustained virologic response rate 12weeks after treatment end in treatment-naive patients with chronic hepatitis C virus genotype 1 infection, with a shorter 24-week treatment duration in most patients.
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evolution of Simeprevir resistant variants over time by ultra deep sequencing in hcv genotype 1b
Journal of Medical Virology, 2014Co-Authors: Norio Akuta, Tetsuya Hosaka, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Kenji Ikeda, Hiromitsu KumadaAbstract:Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of Simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of Simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of Simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting Simeprevir-resistant variants.
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once daily Simeprevir with peginterferon and ribavirin for treatment experienced hcv genotype 1 infected patients in japan the concerto 2 and concerto 3 studies
Journal of Gastroenterology, 2014Co-Authors: Namiki Izumi, Norio Hayashi, Hiromitsu Kumada, Takeshi Okanoue, Hirohito Tsubouchi, Hiroshi Yatsuhashi, Mai Kato, Yuji Komada, Chiharu Seto, Shoichiro GotoAbstract:Background Efficacy of available therapies for patients with HCV who have previously failed treatment is limited. Two Phase III, open-label trials in Japan investigated efficacy and safety of Simeprevir and peginterferon-α-2a/ribavirin (PR) combination therapy in treatment-experienced patients with genotype 1 HCV infection.
M Peeters - One of the best experts on this subject based on the ideXlab platform.
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drug drug interactions with the ns3 4a protease inhibitor Simeprevir
Clinical Pharmacokinectics, 2016Co-Authors: Sivi Ouwerkerkmahadevan, M Peeters, Jan Snoeys, M Beumontmauviel, A SimionAbstract:Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug–drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of Simeprevir, respectively, and should be avoided. Clinical studies have shown that Simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of Simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in Simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.
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evaluation of the pharmacokinetics and renal excretion of Simeprevir in subjects with renal impairment
Drugs in R & D, 2015Co-Authors: Sivi Ouwerkerkmahadevan, M Peeters, M Beumontmauviel, Steven Mortier, Rene Verloes, Carla Truyers, Geert Mannens, Inneke Wynant, A SimionAbstract:Background Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed.
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virology analyses of hcv isolates from genotype 1 infected patients treated with Simeprevir plus peginterferon ribavirin in phase iib iii studies
Journal of Hepatology, 2015Co-Authors: Oliver Lenz, Maria Beumont, Leen Vijgen, M Peeters, Thierry Verbinnen, Bart Fevery, Lotke Tambuyzer, Annemie Buelens, Hugo Ceulemans, Gaston PicchioAbstract:Background & Aims Simeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of chronic HCV infection. Baseline NS3 polymorphisms in all patients and emerging mutations in patients who failed to achieve sustained virologic response (SVR) with Simeprevir plus peginterferon/ribavirin (PR) in Phase IIb/III studies are described. Methods Baseline sequencing data were available for 2007 genotype 1 (GT1)-infected patients. Post-baseline data were available for 197/245 Simeprevir-treated patients who did not achieve SVR. In vitro Simeprevir susceptibility was assessed in a transient replicon assay as site-directed mutants or in chimeric replicons with patient-derived NS3 protease sequences. Results Baseline NS3 polymorphisms at positions associated with reduced in vitro susceptibility to Simeprevir (43, 80, 122, 155, 156, and/or 168; EC 50 fold change >2.0) were uncommon (1.3% [26/2007]), with the exception of Q80K, which confers ∼10-fold reduction in Simeprevir activity in vitro (13.7% [274/2007]; GT1a 29.5% [269/911], GT1b 0.5% [5/1096]). Baseline Q80K had minor effect on initial response to Simeprevir/PR, but resulted in lower SVR rates. Overall, 91.4% of Simeprevir-treated patients [180/197] without SVR had emerging mutations at NS3 positions 80, 122, 155, and/or 168 at failure (mainly R155K in GT1a with and without Q80K, and D168V in GT1b), conferring high-level resistance in vitro (EC 50 fold change >50). Emerging mutations were no longer detectable by population sequencing at study end in 50% [90/180] of patients (median follow-up 28.4weeks). Conclusions Simeprevir treatment failure was usually associated with emerging high-level resistance mutations, which became undetectable over time in half of the patients.
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Simeprevir with peginterferon ribavirin for treatment of chronic hepatitis c virus genotype 1 infection pooled safety analysis from phase iib and iii studies
Journal of Viral Hepatitis, 2015Co-Authors: Michael P Manns, Michael W. Fried, Stefan Zeuzem, Ira M Jacobson, M Peeters, Oliver Lenz, Fred Poordad, Xavier Forns, Sivi Ouwerkerkmahadevan, W JessnerAbstract:Summary This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of Simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were summarised for patients who received Simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon-α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued Simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) [Correction added on 16 January 2015, after first online publication: In the above sentence, the values in ‘Photosensitivity’ were previously incorrect and have now been changed to 3.2% vs 0.6%.] were more prevalent in the Simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for Simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for Simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild-to-moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in Simeprevir-treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for Simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient-reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for Simeprevir due to the use of response-guided therapy. Simeprevir is well tolerated in HCV genotype 1-infected patients.
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fatigue during treatment for hepatitis c virus results of self reported fatigue severity in two phase iib studies of Simeprevir treatment in patients with hepatitis c virus genotype 1 infection
BMC Infectious Diseases, 2014Co-Authors: Jane Scott, Maria Beumont, M Peeters, S Zeuzem, Kathleen Rosa, K Cerri, Donna M Evon, L GillesAbstract:Background: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor Simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330]. Methods: Treatment-naive patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to Simeprevir plus PR (Simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the Simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72. Results: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving Simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving Simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of Simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with Simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study. Conclusions: Combination of Simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with Simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.
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jnj 4178 al 335 odalasvir and Simeprevir for 6 or 8 weeks in hepatitis c virus infected patients without cirrhosis omega 1
Hepatology, 2019Co-Authors: S Zeuzem, Maria Buti, Suzanne Bourgeois, Christophe Moreno, Ewa Janczewska, Susan Greenbloom, Alessio Aghemo, P Lampertico, Seng Gee Lim, P BuggischAbstract:The combination of three direct-acting antiviral agents (AL-335, odalasvir, and Simeprevir: JNJ-4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)-1-infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA-1. This multicenter, randomized, open-label study (NCT02765490) enrolled treatment-naive and interferon (±ribavirin) treatment-experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL-335 800 mg, odalasvir 25 mg, and Simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8-week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a-infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment-related serious AEs. All randomized patients completed treatment. Conclusion: In HCV-infected patients, 6 and 8 weeks of treatment with JNJ-4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.
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fatigue during treatment for hepatitis c virus results of self reported fatigue severity in two phase iib studies of Simeprevir treatment in patients with hepatitis c virus genotype 1 infection
BMC Infectious Diseases, 2014Co-Authors: Jane Scott, Maria Beumont, M Peeters, S Zeuzem, Kathleen Rosa, K Cerri, Donna M Evon, L GillesAbstract:Background: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor Simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330]. Methods: Treatment-naive patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to Simeprevir plus PR (Simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the Simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72. Results: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving Simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving Simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of Simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with Simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study. Conclusions: Combination of Simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with Simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.
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Simeprevir with peginterferon and ribavirin leads to high rates of svr in patients with hcv genotype 1 who relapsed after previous therapy a phase 3 trial
Gastroenterology, 2014Co-Authors: Xavier Forns, Jean-pierre Bronowicki, M Peeters, E Lawitz, S Zeuzem, Ed Gane, Pietro Andreone, Andrzej Horban, Ashley Brown, Oliver LenzAbstract:Background & Aims Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of Simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy. Methods Patients were assigned randomly (2:1) to groups given Simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (Simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group). Results Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6–53.0; P Conclusions In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of Simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving Simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.
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Simeprevir increases rate of sustained virologic response among treatment experienced patients with hcv genotype 1 infection a phase iib trial
Gastroenterology, 2014Co-Authors: S Zeuzem, Graham R. Foster, Michael W. Fried, Christophe Hézode, Ira M Jacobson, Thomas Berg, Edward Gane, P Ferenci, Gideon M Hirschfield, I V NikitinAbstract:Background & Aims Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of Simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. Methods We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive Simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. Results Overall, rates of SVR at 24 weeks were significantly higher in the groups given Simeprevir than those given placebo (61%−80% vs 23%; P Conclusions In treatment-experienced patients, 12, 24, or 48 weeks Simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.
