The Experts below are selected from a list of 2547 Experts worldwide ranked by ideXlab platform

Ira M Jacobson - One of the best experts on this subject based on the ideXlab platform.

  • Refinement of Stopping Rules During Treatment of Hepatitis C Genotype 1 Infection With Boceprevir and Peginterferon/Ribavirin
    2020
    Co-Authors: Ira M Jacobson, Mark S Sulkowski, Stefan Zeuzem, Fred Poordad, Lisa Pedicone, Patrick Marcellin, Rafael Esteban, Savino Bruno, Margaret H Burroughs, Navdeep Boparai
    Abstract:

    In comparison with peginterferon/ribavirin alone, Boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail Boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity 5 33%) without sacrificing a single SVR among 475 successes (specificity 5 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. Conclusion: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In Boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level 100 IU/mL at week 12 and detectable HCV RNA at week 24-maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation. (HEPATOLOGY 2012;56:567-575) C ombination therapy with peginterferon alfa/ ribavirin (P/R) has been the standard approach to the management of chronic hepatitis C virus (HCV) infections for the last decade. Sustained virological response (SVR) rates of 54% to 56% were achieved in the pivotal trials of Abbreviations: HCV, hepatitis C virus; LLD, lower limit of detection; LLQ, lower limit of quantification; P/R, pegintron alfa/ribavirin; RESPOND-2, Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2; SPRINT-2, Serine Protease Inhibitor Therapy 2; SVR, sustained virological response. From th

  • Review Review Series: Host-pathogen interactions Emerging therapies for the treatment of hepatitis C
    2016
    Co-Authors: Christian M Lange, Ira M Jacobson, Charles M Rice, Stefan Zeuzem
    Abstract:

    Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon-a monothera-py in 1992 to the approval of telaprevir- and Boceprevir-based tri-ple therapies with pegylated interferon-a and ribavirin in 2011, the chances of curing patients infected with HCV genotype 1 have improved from <10 % to approximately 70%. Significant further improvements are on the horizon, which may well cure virtually all hepatitis C patients with an all-oral, interferon-free regimen in the very near future. These exciting developments are reviewed in the present article

  • Boceprevir for chronic hcv genotype 1 infection in patients with prior treatment failure to peginterferon ribavirin including prior null response
    Journal of Hepatology, 2014
    Co-Authors: John M. Vierling, Jonathan Mccone, Joseph S Galati, Eric Lawitz, Stuart C. Gordon, M. Davis, Eric M Yoshida, Steven L Flamm, Velimir A Luketic, Ira M Jacobson
    Abstract:

    Background & Aims Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response ( 10 decline in HCV RNA), to peginterferon/ribavirin. Methods Patients in the control arms of Boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44weeks. Patients enrolling >2weeks after end-of-treatment in the prior study received PR for 4weeks before adding Boceprevir. Results Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with 10 decline in HCV-RNA after lead-in and 76% of those with ⩾1-log 10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. Conclusions Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

  • Boceprevir plus peginterferon α-2b/ribavirin in chronic hepatitis C genotype 1: impact of baseline viral load on sustained virologic response.
    Journal of clinical gastroenterology, 2014
    Co-Authors: Stuart C. Gordon, Jean-pierre Bronowicki, K. Rajender Reddy, Ira M Jacobson, Fred Poordad, Maria Buti, Lisa Pedicone, Bruce R. Bacon, Margaret Burroughs
    Abstract:

    BACKGROUND: Baseline viral load is a predictor of treatment outcome in patients with hepatitis C virus (HCV) infection receiving peginterferon and ribavirin. The impact of baseline viral load on sustained virologic response (SVR) after Boceprevir-based therapy is unknown. METHODS: This retrospective analysis included patients with chronic HCV genotype 1 infection who were previously untreated or were previous treatment failures. Virologic response was assessed according to baseline viral load (≤1 million IU/mL, >1 to ≤5 million IU/mL, >5 to ≤10 million IU/mL, and >10 million IU/mL). RESULTS: SVR was higher in patients receiving Boceprevir plus peginterferon and ribavirin than in those receiving peginterferon and ribavirin alone, regardless of baseline viral load. Patients with a baseline viral load ≤1 million IU/mL had the highest SVR (Boceprevir plus peginterferon and ribavirin, 78% to 83%; peginterferon and ribavirin, 33% to 63%). Among patients with baseline viral load >1 million IU/mL, SVR rates were 57% to 68% in patients receiving Boceprevir plus peginterferon and ribavirin, and 11% to 41% in patients receiving peginterferon and ribavirin. Relapse was higher in patients receiving peginterferon and ribavirin (previously untreated, 12% to 40%; previous treatment failures, 17% to 67%) than in those receiving Boceprevir plus peginterferon and ribavirin (previously untreated, 3% to 12%; previous treatment failure, 9% to 16%), irrespective of baseline viral load. CONCLUSIONS: The efficacy of Boceprevir plus peginterferon and ribavirin was unaffected by baseline viral loads >1 million IU/mL, whereas viral burden >1 million IU/mL was associated with lower SVR with peginterferon and ribavirin. Relapse rates were lower with Boceprevir plus peginterferon and ribavirin than with peginterferon and ribavirin, and were unaffected by baseline viral load.

  • emerging therapies for the treatment of hepatitis c
    Embo Molecular Medicine, 2014
    Co-Authors: Christian M Lange, Ira M Jacobson, Charles M Rice, S Zeuzem
    Abstract:

    Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon-α monotherapy in 1992 to the approval of telaprevir- and Boceprevir-based triple therapies with pegylated interferon-α and ribavirin in 2011, the chances of curing patients infected with HCV genotype 1 have improved from <10% to approximately 70%. Significant further improvements are on the horizon, which may well cure virtually all hepatitis C patients with an all-oral, interferon-free regimen in the very near future. These exciting developments are reviewed in the present article.

Christophe Hezode - One of the best experts on this subject based on the ideXlab platform.

  • Patient disposition in DYNAMO 1.
    2016
    Co-Authors: Heiner Wedemeyer, Christophe Hezode, Xavier Forns, Samuel S. Lee, Astrid Scalori, Athina Voulgari, Sophie Le Pogam, Isabel Nájera, James A. Thommes
    Abstract:

    BOC, Boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin.

  • 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).
    2016
    Co-Authors: Heiner Wedemeyer, Christophe Hezode, Xavier Forns, Samuel S. Lee, Astrid Scalori, Athina Voulgari, Sophie Le Pogam, Isabel Nájera, James A. Thommes
    Abstract:

    BOC, Boceprevir; MCB, mericitabine; P/R, peginterferon alfa-2a + ribavirin; TVR, telaprevir.

  • Study designs of DYNAMO 1 (a) and DYNAMO 2 (b).
    2016
    Co-Authors: Heiner Wedemeyer, Christophe Hezode, Xavier Forns, Samuel S. Lee, Astrid Scalori, Athina Voulgari, Sophie Le Pogam, Isabel Nájera, James A. Thommes
    Abstract:

    BOC, Boceprevir 800 mg TID (at recommended intervals of 7–9 hours); MCB, mericitabine 1000 mg BID; P/R, peginterferon alfa-2a 180 μg once/week + ribavirin 1000 mg/day (

  • 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, 2015
    Co-Authors: Jerome Boursier, Christophe Hezode, Jean-pierre Bronowicki, Dominique Larrey, Alexandra Ducancelle, J Vergniol, P Veillon, Valerie Moal, C Dufour, Fabien Zoulim
    Abstract:

    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, 2014
    Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Marc Bourliere
    Abstract:

    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.

Stuart C. Gordon - One of the best experts on this subject based on the ideXlab platform.

  • safety profile of Boceprevir and telaprevir in chronic hepatitis c real world experience from hcv target
    Journal of Hepatology, 2015
    Co-Authors: Stuart C. Gordon, Andrew J Muir, Joseph K Lim, Brian L Pearlman, Curtis K Argo, Ananthakrishnan Ramani, Benedict Maliakkal, Imtiaz Alam, Thomas G Stewart, Monika Vainorius
    Abstract:

    Background & Aims The safety profiles of Boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated. Methods In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or Boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up. Results A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response. Conclusions In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.

  • cost effectiveness analysis of sofosbuvir plus peginterferon ribavirin in the treatment of chronic hepatitis c virus genotype 1 infection
    Alimentary Pharmacology & Therapeutics, 2014
    Co-Authors: Sammy Saab, Mark S Sulkowski, Stuart C. Gordon, Haesuk Park, Ali Ahmed, Zobair M Younossi
    Abstract:

    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.

  • Boceprevir for chronic hcv genotype 1 infection in patients with prior treatment failure to peginterferon ribavirin including prior null response
    Journal of Hepatology, 2014
    Co-Authors: John M. Vierling, Jonathan Mccone, Joseph S Galati, Eric Lawitz, Stuart C. Gordon, M. Davis, Eric M Yoshida, Steven L Flamm, Velimir A Luketic, Ira M Jacobson
    Abstract:

    Background & Aims Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response ( 10 decline in HCV RNA), to peginterferon/ribavirin. Methods Patients in the control arms of Boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44weeks. Patients enrolling >2weeks after end-of-treatment in the prior study received PR for 4weeks before adding Boceprevir. Results Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with 10 decline in HCV-RNA after lead-in and 76% of those with ⩾1-log 10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. Conclusions Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

  • Boceprevir plus peginterferon α-2b/ribavirin in chronic hepatitis C genotype 1: impact of baseline viral load on sustained virologic response.
    Journal of clinical gastroenterology, 2014
    Co-Authors: Stuart C. Gordon, Jean-pierre Bronowicki, K. Rajender Reddy, Ira M Jacobson, Fred Poordad, Maria Buti, Lisa Pedicone, Bruce R. Bacon, Margaret Burroughs
    Abstract:

    BACKGROUND: Baseline viral load is a predictor of treatment outcome in patients with hepatitis C virus (HCV) infection receiving peginterferon and ribavirin. The impact of baseline viral load on sustained virologic response (SVR) after Boceprevir-based therapy is unknown. METHODS: This retrospective analysis included patients with chronic HCV genotype 1 infection who were previously untreated or were previous treatment failures. Virologic response was assessed according to baseline viral load (≤1 million IU/mL, >1 to ≤5 million IU/mL, >5 to ≤10 million IU/mL, and >10 million IU/mL). RESULTS: SVR was higher in patients receiving Boceprevir plus peginterferon and ribavirin than in those receiving peginterferon and ribavirin alone, regardless of baseline viral load. Patients with a baseline viral load ≤1 million IU/mL had the highest SVR (Boceprevir plus peginterferon and ribavirin, 78% to 83%; peginterferon and ribavirin, 33% to 63%). Among patients with baseline viral load >1 million IU/mL, SVR rates were 57% to 68% in patients receiving Boceprevir plus peginterferon and ribavirin, and 11% to 41% in patients receiving peginterferon and ribavirin. Relapse was higher in patients receiving peginterferon and ribavirin (previously untreated, 12% to 40%; previous treatment failures, 17% to 67%) than in those receiving Boceprevir plus peginterferon and ribavirin (previously untreated, 3% to 12%; previous treatment failure, 9% to 16%), irrespective of baseline viral load. CONCLUSIONS: The efficacy of Boceprevir plus peginterferon and ribavirin was unaffected by baseline viral loads >1 million IU/mL, whereas viral burden >1 million IU/mL was associated with lower SVR with peginterferon and ribavirin. Relapse rates were lower with Boceprevir plus peginterferon and ribavirin than with peginterferon and ribavirin, and were unaffected by baseline viral load.

  • analysis of Boceprevir resistance associated amino acid variants ravs in two phase 3 Boceprevir clinical studies
    Virology, 2013
    Co-Authors: Richard J O Barnard, Stefan Zeuzem, Stuart C. Gordon, Fred Poordad, Xiao Tong, Robert Ralston, John A Howe, Robert A Ogert, Vilma Sniukiene, Julie Strizki
    Abstract:

    Abstract Background We investigated the frequency of RAVs among patients failing to achieve SVR in two clinical trials. We also investigated the impact of interferon responsiveness on RAVs and specific baseline RAVs relationship with Boceprevir treatment failure. Methods Data are from 1020 patients enrolled into either SPRINT-2 or RESPOND-2; patients received a 4-week PR lead-in prior to receiving Boceprevir or placebo. RAVs were analyzed via population-based sequence analysis of the NS3 protease gene (success rate of >90% at a virus level of ≥10,000 IU/mL) Results The high SVR rate in patients who received Boceprevir resulted in a low rate of RAVs; 7% was detected at baseline in all patients, which rose to 15% after treatment. However, RAVs were detected in 53% of patients that failed to achieve SVR, which declined to 22.8% 6–14 months following cessation of Boceprevir therapy. Baseline RAVs alone were not predictive of virologic outcome; poor interferon responsiveness was highly predictive of non-SVR. RAVs were more frequently detected in poor interferon responders. Conclusions We detected no association between the presence of baseline amino acid variants at Boceprevir resistance-associated loci and outcome in the context of good IFN response.

Eric Lawitz - One of the best experts on this subject based on the ideXlab platform.

  • Boceprevir for chronic hcv genotype 1 infection in patients with prior treatment failure to peginterferon ribavirin including prior null response
    Journal of Hepatology, 2014
    Co-Authors: John M. Vierling, Jonathan Mccone, Joseph S Galati, Eric Lawitz, Stuart C. Gordon, M. Davis, Eric M Yoshida, Steven L Flamm, Velimir A Luketic, Ira M Jacobson
    Abstract:

    Background & Aims Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response ( 10 decline in HCV RNA), to peginterferon/ribavirin. Methods Patients in the control arms of Boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44weeks. Patients enrolling >2weeks after end-of-treatment in the prior study received PR for 4weeks before adding Boceprevir. Results Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with 10 decline in HCV-RNA after lead-in and 76% of those with ⩾1-log 10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. Conclusions Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

  • 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, 2013
    Co-Authors: G T Everson, Marc Bourliere, Eric Lawitz, Christophe Hezode, K Sims, Maribel Rodrigueztorres, V Loustaudratti, Vinod K Rustgi, Howard J Schwartz, Harvey A Tatum
    Abstract:

    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.

  • Boceprevir with peginterferon alfa 2a ribavirin is effective for previously treated chronic hepatitis c genotype 1 infection
    Clinical Gastroenterology and Hepatology, 2013
    Co-Authors: Steven L Flamm, Marc Bourliere, John M. Vierling, Eric Lawitz, Christophe Hezode, Ira M Jacobson, Bruce R. Bacon, Claus Niederau, Morris Sherman, Venkata S Goteti
    Abstract:

    Background & Aims The addition of Boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with Boceprevir plus peginterferon alfa-2a–ribavirin (PEG2a/R) in patients with identical study entry criteria. Methods In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or Boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended. Results The addition of Boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group ( P 10 decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log 10 decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log 10 decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with Boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin 3 ). Conclusions The addition of Boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065.

  • Boceprevir for previously treated chronic hcv genotype 1 infection
    The New England Journal of Medicine, 2011
    Co-Authors: Bruce R. Bacon, John M. Vierling, Eric Lawitz, Stefan Zeuzem, Stuart C. Gordon, Fred Poordad, Patrick Marcellin, Zachary Goodman, Heather L Sings, Navdeep Boparai
    Abstract:

    A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two Boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log 10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the Boceprevir groups than in the control group, and erythropoietin was adminis­ tered in 41 to 46% of Boceprevir­treated patients and 21% of controls. Conclusions The addition of Boceprevir to peginterferon–ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon– ribavirin alone. (Funded by Scher­ ing­Plough [now Merck]; HCV RESPOND­2 ClinicalTrials.gov number, NCT00708500.)

  • efficacy of Boceprevir an ns3 protease inhibitor in combination with peginterferon alfa 2b and ribavirin in treatment naive patients with genotype 1 hepatitis c infection sprint 1 an open label randomised multicentre phase 2 trial
    The Lancet, 2010
    Co-Authors: Eric Lawitz, Jonathan Mccone, Joseph S Galati, David Pound, John M. Vierling, Natarajan Ravendhran, Stuart C. Gordon, M. Davis, Lorenzo Rossaro
    Abstract:

    Findings Patients in all four Boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44–64], p=0·013 for PRB28; 58/103 [56%, 44–66], p=0·005 for PR4/PRB24; 69/103 [67%, 57–76], p<0·0001 for PRB48; and 77/103 [75%, 65–83], p<0·0001 for PR4/PRB44; vs 39/104 [38%, 28–48] for PR48 control). Lowdose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.

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, 2014
    Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Marc Bourliere
    Abstract:

    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, 2014
    Co-Authors: Christophe Hezode, V Canva, Thierry Poynard, Didier Samuel, Celine Dorival, Fabien Zoulim, Helene Fontaine, Dominique Larrey, Victor De Ledinghen, Marc Bourliere
    Abstract:

    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, 2013
    Co-Authors: G T Everson, Marc Bourliere, Eric Lawitz, Christophe Hezode, K Sims, Maribel Rodrigueztorres, V Loustaudratti, Vinod K Rustgi, Howard J Schwartz, Harvey A Tatum
    Abstract:

    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.

  • Boceprevir with peginterferon alfa 2a ribavirin is effective for previously treated chronic hepatitis c genotype 1 infection
    Clinical Gastroenterology and Hepatology, 2013
    Co-Authors: Steven L Flamm, Marc Bourliere, John M. Vierling, Eric Lawitz, Christophe Hezode, Ira M Jacobson, Bruce R. Bacon, Claus Niederau, Morris Sherman, Venkata S Goteti
    Abstract:

    Background & Aims The addition of Boceprevir to therapy with peginterferon alfa-2b and ribavirin results in significantly higher rates of sustained virologic response (SVR) in previously treated patients with chronic hepatitis C virus (HCV) genotype-1 infection, compared with peginterferon alfa-2b and ribavirin alone. We assessed SVR with Boceprevir plus peginterferon alfa-2a–ribavirin (PEG2a/R) in patients with identical study entry criteria. Methods In a double-blind, placebo-controlled trial, 201 patients with HCV genotype-1 who had relapsed or not responded to previous therapy were assigned to groups (1:2) and given a 4-week lead-in phase of PEG2a/R, followed by placebo plus PEG2a/R for 44 weeks (PEG2a/R) or Boceprevir plus PEG2a/R for 44 weeks (BOC/PEG2a/R). The primary end point was SVR 24 weeks after therapy ended. Results The addition of Boceprevir after 4 weeks of lead-in therapy with PEG2a/R significantly increased the rate of SVR from 21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group ( P 10 decline in HCV RNA at week 4), 39% in the BOC/PEG2a/R group had SVRs, compared with none of the patients in the PEG2a/R group. Among patients with good response to interferon (≥1-log 10 decline), 71% in the BOC/PEG2a/R group had SVRs, compared with 25% in the PEG2a/R group. A ≥1-log 10 decline in HCV RNA at treatment week 4 was the strongest independent predictor of SVR, exceeding that of IL-28B genotype. Among 8 patients who began the study with HCV amino acid variants associated with Boceprevir resistance, 3 (38%) achieved SVRs. Fifty percent of patients in the BOC/PEG2a/R group developed anemia (hemoglobin 3 ). Conclusions The addition of Boceprevir after 4 weeks of lead-in therapy with PEG2a/R caused significantly higher rates of SVR in previously treated patients with chronic HCV genotype-1 infection, compared with patients given only PEG2a/R. ClinicalTrials.gov Identifier: NCT00845065.