The Experts below are selected from a list of 3423 Experts worldwide ranked by ideXlab platform
Christophe Hezode - One of the best experts on this subject based on the ideXlab platform.
-
Patient disposition in DYNAMO 2.
2016Co-Authors: Heiner Wedemeyer, Christophe Hezode, Xavier Forns, Samuel S. Lee, Astrid Scalori, Athina Voulgari, Sophie Le Pogam, Isabel Nájera, James A. ThommesAbstract:MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, Telaprevir.
-
SVR12 rates by treatment arm in the overall populations and by HCV genotype and presence/absence of bridging fibrosis or cirrhosis in DYNAMO 1 (a) and DYNAMO 2 (b).
2016Co-Authors: Heiner Wedemeyer, Christophe Hezode, Xavier Forns, Samuel S. Lee, Astrid Scalori, Athina Voulgari, Sophie Le Pogam, Isabel Nájera, James A. ThommesAbstract:BOC, boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, Telaprevir.
-
the cupic algorithm an accurate model for the prediction of sustained viral response under Telaprevir or boceprevir triple therapy in cirrhotic patients
Journal of Viral Hepatitis, 2015Co-Authors: Jerome Boursier, Christophe Hezode, Jean-pierre Bronowicki, Dominique Larrey, Alexandra Ducancelle, J Vergniol, P Veillon, Valerie Moal, C Dufour, Fabien ZoulimAbstract:Triple therapy using boceprevir or Telaprevir remains the reference treatment for genotype 1 chronic hepatitis C in countries where new interferon-free regimens have not yet become available. Antiviral treatment is highly required in cirrhotic patients, but they represent a difficult-to-treat population. We aimed to develop a simple algorithm for the prediction of sustained viral response (SVR) in cirrhotic patients treated with triple therapy. A total of 484 cirrhotic patients from the ANRS CO20 CUPIC cohort treated with triple therapy were randomly distributed into derivation and validation sets. A total of 52.1% of patients achieved SVR. In the derivation set, a D0 score for the prediction of SVR before treatment initiation included the following independent predictors collected at day 0: prior treatment response, gamma-GT, platelets, Telaprevir treatment, viral load. To refine the prediction at the early phase of the treatment, a W4 score included as additional parameter the viral load collected at week 4. The D0 and W4 scores were combined in the CUPIC algorithm defining three subgroups: 'no treatment initiation or early stop at week 4', 'undetermined' and 'SVR highly probable'. In the validation set, the rates of SVR in these three subgroups were, respectively, 11.1%, 50.0% and 82.2% (P < 0.001). By replacing the variable 'prior treatment response' with 'IL28B genotype', another algorithm was derived for treatment-naive patients with similar results. The CUPIC algorithm is an easy-to-use tool that helps physicians weigh their decision between immediately treating cirrhotic patients using boceprevir/Telaprevir triple therapy or waiting for new drugs to become available in their country.
-
effectiveness of Telaprevir or boceprevir in treatment experienced patients with hcv genotype 1 infection and cirrhosis
Gastroenterology, 2014Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Marc BourliereAbstract:BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either Telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given Telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with Telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.
-
effectiveness of Telaprevir or boceprevir in treatment experienced patients with hcv genotype 1 infection and cirrhosis
Gastroenterology, 2014Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Victor De Ledinghen, Marc BourliereAbstract:BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either Telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given Telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with Telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.
Ira M Jacobson - One of the best experts on this subject based on the ideXlab platform.
-
daclatasvir vs Telaprevir plus peginterferon alfa ribavirin for hepatitis c virus genotype 1
World Journal of Gastroenterology, 2016Co-Authors: Ira M Jacobson, Peter Ferenci, Stefan Zeuzem, Robert Flisiak, Brygida Knysz, Stefan Lueth, Ewa Janczewska, Moisés Diago, Dorota Zarebskamichaluk, Anna Linda ZignegoAbstract:Daclatasvir vs Telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1
-
vx 222 a non nucleoside ns5b polymerase inhibitor in Telaprevir based regimens for genotype 1 hepatitis c virus infection
European Journal of Gastroenterology & Hepatology, 2014Co-Authors: Adrian M Di Bisceglie, Ira M Jacobson, Katia Alves, David R Nelson, Mark S Sulkowski, Ed Gane, Cynthia Desouza, Shelley George, Tara L. KiefferAbstract:ObjectiveTo investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various Telaprevir-based regimens for treatment of genotype 1 HCV.MethodsIn total, 152 t
-
once daily simeprevir tmc435 with pegylated interferon and ribavirin in treatment naive genotype 1 hepatitis c the randomized pillar study
Hepatology, 2013Co-Authors: Michael W. Fried, Peter Ferenci, Patrick Marcellin, Ira M Jacobson, Robert Flisiak, Maria Buti, I V Nikitin, Gregory J. Dore, Michael P Manns, Fred PoordadAbstract:The availability of direct-acting antiviral agents has recently transformed the treatment of chronic hepatitis C (CHC).1,2 Triple-therapy regimens that include nonstructural protein (NS)3/4A protease inhibitors, such as boceprevir and Telaprevir, combined with pegylated interferon (Peg-IFN) and ribavirin (RBV) significantly improve the rate of sustained virologic response (SVR) for patients with genotype 1 CHC infection, compared with Peg-IFN and RBV alone.3,4 Furthermore, many patients may qualify for a shortened duration of therapy by incorporating a response-guided therapy (RGT) algorithm that determines the duration of therapy according to on-treatment virologic response milestones.5 However, these regimens have also increased the complexity of treatment for patients and amplified the adverse events (AEs) associated with hepatitis C therapy.6,7 Strict adherence to three-times-daily dosing is required for boceprevir and Telaprevir, along with recommendations to be administered with food (with a specific fat content for Telaprevir) to enhance absorption of medications.6 Anemia is more frequent and severe when either of these agents is used with Peg-IFN and RBV, whereas skin rash is more common with Telaprevir-containing regimens.3,4 Thus, effective treatments with simplified dosing schedules and improved AE profiles would benefit patients with CHC. Simeprevir (SMV; TMC435) is an oral, once-daily (QD), investigational hepatitis C virus (HCV) NS3/4A macrocyclic protease inhibitor with potent antiviral activity in patients infected with genotype 1 as well as antiviral activity demonstrated against isolates of genotypes 2, 4, 5, and 6.8,9 In preclinical studies, the replicon half-maximal effective concentration (EC50) for SMV ranged from 8 to 28 nM, and the liver-to-plasma concentration ratio was high (ratio of 39).10 In a phase I study, patients with hepatitis C genotype 1 treated with a 5-day course of SMV monotherapy exhibited a median maximal reduction of HCV RNA of 3.9 log10, which compares favorably to that observed with boceprevir (~2.45 log10 over 7 days) and Telaprevir (~4.4 log10 over 14 days).8,11,12 Manns et al. administered triple therapy with SMV (dose range: 25-200 mg QD) plus Peg-IFN-α-2a and RBV in a phase IIa study for up to 28 days.13 The majority of patients, both treatment naive and treatment experienced, had HCV RNA below the lower level of quantification (<25 IU/mL) of the HCV RNA assay by day 28 of therapy.13 The aim of the current study was to assess the efficacy and safety of two different doses of SMV administered QD for two different durations in combination with Peg-IFN and RBV in treatment-naive patients infected with HCV genotype 1.
-
the first wave hcv ns3 protease inhibitors Telaprevir and boceprevir
Antiviral Therapy, 2012Co-Authors: Kristen M Marks, Ira M JacobsonAbstract:Boceprevir and Telaprevir are peptidomimetic serine protease inhibitors that have been recently approved for the treatment of HCV chronic infection. The addition of these drugs to the prior standard of care, pegylated interferon and ribavirin, improves sustained virological response rates for treatment-naive and treatment-experienced patients and shortens the duration of treatment for over half of treatment-naive patients. This review describes the clinical data supporting the approval and use of Telaprevir and boceprevir, the algorithm for the use of these drugs, their adverse effects, as well as their important drug-drug interactions.
-
Telaprevir for previously untreated chronic hepatitis c virus infection
The New England Journal of Medicine, 2011Co-Authors: Ira M Jacobson, Peter Ferenci, Andrew J. Muir, Rajender K Reddy, Patrick Marcellin, Adrian M Di Bisceglie, Geoffrey Dusheiko, Natalie Bzowej, Robert FlisiakAbstract:A B S T R AC T Background In phase 2 trials, Telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. Methods In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving Telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon–ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving Telaprevir with peginterferon–ribavirin for 8 weeks and placebo with peginterferon–ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon–ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks of peginterferon–ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Results Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with Telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving Telaprevir than among those receiving peginterferon–ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Conclusions Telaprevir with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.)
Marc Bourliere - One of the best experts on this subject based on the ideXlab platform.
-
effectiveness of Telaprevir or boceprevir in treatment experienced patients with hcv genotype 1 infection and cirrhosis
Gastroenterology, 2014Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Marc BourliereAbstract:BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either Telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given Telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with Telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.
-
effectiveness of Telaprevir or boceprevir in treatment experienced patients with hcv genotype 1 infection and cirrhosis
Gastroenterology, 2014Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Victor De Ledinghen, Marc BourliereAbstract:BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either Telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given Telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with Telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.
-
1423 interim analysis of an interferon ifn and ribavirin rbv free regimen of daclatasvir dcv asunaprevir asv and bms 791325 in treatment naive hepatitis c virus genotype 1 infected patients
Journal of Hepatology, 2013Co-Authors: G T Everson, Marc Bourliere, Eric Lawitz, Christophe Hezode, K Sims, Maribel Rodrigueztorres, V Loustaudratti, Vinod K Rustgi, Howard J Schwartz, Harvey A TatumAbstract:13.6±1.8 g/dL [8.8–17.5], respectively. After 12W, a complete early virological response was obtained in 34 (83%) boceprevir patients and in 35 (61%) Telaprevir patients (p = 0.026). Among 17 boceprevir and 16 Telaprevir patients, 14 (82%) and 7 (43%) achieved an end of treatment response (EOT) with an undetetectable viral load, respectively (p = 0.032). Among 9 boceprevir and 5 Telaprevir patients, 6 and 1 achieved SVR12, respectively. Among 6 patients in the boceprevir group, 3 achieved SVR24. In the Telaprevir group, 29 patients discontinued therapy (serious adverse events, n = 13; virological breakthrough, n = 6; non-response, n = 9). In the boceprevir group, 14 patients discontinued therapy (serious adverse events, n = 5; virological breakthrough, n = 2; non-response, n = 4; retransplantation, n = 1). Four patients died in a context of infectious disorders: boceprevir, n = 2 (W20/W24); Telaprevir, n = 2 (W2/W9). The most common side effect was anemia in 85% of patients: 95% and 96% in boceprevir and Telaprevir groups received erythropoietin alone or combined with ribavirin dose reduction. Conclusion: In liver transplanted patients, EOT rate was 82% and 38% with boceprevir and Telaprevir, respectively. Among the overall population, 44% of patients discontinued therapy because of treatment failure or occurrence of serious adverse events.
-
dermatological side effects of hepatitis c and its treatment patient management in the era of direct acting antivirals
Journal of Hepatology, 2012Co-Authors: Patrice Cacoub, Marc Bourliere, Christophe Hezode, Geoffrey Dusheiko, Jann Lubbe, N Dupin, P Buggisch, Odile Picard, Ramon M Pujol, Siegfried SegaertAbstract:Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In Telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to Telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with Telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between Telaprevir-related dermatitis and SCAR. The Telaprevir prescribing information does not require Telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate Telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping Telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.
-
Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.
New England Journal of Medicine, 2009Co-Authors: Christophe Hezode, Marc Bourliere, Peter Ferenci, Tobias Goeser, Jean-pierre Bronowicki, Nicole Forestier, Geoffrey Dusheiko, Stanislas Pol, Shahin Gharakhanian, Leif BengtssonAbstract:BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of Telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received Telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received Telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received Telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the Telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three Telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)
Ann D Kwong - One of the best experts on this subject based on the ideXlab platform.
-
hepatitis c virus variants with decreased sensitivity to direct acting antivirals daas were rarely observed in daa naive patients prior to treatment
Journal of Virology, 2013Co-Authors: Doug J Bartels, James C Sullivan, Ann D Kwong, Sandra De Meyer, Eileen Z Zhang, Jennifer Dorrian, Ann Tigges, Darin Takemoto, Elizabeth Dondero, Gaston PicchioAbstract:The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC(50)]) to Telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC(50)) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including Telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a Telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the Telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.
-
discovery and development of Telaprevir an ns3 4a protease inhibitor for treating genotype 1 chronic hepatitis c virus
Nature Biotechnology, 2011Co-Authors: Ann D Kwong, Robert S Kauffman, Patricia Hurter, Peter R MuellerAbstract:Discovery and development of Telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus
-
discovery and development of Telaprevir an ns3 4a protease inhibitor for treating genotype 1 chronic hepatitis c virus
Nature Biotechnology, 2011Co-Authors: Ann D Kwong, Robert S Kauffman, Patricia Hurter, Peter R MuellerAbstract:Infection with hepatitis C virus (HCV) is a major medical problem with over 170 million people infected worldwide. Substantial morbidity and mortality are associated with hepatic manifestations (cirrhosis and hepatocellular carcinoma), which develop with increasing frequency in people infected with HCV for more than 20 years. Less well known is the burden of HCV disease associated with extrahepatic manifestations (diabetes, B-cell proliferative disorders, depression, cognitive disorders, arthritis and Sjogren's syndrome). For patients infected with genotype 1 HCV, treatment with polyethylene glycol decorated interferon (peginterferon) α and ribavirin (PR) is associated with a low (40-50%) success rate, substantial treatment-limiting side effects and a long (48-week) duration of treatment. In the past 15 years, major scientific advances have enabled the development of new classes of HCV therapy, the direct-acting antiviral agents, also known as specifically targeted antiviral therapy for hepatitis C (STAT-C). In combination with PR, the HCV NS3-4A protease inhibitor Telaprevir has recently been approved for treatment of genotype 1 chronic HCV in the United States, Canada, European Union and Japan. Compared with PR, Telaprevir combination therapy offers significantly improved viral cure rates and the possibility of shortened treatment duration for diverse patient populations. Developers of innovative drugs have to blaze a new path with few validated sign posts to guide the way. Indeed, Telaprevir's development was once put on hold because of its performance in a standard IC(50) assay. Data from new hypotheses and novel experiments were required to justify further investment and reduce risk that the drug might fail in the clinic. In addition, the poor drug-like properties of Telaprevir were a formidable hurdle, which the manufacturing and formulation teams had to overcome to make the drug. Finally, novel clinical trial designs were developed to improve efficacy and shorten treatment in parallel instead of sequentially. Lessons learned from the development of Telaprevir suggest that makers of innovative medicines cannot rely solely on traditional drug discovery metrics, but must develop innovative, scientifically guided pathways for success.
-
phenotypic characterization of resistant val36 variants of hepatitis c virus ns3 4a serine protease
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Yi Zhou, Doug J Bartels, Ann M Tigges, Brian L Hanzelka, Debra L Brennan, Lora Swenson, Ann D KwongAbstract:In patients chronically infected with hepatitis C virus (HCV) strains of genotype 1, rapid and dramatic antiviral activity has been observed with Telaprevir (VX-950), a highly selective and potent inhibitor of the HCV NS3-4A serine protease. HCV variants with substitutions in the NS3 protease domain were observed in some patients during Telaprevir dosing. In this study, purified protease domain proteins and reconstituted HCV subgenomic replicons were used for phenotypic characterization of many of these substitutions. V36A/M or T54A substitutions conferred less than eightfold resistance to Telaprevir. Variants with double substitutions at Val 36 plus Thr 54 had ∼20-fold resistance to Telaprevir, and variants with double substitutions at Val 36 plus Arg 155 or Ala 156 had >40-fold resistance to Telaprevir. An X-ray structure of the HCV strain H protease domain containing the V36M substitution in a cocomplex with an NS4A cofactor peptide was solved at a 2.4-A resolution. Except for the side chain of Met 36 , the V36M variant structure is identical to that of the wild-type apoenzyme. The in vitro replication capacity of most variants was significantly lower than that of the wild-type replicon in cells, which is consistent with the impaired in vivo fitness estimated from Telaprevir-dosed patients. Finally, the sensitivity of these replicon variants to alpha interferon or ribavirin remained unchanged compared to that of the wild-type.
-
Telaprevir and pegylated interferon alpha 2a inhibit wild type and resistant genotype 1 hepatitis c virus replication in patients
Hepatology, 2007Co-Authors: Tara L. Kieffer, Hendrik W. Reesink, Nicole Forestier, Ann D Kwong, Christoph Sarrazin, Janice S Miller, M W Welker, Stefan ZeuzemAbstract:Telaprevir (VX-950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (≥5%), mutations were identified that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to Telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given Telaprevir or Telaprevir + pegylated interferon–alpha-2a (PEG-IFN–alpha-2a) for 14 days. In 4 patients who had a viral rebound on Telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given Telaprevir alone or with Telaprevir/PEG-IFN–alpha-2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to Telaprevir is due to a sharp reduction in wild-type virus, which uncovers pre-existing Telaprevir-resistant variants. In patients given Telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of Telaprevir and PEG-IFN–alpha-2a inhibited both wild-type and resistant variants. In the present study, every patient who began PEG-IFN–alpha-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that Telaprevir-resistant variants are sensitive to PEG-IFN–alpha-2a and ribavirin. (HEPATOLOGY 2007.)
Graham R. Foster - One of the best experts on this subject based on the ideXlab platform.
-
Efficacy and safety profile of boceprevir- or Telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study.
Annals of Gastroenterology, 2017Co-Authors: Alessandra Mangia, Manuela Curescu, Graham R. Foster, George V. Papatheodoridis, Christoph P. Berg, François Habersetzer, Spilios Manolakopoulos, Elisa Negri, Silke AhlersAbstract:BACKGROUND: The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, Telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. METHODS: PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naive and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). RESULTS: SVR12 rates in treatment-naive genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of Telaprevir plus peginterferon alfa-2a/ribavirin and Telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naive patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. CONCLUSION: The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.
-
limited impact of il28b genotype on response rates in Telaprevir treated patients with prior treatment failure
Journal of Hepatology, 2013Co-Authors: Stanislas Pol, Eric Lawitz, Graham R. Foster, Stefan Zeuzem, Pietro Andreone, Zobair M Younossi, Stuart K Roberts, Jeroen Aerssens, R Focaccia, Andrzej HorbanAbstract:Background & Aims Nucleotide polymorphisms upstream of the interleukin 28B ( IL28B ) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naive patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in Telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. Methods Treatment-experienced patients were randomized to 12weeks of Telaprevir (750mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180μg/week) and ribavirin (1000–1200mg/day) for 48weeks overall. Data from Telaprevir arms were pooled. Results Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled Telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with Telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. Conclusions Our findings suggest that IL28B genotype has a limited impact on SVR rates with Telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for Telaprevir-based therapy.
-
sustained virologic response rates with Telaprevir by response after 4 weeks of lead in therapy in patients with prior treatment failure
Journal of Hepatology, 2013Co-Authors: Graham R. Foster, Moisés Diago, Pietro Andreone, Paul J Pockros, Zobair M Younossi, Eric Lawitz, Stanislas Pol, Stuart K Roberts, I LonjondomanecAbstract:Background & Aims For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. Methods In REALIZE, treatment-experienced patients randomized to the lead-in Telaprevir arm received 4weeks of PegIFN-α-2a (180μg/week) and ribavirin (1000–1200mg/day), then 12weeks of Telaprevir (750mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in Telaprevir arm with available week 4 on-treatment response data ( n =240). Results After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in Telaprevir arm had ⩾1log 10 HCV RNA reduction. Sustained virologic response (SVR) rates for Telaprevir-treated patients with ⩾1 versus 10 HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. Conclusions In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding Telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding Telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.
-
uk consensus guidelines for the use of the protease inhibitors boceprevir and Telaprevir in genotype 1 chronic hepatitis c infected patients
Alimentary Pharmacology & Therapeutics, 2012Co-Authors: Prakash Ramachandran, Graham R. Foster, A Fraser, Kosh Agarwal, Andrew Austin, A Brown, R Fox, P C Hayes, Clifford Leen, P R MillsAbstract:SUMMARYBackgroundThe nonstructural 3 serine protease inhibitors (PIs), boceprevir and telapre-vir, represent the first in a new generation of directly acting antiviralsagainst genotype 1 hepatitis C (HCV) infection. When used in combinationwith pegylated interferon and ribavirin, these drugs greatly improve sus-tained virological response rates in both treatment-naive patients andpatients who have had previous virological failure on treatment. However,the addition of these new agents will increase the complexity of therapeuticregimens, the rates of side-effects and costs.AimsTo review concisely the current evidence and to suggest current best prac-tice, for the use of Telaprevir and boceprevir in the management of chronicgenotype 1 HCV infection.MethodsThese guidelines for the use of boceprevir and Telaprevir have been formu-lated following extensive review of the current literature, are based on theconsensus opinion of a panel of national experts, and have been openly dis-cussed and debated at a national meeting of HCV care providers.ResultsWe have made recommendations on a number of the key practical issuesfacing HCV care providers: (i) Which patients to treat?; (ii) Standards forthe provision of care; (iii) Pre-treatment considerations; (iv) Which treat-ment regimens to use?; (v) Stopping rules; and (vi) Management of adverseeffects. Finally, we have produced suggested algorithms for the assessmentand treatment of these patients.ConclusionsThese UK Consensus guidelines indicate the current best practice for theuse of boceprevir and Telaprevir in the management of genotype 1 chronicHCV infection.Aliment Pharmacol Ther 2012; 35: 647–662
-
Telaprevir alone or with peginterferon and ribavirin reduces hcv rna in patients with chronic genotype 2 but not genotype 3 infections
Gastroenterology, 2011Co-Authors: Graham R. Foster, Giampiero Carosi, Christophe Hezode, Jean-pierre Bronowicki, Ola Weiland, Rolf Van Heeswijk, Lieselotte Verlinden, Ben Van Baelen, Gaston Picchio, Maria BeumontAbstract:Background & Aims We evaluated antiviral activity of 2 weeks therapy with Telaprevir alone, peginterferon alfa-2a and ribavirin (PR), or all 3 drugs (TPR) in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2 or 3 infections. Methods We performed a randomized, multicenter, partially blinded study of patients (23 with HCV genotype 2, 26 with genotype 3) who received Telaprevir (750 mg every 8 h), placebo plus PR (peginterferon, 180 μg, once weekly and ribavirin, 400 mg, twice daily), or TPR for 15 days, followed by PR for 22 or 24 weeks. Plasma levels of HCV RNA were quantified. Results Levels of HCV RNA decreased in all patients with HCV genotype 2, including those who received Telaprevir monotherapy. The decrease was more rapid among patients who received Telaprevir. By day 15, 0% (Telaprevir), 40% (TPR), and 22% (PR) of patients with HCV genotype 2 had undetectable levels of HCV RNA; rates of sustained virologic response were 56%, 100%, and 89%, respectively. Overall, 6 of 9 HCV genotype 2 patients that received only Telaprevir had viral breakthrough within 15 days after an initial response. HCV RNA levels decreased slightly among patients with HCV genotype 3 who received Telaprevir and decreased rapidly among patients given PR or TPR (Telaprevir had no synergistic effects with PR). Sustained virologic response rates were 50%, 67%, and 44% among patients given Telaprevir, TPR, or PR respectively; 7 patients with HCV genotype 3 relapsed after therapy (2 given Telaprevir, 3 given TPR, and 2 given PR) and 3 patients with HCV genotype 3 had viral breakthrough during Telaprevir monotherapy. The incidence of adverse events was similar among groups. Conclusions Telaprevir monotherapy for 2 weeks reduces levels of HCV RNA in patients with chronic HCV genotype 2 infections, but has limited activity in patients with HCV genotype 3.
