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Peggy Hwang - One of the best experts on this subject based on the ideXlab platform.
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Elbasvir/Grazoprevir for HCV Infection in Russia: A Randomized Trial
Hepatic medicine : evidence and research, 2020Co-Authors: K. V. Zhdanov, Peggy Hwang, Li Wen Liang, Vasily Isakov, Eduard Burnevich, Svetlana Kizhlo, Igor G. Bakulin, Vadim Pokrovsky, Rohit Talwani, Barbara A. HaberAbstract:Purpose Hepatitis C virus (HCV) infection is a major healthcare concern in Russia, where almost 5 million individuals are viremic. Elbasvir/Grazoprevir is a fixed-dose combination therapy for the treatment of HCV genotype 1 and genotype 4 infection. The present analysis aimed to assess the safety and efficacy of elbasvir/Grazoprevir in individuals with HCV infection enrolled at Russian study sites in the C-CORAL study. Patients and Methods C-CORAL (Protocol PN-5172-067; NCT02251990) was a Phase 3, placebo-controlled, double-blind study conducted throughout Asia and Russia. Treatment-naive participants with chronic HCV infection were randomly assigned to receive immediate or deferred treatment with elbasvir 50 mg/Grazoprevir 100 mg once daily for 12 weeks. Participants in the immediate-treatment group received elbasvir/Grazoprevir for 12 weeks, and those in the deferred-treatment group received placebo for 12 weeks, followed by open-label elbasvir/Grazoprevir for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12). Results One hundred and nineteen Russian participants were randomized (immediate-treatment group, n=88; deferred-treatment group, n=31). Most participants were white (99%) with HCV genotype 1b infection (97%) and mild-to-moderate (F0-F2) fibrosis (70%). SVR12 was achieved by 98.9% participants in the immediate-treatment group and by 100% of those receiving deferred elbasvir/Grazoprevir in the deferred-treatment group. One participant relapsed with nonstructural protein 5A (NS5A) L28M and Y93H resistance-associated substitutions at baseline and at time of failure. Drug-related adverse events were reported by 19% of participants receiving elbasvir/Grazoprevir in the immediate-treatment group and by 16% of those receiving placebo in the deferred-treatment group. No serious adverse event or deaths occurred, and no participant discontinued treatment owing to an adverse event. Conclusion Elbasvir/Grazoprevir for 12 weeks was highly effective in treatment-naive Russian individuals with HCV genotype 1b infection.
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safety and efficacy of elbasvir Grazoprevir in asian participants with hepatitis c virus genotypes 1 and 4 infection
Journal of Gastroenterology and Hepatology, 2019Co-Authors: Lai Wei, Xu Min Zhao, Peggy Hwang, Hiromitsu Kumada, Ponni V Perumalswami, Tawesak Tanwandee, Wendy Cheng, Jeong Heo, Pinnan Cheng, Ernest AsanteappiahAbstract:BACKGROUND AND AIM Estimates suggest that in Asia, more than 31 million individuals have hepatitis C virus infection. The present analysis was conducted to assess the efficacy and safety of elbasvir/Grazoprevir in Asian participants enrolled in the elbasvir/Grazoprevir phase 2/3 clinical trials. METHODS This is an integrated analysis of data from 12 international phase 2/3 clinical trials. Asian participants with chronic hepatitis C virus genotype 1 or 4 infection who received elbasvir 50 mg/Grazoprevir 100 mg once daily for 12 weeks or elbasvir/Grazoprevir plus ribavirin for 16 weeks were included in this analysis. The primary end point was sustained virologic response at 12 weeks after completion of therapy (SVR12). RESULTS Seven hundred eighty Asian participants from 15 countries were included in this analysis. SVR12 was achieved by 756/780 (96.9%) of all participants, including 748/772 (96.9%) of those who received elbasvir/Grazoprevir for 12 weeks and 8/8 (100%) of those who received elbasvir/Grazoprevir plus ribavirin for 16 weeks. In the genotype 1b-infected population, the SVR12 rate was 691/709 (97.5%), and there was no impact of age, high baseline viral load, or presence of cirrhosis. The most frequently reported adverse events were nasopharyngitis (8.0%), upper respiratory tract infection (5.4%), and diarrhea (5.2%). Twenty participants receiving elbasvir/Grazoprevir for 12 weeks reported a total of 25 serious adverse events, and 7 (0.9%) discontinued treatment because of an adverse event. CONCLUSION Elbasvir/Grazoprevir administered for 12 weeks is an effective and generally well-tolerated treatment option for Asian individuals with hepatitis C virus genotype 1b infection.
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Safety and efficacy of elbasvir/Grazoprevir in Asian participants with hepatitis C virus genotypes 1 and 4 infection.
Journal of gastroenterology and hepatology, 2019Co-Authors: Lai Wei, Peggy Hwang, Hiromitsu Kumada, Ponni V Perumalswami, Tawesak Tanwandee, Wendy Cheng, Jeong Heo, Pinnan Cheng, Xu Min ZhaoAbstract:BACKGROUND AND AIM Estimates suggest that in Asia, more than 31 million individuals have hepatitis C virus infection. The present analysis was conducted to assess the efficacy and safety of elbasvir/Grazoprevir in Asian participants enrolled in the elbasvir/Grazoprevir phase 2/3 clinical trials. METHODS This is an integrated analysis of data from 12 international phase 2/3 clinical trials. Asian participants with chronic hepatitis C virus genotype 1 or 4 infection who received elbasvir 50 mg/Grazoprevir 100 mg once daily for 12 weeks or elbasvir/Grazoprevir plus ribavirin for 16 weeks were included in this analysis. The primary end point was sustained virologic response at 12 weeks after completion of therapy (SVR12). RESULTS Seven hundred eighty Asian participants from 15 countries were included in this analysis. SVR12 was achieved by 756/780 (96.9%) of all participants, including 748/772 (96.9%) of those who received elbasvir/Grazoprevir for 12 weeks and 8/8 (100%) of those who received elbasvir/Grazoprevir plus ribavirin for 16 weeks. In the genotype 1b-infected population, the SVR12 rate was 691/709 (97.5%), and there was no impact of age, high baseline viral load, or presence of cirrhosis. The most frequently reported adverse events were nasopharyngitis (8.0%), upper respiratory tract infection (5.4%), and diarrhea (5.2%). Twenty participants receiving elbasvir/Grazoprevir for 12 weeks reported a total of 25 serious adverse events, and 7 (0.9%) discontinued treatment because of an adverse event. CONCLUSION Elbasvir/Grazoprevir administered for 12 weeks is an effective and generally well-tolerated treatment option for Asian individuals with hepatitis C virus genotype 1b infection.
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elbasvir Grazoprevir in people with hepatitis c genotype 1 infection and child pugh class b cirrhosis the c salt study
Clinical and translational gastroenterology, 2019Co-Authors: Ira M Jacobson, Luzelena Caro, Michael N Robertson, Peggy Hwang, Fred Poordad, Roberto J Firpimorell, Gregory T Everson, Elizabeth C Verna, S Bhanja, Edgar D CharlesAbstract:INTRODUCTION:Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus Grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis.METHODS:In this 12-week,
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Elbasvir/Grazoprevir in People With Hepatitis C Genotype 1 Infection and Child-Pugh Class B Cirrhosis: The C-SALT Study.
Clinical and translational gastroenterology, 2019Co-Authors: Ira M Jacobson, Luzelena Caro, Michael N Robertson, Peggy Hwang, Fred Poordad, Gregory T Everson, Elizabeth C Verna, S Bhanja, Roberto J. Firpi-morell, Edgar D CharlesAbstract:INTRODUCTION:Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus Grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis.METHODS:In this 12-week,
Michael N Robertson - One of the best experts on this subject based on the ideXlab platform.
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elbasvir Grazoprevir in people with hepatitis c genotype 1 infection and child pugh class b cirrhosis the c salt study
Clinical and translational gastroenterology, 2019Co-Authors: Ira M Jacobson, Luzelena Caro, Michael N Robertson, Peggy Hwang, Fred Poordad, Roberto J Firpimorell, Gregory T Everson, Elizabeth C Verna, S Bhanja, Edgar D CharlesAbstract:INTRODUCTION:Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus Grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis.METHODS:In this 12-week,
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Elbasvir/Grazoprevir in People With Hepatitis C Genotype 1 Infection and Child-Pugh Class B Cirrhosis: The C-SALT Study.
Clinical and translational gastroenterology, 2019Co-Authors: Ira M Jacobson, Luzelena Caro, Michael N Robertson, Peggy Hwang, Fred Poordad, Gregory T Everson, Elizabeth C Verna, S Bhanja, Roberto J. Firpi-morell, Edgar D CharlesAbstract:INTRODUCTION:Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus Grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis.METHODS:In this 12-week,
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The pharmacogenetics of OATP1B1 variants and their impact on the pharmacokinetics and efficacy of elbasvir/Grazoprevir.
Pharmacogenomics, 2019Co-Authors: Zifang Guo, Luzelena Caro, Michael N Robertson, Peggy Hwang, Patricia A. Hoover, Christen Wudarski, Kristina Maiuri, Ying-hong Wang, Robin Mogg, Devan V. MehrotraAbstract:Aim: To evaluate the effect of SLCO1B1 genetic variants on Grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of Grazoprevir area under curve (AUC)0-24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06-1.21), two copies, 1.43 (1.16-1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87-1.00); two copies, 0.78 (0.61-1.00). The rs2306283 variant was not associated with Grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in Grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.
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efficacy and safety of elbasvir Grazoprevir in participants with hepatitis c virus genotype 1 4 or 6 infection from the asia pacific region and russia final results from the randomized c coral study
Journal of Gastroenterology and Hepatology, 2018Co-Authors: Lai Wei, Xu Min Zhao, Michael N Robertson, Peggy Hwang, Ji Dong Jia, Fusheng Wang, Jun Qi Niu, Li Wen Liang, Zaiqi Wang, Paul IngravalloAbstract:BACKGROUND AND AIM Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/Grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/Grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/Grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS Elbasvir/Grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.
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Efficacy and safety of elbasvir/Grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study.
Journal of gastroenterology and hepatology, 2018Co-Authors: Lai Wei, Xu Min Zhao, Peggy Hwang, Ji Dong Jia, Fusheng Wang, Jun Qi Niu, Li Wen Liang, Zaiqi Wang, Michael N RobertsonAbstract:BACKGROUND AND AIM Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/Grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/Grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/Grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS Elbasvir/Grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.
Ernest Asanteappiah - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of elbasvir Grazoprevir in asian participants with hepatitis c virus genotypes 1 and 4 infection
Journal of Gastroenterology and Hepatology, 2019Co-Authors: Lai Wei, Xu Min Zhao, Peggy Hwang, Hiromitsu Kumada, Ponni V Perumalswami, Tawesak Tanwandee, Wendy Cheng, Jeong Heo, Pinnan Cheng, Ernest AsanteappiahAbstract:BACKGROUND AND AIM Estimates suggest that in Asia, more than 31 million individuals have hepatitis C virus infection. The present analysis was conducted to assess the efficacy and safety of elbasvir/Grazoprevir in Asian participants enrolled in the elbasvir/Grazoprevir phase 2/3 clinical trials. METHODS This is an integrated analysis of data from 12 international phase 2/3 clinical trials. Asian participants with chronic hepatitis C virus genotype 1 or 4 infection who received elbasvir 50 mg/Grazoprevir 100 mg once daily for 12 weeks or elbasvir/Grazoprevir plus ribavirin for 16 weeks were included in this analysis. The primary end point was sustained virologic response at 12 weeks after completion of therapy (SVR12). RESULTS Seven hundred eighty Asian participants from 15 countries were included in this analysis. SVR12 was achieved by 756/780 (96.9%) of all participants, including 748/772 (96.9%) of those who received elbasvir/Grazoprevir for 12 weeks and 8/8 (100%) of those who received elbasvir/Grazoprevir plus ribavirin for 16 weeks. In the genotype 1b-infected population, the SVR12 rate was 691/709 (97.5%), and there was no impact of age, high baseline viral load, or presence of cirrhosis. The most frequently reported adverse events were nasopharyngitis (8.0%), upper respiratory tract infection (5.4%), and diarrhea (5.2%). Twenty participants receiving elbasvir/Grazoprevir for 12 weeks reported a total of 25 serious adverse events, and 7 (0.9%) discontinued treatment because of an adverse event. CONCLUSION Elbasvir/Grazoprevir administered for 12 weeks is an effective and generally well-tolerated treatment option for Asian individuals with hepatitis C virus genotype 1b infection.
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efficacy of elbasvir and Grazoprevir in participants with hepatitis c virus genotype 4 infection a pooled analysis
Liver International, 2018Co-Authors: Tarik Asselah, Hendrik W Reesink, Jan Gerstoft, Victor De Ledinghen, Paul J Pockros, Michael N Robertson, Peggy Hwang, Ernest Asanteappiah, Janice Wahl, Bachyen NguyenAbstract:BACKGROUND & AIMS The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir 50 mg and Grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/Grazoprevir. METHODS Treatment-naive and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy). RESULTS Overall, among GT4-infected participants treated with 12 or 16 weeks of elbasvir/Grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naive participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naive participants treated with 12 weeks of elbasvir/Grazoprevir and 100% (8/8) in treatment-experienced participants treated with 16 weeks of elbasvir/Grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype. CONCLUSIONS The regimens of 12 weeks of elbasvir/Grazoprevir without ribavirin, and 16 weeks of elbasvir/Grazoprevir plus ribavirin, were efficacious in HCV GT4-infected treatment-naive and treatment-experienced participants respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of elbasvir/Grazoprevir in GT4-infected participants.
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antiviral activity and resistance analysis of ns3 4a protease inhibitor Grazoprevir and ns5a inhibitor elbasvir in hepatitis c virus gt4 replicons
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Ernest Asanteappiah, Stephanie Curry, Patricia Mcmonagle, Paul Ingravallo, Robert Chase, Anita Y M Howe, David C Nickle, Ping Qiu, Frederick C LahserAbstract:Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-Grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For Grazoprevir, the 50% effective concentration (EC50) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC50 for Grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n = 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced Grazoprevir antiviral activity by 137- and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n = 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir. The activity profiles of Grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.
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unraveling the structural basis of Grazoprevir potency against clinically relevant substitutions in hepatitis c virus ns3 4a protease from genotype 1a
Journal of Biological Chemistry, 2017Co-Authors: Zhuyan Guo, Stephanie Curry, Patricia Mcmonagle, Paul Ingravallo, Robert Chase, Stuart Black, Ernest AsanteappiahAbstract:Grazoprevir is a potent pan-genotype and macrocyclic inhibitor of hepatitis C virus (HCV) NS3/4A protease and was developed for treating chronic HCV infection. In HCV genotype (GT) 1a, Grazoprevir maintains potent activity against a majority of NS3 resistance-associated amino acid substitutions, including the highly prevalent and naturally occurring Q80K polymorphism that impacts simeprevir, another NS3/4A protease inhibitor. The basis for an unexpected difference in the clinical impact of some NS3 substitutions was investigated. Phenotypic analysis of resistance-associated substitutions identified in NS3 from GT1a-infected patients who failed therapy with Grazoprevir (in combination with elbasvir, an inhibitor of HCV NS5A protein) showed that positions 56, 156, and 168 in NS3 were most impactful because they diminished protein-inhibitor interactions. Although an amino acid substitution from aspartic acid to alanine at position 168 (D168A) reduced the potency of Grazoprevir, its combination with R155K unexpectedly nullified this effect. Molecular dynamics and free-energy surface studies indicated that Asp-168 is important in anchoring Arg-155 for ligand binding but is not critical for Lys-155 because of the inherent flexibility of its side chain. Moreover, modeling studies supported a strong direct cation-heterocycle interaction between the Lys-155 side chain of the double substitution, R155K/D168A, and the lone pair on the quinoxaline in Grazoprevir. This unique interaction provides a structural basis for Grazoprevir's higher potency than simeprevir, an inhibitor to which the double substitution confers a significant reduction in potency. Our findings are consistent with the detection of R155K/D168A in NS3 from virologic failures treated with simeprevir but not Grazoprevir.
Anita Y M Howe - One of the best experts on this subject based on the ideXlab platform.
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Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons
Antimicrobial agents and chemotherapy, 2017Co-Authors: Ernest Asante-appiah, Stephanie Curry, Patricia Mcmonagle, Paul Ingravallo, Robert Chase, Anita Y M Howe, David C Nickle, Ping Qiu, Frederick C LahserAbstract:Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-Grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For Grazoprevir, the 50% effective concentration (EC50) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC50 for Grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n = 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced Grazoprevir antiviral activity by 137- and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n = 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir. The activity profiles of Grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.
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antiviral activity and resistance analysis of ns3 4a protease inhibitor Grazoprevir and ns5a inhibitor elbasvir in hepatitis c virus gt4 replicons
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Ernest Asanteappiah, Stephanie Curry, Patricia Mcmonagle, Paul Ingravallo, Robert Chase, Anita Y M Howe, David C Nickle, Ping Qiu, Frederick C LahserAbstract:Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-Grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For Grazoprevir, the 50% effective concentration (EC50) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC50 for Grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n = 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced Grazoprevir antiviral activity by 137- and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n = 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir. The activity profiles of Grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.
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safety and efficacy of elbasvir Grazoprevir in patients with hepatitis c virus infection and compensated cirrhosis an integrated analysis
Gastroenterology, 2017Co-Authors: Ira M Jacobson, Eric Lawitz, Paul Y Kwo, Chengyuan Peng, Michael N Robertson, Peggy Hwang, Janice Wahl, Christophe Hezode, Anita Y M Howe, Eliav BarrAbstract:Background & Aims Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and Grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. Methods We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/Grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12−18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA Results Among treatment-naive and treatment-experienced patients receiving elbasvir/Grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/Grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naive patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/Grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/Grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/Grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/Grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/Grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. Conclusions In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/Grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/Grazoprevir had little effect on the proportion of treatment-naive or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/Grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.
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Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis
Gastroenterology, 2017Co-Authors: Ira M Jacobson, Eric Lawitz, Paul Y Kwo, Chengyuan Peng, Michael N Robertson, Peggy Hwang, Janice Wahl, Christophe Hezode, Anita Y M Howe, Eliav BarrAbstract:Background & Aims Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and Grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. Methods We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/Grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12−18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA Results Among treatment-naive and treatment-experienced patients receiving elbasvir/Grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/Grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naive patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/Grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/Grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/Grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/Grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/Grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. Conclusions In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/Grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/Grazoprevir had little effect on the proportion of treatment-naive or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/Grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.
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efficacy and safety of Grazoprevir ribavirin for 12 or 24 weeks in treatment naive patients with hepatitis c virus genotype 1 infection
Journal of Viral Hepatitis, 2016Co-Authors: Edward Gane, Janice Wahl, Anita Y M Howe, Ben Z Ari, L Mollison, E Zuckerman, R Bruck, Yaacov Baruch, S BhanjaAbstract:Summary Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of Grazoprevir-based regimens (NCT01710501; protocol P039).
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Grazoprevir ruzasvir and uprifosbuvir for hepatitis c virus after ns5a treatment failure
Hepatology, 2017Co-Authors: David L Wyles, Edward Gane, Ira M Jacobson, Ziv Benari, Alex Lund Laursen, Heiner Wedemeyer, Jesper Bach Hansen, Annie Luetkemeyer, Ronald Nahass, Stephen PiankoAbstract:People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with Grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of Grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. CONCLUSION Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).
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Grazoprevir ruzasvir and uprifosbuvir for hepatitis c virus after ns5a treatment failure
Hepatology, 2017Co-Authors: David L Wyles, Edward Gane, Ira M Jacobson, Ziv Benari, Alex Lund Laursen, Heiner Wedemeyer, Jesper Bach Hansen, Annie Luetkemeyer, Ronald Nahass, Stephen PiankoAbstract:People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all-oral regimen were retreated with Grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was undetectable HCV RNA (<15 IU/mL) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of Grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor–containing therapy. This article is protected by copyright. All rights reserved.
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safety and efficacy of an 8 week regimen of Grazoprevir plus ruzasvir plus uprifosbuvir compared with Grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis c virus genotypes 1 2 or 3 c crest 1 and c cre
The Lancet Gastroenterology & Hepatology, 2017Co-Authors: Edward Gane, Stefan Zeuzem, Stephen Pianko, Stuart K Roberts, Alexander J Thompson, Eli Zuckerman, Ziv Benari, Graham R Foster, Kosh Agarwal, Alex Lund LaursenAbstract:Summary Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with Grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: Grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); Grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); Grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or Grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, Grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the Grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the Grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), Grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or Grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two ( Interpretation These results support further evaluation of the three-drug direct-acting antiviral agent regimen of Grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV–HIV co-infection. Funding Merck & Co, Inc.
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Grazoprevir, Ruzasvir, and Uprifosbuvir for HCV After NS5A Treatment Failure
Hepatology (Baltimore Md.), 2017Co-Authors: David L Wyles, Edward Gane, Ira M Jacobson, Alex Lund Laursen, Heiner Wedemeyer, Jesper Bach Hansen, Annie Luetkemeyer, Ronald Nahass, Ziv Ben-ari, Stephen PiankoAbstract:People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all-oral regimen were retreated with Grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was undetectable HCV RNA (
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Grazoprevir ruzasvir and uprifosbuvir for hcv after ns5a treatment failure
Hepatology, 2017Co-Authors: David L Wyles, Edward Gane, Ira M Jacobson, Ziv Benari, Alex Lund Laursen, Heiner Wedemeyer, Jesper Bach Hansen, Annie Luetkemeyer, Ronald Nahass, Stephen PiankoAbstract:People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all-oral regimen were retreated with Grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was undetectable HCV RNA (<15 IU/mL) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of Grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor–containing therapy. This article is protected by copyright. All rights reserved.
