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Zhi Hong - One of the best experts on this subject based on the ideXlab platform.

  • Phosphorylation of Ribavirin and Viramidine by Adenosine Kinase and Cytosolic 5'-Nucleotidase II: Implications for Ribavirin Metabolism in Erythrocytes
    Antimicrobial agents and chemotherapy, 2005
    Co-Authors: Gary Larson, Heli Walker, Jae Hoon Shim, Zhi Hong
    Abstract:

    Many nucleoside analog drugs, such as Ribavirin and viramidine, are activated or metabolized in vivo through 5′-phosphorylation. In this report, we determined the steady-state kinetic parameters for 5′-monophosphorylation of Ribavirin and viramidine by adenosine kinase. The apparent Km for Ribavirin is 540 μM, and kcat is 1.8 min−1. Its catalytic efficiency of 3.3 × 10−3 min−1 · μM−1 is 1,200-fold lower than that of adenosine. In contrast to the common belief that Ribavirin is exclusively phosphorylated by adenosine kinase, cytosolic 5′-nucleotidase II was found to catalyze Ribavirin phosphorylation in vitro. The reaction is optimally stimulated by the physiological concentration of ATP or 2,3-bisphosphoglycerate. In phosphate-buffered saline plus ATP and 2,3-bisphosphoglycerate, the apparent Km for Ribavirin is 88 μM, and kcat is 4.0 min−1. These findings suggest that cytosolic 5′-nucleotidase II may be involved in Ribavirin phosphorylation in vivo. Like Ribavirin, viramidine was found to be phosphorylated by either adenosine kinase or cytosolic 5′-nucleotidase II, albeit with a much lower activity. The catalytic efficiency for viramidine phosphorylation is 10- to 330-fold lower than that of Ribavirin, suggesting that other nucleoside kinase(s) may be involved in viramidine phosphorylation in vivo. Both Ribavirin and viramidine are not phosphorylated by deoxycytidine kinase and uridine-cytidine kinase. The coincidence of presence of high concentrated 2,3-bisphosphoglycerate in erythrocytes suggests that cytosolic 5′-nucleotidase II could play an important role in phosphorylating Ribavirin and contribute to anabolism of Ribavirin triphosphate in erythrocytes. Elucidation of Ribavirin and viramidine phosphorylation mechanism should shed light on their in vivo metabolism, especially the Ribavirin-induced hemolytic anemia in erythrocytes.

  • activation and deactivation of a broad spectrum antiviral drug by a single enzyme adenosine deaminase catalyzes two consecutive deamination reactions
    Antimicrobial Agents and Chemotherapy, 2003
    Co-Authors: Heli Walker, Johnson Y N Lau, Zhi Hong
    Abstract:

    Ribavirin is an approved broad-spectrum antiviral drug. A liver-targeting prodrug of Ribavirin, viramidine, is in clinical trial in an attempt to provide a better therapeutic index. The conversion of viramidine to Ribavirin, and of Ribavirin to an inactive metabolite through adenosine deaminase, is reported. Kinetic analysis indicates that adenosine deaminase is likely involved in activation of viramidine in vivo, and the process is highly pH sensitive. The differential activities of two consecutive deamination reactions are kinetically studied and interpreted based on adenosine deaminase structural information. A comprehensive understanding of the viramidine and Ribavirin deamination mechanism should help in designing better nucleoside therapeutics in the future.

  • Viramidine, a prodrug of Ribavirin, shows better liver-targeting properties and safety profiles than Ribavirin in animals.
    Antiviral chemistry & chemotherapy, 2003
    Co-Authors: Chin-chung Lin, Li-tain Yeh, Domenico Vitarella, Zhi Hong
    Abstract:

    Ribavirin, part of the current first line combination therapy for the treatment of chronic hepatitis C, may cause haemolytic anaemia and poses a significant challenge to the clinical management of the disease. Viramidine, a prodrug of Ribavirin, is currently under development. In-vitro partition demonstrated that viramidine had less association with RBCs than Ribavirin in rat, monkey and man, and thus has less liability for haemolytic anaemia than Ribavirin. In a whole body autoradiography study in rats following oral dosing (30 mg/kg) of [ 14 C]Ribavirin or [ 14 C]viramidine to monkeys, viramidine produced 32% higher radioactivity in the liver than Ribavirin, indicating a better liver-targeting properties. In portal vein-cannulated cynomolgus monkeys following single oral dosing (30 mg/kg) of [ 3 H]viramidine or [ 3 H]Ribavirin, viramidine retained 3X higher radioactivity in the liver than Ribavirin. Viramidine dosing also produced a higher viramidine to Ribavirin ratio in portal plasma than in systemic plasma, indicating that the liver was the main site for the viramidine conversion to Ribavirin and subsequent trapping of the drug. After multiple oral dosing (10 mg/kg) of [ 14 C]Ribavirin or [ 14 C]viramidine to monkey, viramidine yielded three times the drug level in the liver but only half in RBCs compared to Ribavirin. Viramidine and Ribavirin had comparable toxicity profiles in a 28-day toxicity study in rats. In contrast, viramidine had much better safety profiles than Ribavirin in a 28-day toxicity study in monkeys. In conclusion, viramidine has better liver-targeting properties and safety profiles than Ribavirin in animals.

  • Pleiotropic mechanisms of Ribavirin antiviral activities.
    Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques, 2002
    Co-Authors: Zhi Hong, Craig E Cameron
    Abstract:

    Renewed interest in the mechanism of action of Ribavirin results from its synergistic enhancement of interferon therapy and the need to develop more efficacious agents to treat hepatitis C virus infection. Since the discovery of Ribavirin over 30 years ago by scientists at ICN Pharmaceuticals, many mechanisms of action for Ribavirin have been proposed. These include inhibition of host inosine monophosphate dehydrogenase by Ribavirin monophosphate, inhibition of viral capping enzymes, inhibition of viral RNA synthesis by Ribavirin triphosphate, lethal mutagenesis of viral RNA genomes resulting from promiscuous incorporation of Ribavirin triphosphate by the viral RNA polymerase, and modulation of the host immune responses. In this article, we will briefly review the evidence for these mechanisms, emphasizing recent findings. In addition, we will discuss strategies for development of nucleoside analogs that may replace Ribavirin in the future.

  • the broad spectrum antiviral ribonucleoside Ribavirin is an rna virus mutagen
    Nature Medicine, 2000
    Co-Authors: Shane Crotty, Jamie J Arnold, Raul Andino, David Maag, Weidong Zhong, Zhi Hong, Craig E Cameron
    Abstract:

    The ribonucleoside analog Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) shows antiviral activity against a variety of RNA viruses and is used in combination with interferon-α to treat hepatitis C virus infection. Here we show in vitro use of Ribavirin triphosphate by a model viral RNA polymerase, poliovirus 3Dpol. Ribavirin incorporation is mutagenic, as it templates incorporation of cytidine and uridine with equal efficiency. Ribavirin reduces infectious poliovirus production to as little as 0.00001% in cell culture. The antiviral activity of Ribavirin correlates directly with its mutagenic activity. These data indicate that Ribavirin forces the virus into `error catastrophe'. Thus, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents.

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

  • efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir mk 5172 and elbasvir mk 8742 with or without Ribavirin for hepatitis c virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous
    The Lancet, 2015
    Co-Authors: Eric Lawitz, Brian L Pearlman, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, William Sievert, Edward Gane, Reem Ghalib
    Abstract:

    Summary Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]). Interpretation Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.

  • efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir mk 5172 and elbasvir mk 8742 with or without Ribavirin for hepatitis c virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous
    The Lancet, 2015
    Co-Authors: Eric Lawitz, Brian L Pearlman, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, William Sievert, Edward Gane, Reem Ghalib
    Abstract:

    Summary Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]). Interpretation Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.

  • Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without Ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with prev
    Lancet, 2015
    Co-Authors: Eric Lawitz, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, Edward Gane, Brian Pearlman, Edward Tam, William Sievert
    Abstract:

    There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]). Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

  • Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection—A Randomized Trial
    Gastroenterology, 2013
    Co-Authors: Fred Poordad, Eric Lawitz, K. Rajender Reddy, Stefan Zeuzem, Christophe Hézode, Nezam Afdhal, Samuel Lee, Jose Luis Calleja, Robert Brown, Antonio Craxi
    Abstract:

    Background & Aims Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and Ribavirin can lead to anemia, which has been managed by reducing Ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. Methods Patients (n = 687) received 4 weeks of peginterferon and Ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and Ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by Ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251). Results Rates of SVR were comparable between patients whose anemia was managed by Ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of Ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received

Jean-pierre Bronowicki - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir mk 5172 and elbasvir mk 8742 with or without Ribavirin for hepatitis c virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous
    The Lancet, 2015
    Co-Authors: Eric Lawitz, Brian L Pearlman, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, William Sievert, Edward Gane, Reem Ghalib
    Abstract:

    Summary Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]). Interpretation Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.

  • efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir mk 5172 and elbasvir mk 8742 with or without Ribavirin for hepatitis c virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous
    The Lancet, 2015
    Co-Authors: Eric Lawitz, Brian L Pearlman, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, William Sievert, Edward Gane, Reem Ghalib
    Abstract:

    Summary Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]). Interpretation Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.

  • Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without Ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with prev
    Lancet, 2015
    Co-Authors: Eric Lawitz, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, Edward Gane, Brian Pearlman, Edward Tam, William Sievert
    Abstract:

    There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]). Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

  • Boceprevir Plus Peginterferon α-2b/Ribavirin in Chronic Hepatitis C Genotype 1
    Journal of Clinical Gastroenterology, 2014
    Co-Authors: Stuart Gordon, Jean-pierre Bronowicki, K. Rajender Reddy, Ira Jacobson, Fred Poordad, Bruce Bacon, Maria Buti, Lisa Pedicone, Margaret Burroughs, Clifford Brass
    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.

  • effect of Ribavirin in genotype 1 patients with hepatitis c responding to pegylated interferon alfa 2a plus Ribavirin
    Gastroenterology, 2006
    Co-Authors: Jean-pierre Bronowicki, Tarik Asselah, D Ouzan, Herve Desmorat, J P Zarski, J Foucher, Marc Bourliere, C Renou, Albert Tran, P Melin
    Abstract:

    Background & Aims: Pegylated interferon alfa-Ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which Ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of Ribavirin in HCV clearance during therapy and to evaluate the consequences of Ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. Methods: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 μg/wk, plus Ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. Results: Responders at week 24 who stopped Ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop Ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of Ribavirin may not be needed when HCV RNA is undetectable at week 2. Conclusions: We made 3 conclusions from this study. First, Ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, Ribavirin must be administered for the full treatment duration in most genotype 1–infected patients who respond; third, baseline parameters may help identify patients who could discontinue Ribavirin or reduce the dose without losing their chance of success.

Craig E Cameron - One of the best experts on this subject based on the ideXlab platform.

  • Quasispecies, Error Catastrophe, and the Antiviral Activity of Ribavirin
    Virology, 2002
    Co-Authors: Jason D. Graci, Craig E Cameron
    Abstract:

    Ribavirin is the first synthetic, broad-spectrum antiviral nucleoside. Despite its more than 30 year history, the mechanism of action of this compound remains unclear and somewhat controversial. Recent data suggest the possibility that the activity of Ribavirin against RNA viruses is a reflection of incorporation of Ribavirin into the viral genome. Because Ribavirin incorporation is not specific, this event leads to lethal mutagenesis of the virus population. The data supporting this new proposal for the mechanism of action of Ribavirin are reviewed herein. In addition, we discuss briefly the challenges that remain for development of lethal mutagenesis as an effective antiviral strategy.

  • Pleiotropic mechanisms of Ribavirin antiviral activities.
    Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques, 2002
    Co-Authors: Zhi Hong, Craig E Cameron
    Abstract:

    Renewed interest in the mechanism of action of Ribavirin results from its synergistic enhancement of interferon therapy and the need to develop more efficacious agents to treat hepatitis C virus infection. Since the discovery of Ribavirin over 30 years ago by scientists at ICN Pharmaceuticals, many mechanisms of action for Ribavirin have been proposed. These include inhibition of host inosine monophosphate dehydrogenase by Ribavirin monophosphate, inhibition of viral capping enzymes, inhibition of viral RNA synthesis by Ribavirin triphosphate, lethal mutagenesis of viral RNA genomes resulting from promiscuous incorporation of Ribavirin triphosphate by the viral RNA polymerase, and modulation of the host immune responses. In this article, we will briefly review the evidence for these mechanisms, emphasizing recent findings. In addition, we will discuss strategies for development of nucleoside analogs that may replace Ribavirin in the future.

  • the broad spectrum antiviral ribonucleoside Ribavirin is an rna virus mutagen
    Nature Medicine, 2000
    Co-Authors: Shane Crotty, Jamie J Arnold, Raul Andino, David Maag, Weidong Zhong, Zhi Hong, Craig E Cameron
    Abstract:

    The ribonucleoside analog Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) shows antiviral activity against a variety of RNA viruses and is used in combination with interferon-α to treat hepatitis C virus infection. Here we show in vitro use of Ribavirin triphosphate by a model viral RNA polymerase, poliovirus 3Dpol. Ribavirin incorporation is mutagenic, as it templates incorporation of cytidine and uridine with equal efficiency. Ribavirin reduces infectious poliovirus production to as little as 0.00001% in cell culture. The antiviral activity of Ribavirin correlates directly with its mutagenic activity. These data indicate that Ribavirin forces the virus into `error catastrophe'. Thus, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents.

  • the broad spectrum antiviral ribonucleoside Ribavirin is an rna virus mutagen
    Nature Medicine, 2000
    Co-Authors: Shane Crotty, Jamie J Arnold, Raul Andino, David Maag, Weidong Zhong, Zhi Hong, Johnson Y N Lau, Craig E Cameron
    Abstract:

    The ribonucleoside analog Ribavirin (1-beta-D-ribofuranosyl-1,2, 4-triazole-3-carboxamide) shows antiviral activity against a variety of RNA viruses and is used in combination with interferon-alpha to treat hepatitis C virus infection. Here we show in vitro use of Ribavirin triphosphate by a model viral RNA polymerase, poliovirus 3Dpol. Ribavirin incorporation is mutagenic, as it templates incorporation of cytidine and uridine with equal efficiency. Ribavirin reduces infectious poliovirus production to as little as 0. 00001% in cell culture. The antiviral activity of Ribavirin correlates directly with its mutagenic activity. These data indicate that Ribavirin forces the virus into 'error catastrophe'. Thus, mutagenic ribonucleosides may represent an important class of anti-RNA virus agents.

Reem Ghalib - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir mk 5172 and elbasvir mk 8742 with or without Ribavirin for hepatitis c virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous
    The Lancet, 2015
    Co-Authors: Eric Lawitz, Brian L Pearlman, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, William Sievert, Edward Gane, Reem Ghalib
    Abstract:

    Summary Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]). Interpretation Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.

  • efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir mk 5172 and elbasvir mk 8742 with or without Ribavirin for hepatitis c virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous
    The Lancet, 2015
    Co-Authors: Eric Lawitz, Brian L Pearlman, Laura Lester, Wayne Ghesquiere, Dominique Guyader, Laurent Alric, Jean-pierre Bronowicki, William Sievert, Edward Gane, Reem Ghalib
    Abstract:

    Summary Background There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus Ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without Ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. Methods The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without Ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without Ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. Findings We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with Ribavirin and 29 with no Ribavirin) and 63 to the 18-week regimen (32 with Ribavirin and 31 with no Ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with Ribavirin and 33 with no Ribavirin) and 65 to the 18-week regimen (33 with Ribavirin and 32 with no Ribavirin. High SVR12 rates were achieved irrespective of the use of Ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74–98; 28/31; cohort 1, 12 weeks, Ribavirin-containing) to 100% (95% CI 89–100; 33/33; cohort 2, 18 weeks, Ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without Ribavirin, 97% (95% CI 82–100, 28/29) of patients in cohort 1 and 91% (76–98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21–32]), headache (58 patients, 23% [95% CI 18–29]), and asthenia (35 patients, 14% [95% CI 10–19]). Interpretation Treatment with grazoprevir plus elbasvir, both with and without Ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.