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Diana M Brainard - One of the best experts on this subject based on the ideXlab platform.
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Sofosbuvir velpatasvir voxilaprevir for patients with hcv who previously received a Sofosbuvir velpatasvir containing regimen results from a retreatment study
Journal of Viral Hepatitis, 2019Co-Authors: Peter Ruane, Diana M Brainard, Robert H Hyland, Hadas Dvorysobol, Tram Tran, Luisa M Stamm, Simone I Strasser, Jiang Shao, Edward Gane, L. NybergAbstract:This study evaluated 12-week retreatment with Sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a Sofosbuvir- and velpatasvir-containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last Sofosbuvir/velpatasvir/voxilaprevir dose.
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effects of Sofosbuvir based hepatitis c treatment on the pharmacokinetics of tenofovir in hiv hcv coinfected individuals receiving tenofovir disoproxil fumarate
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: Christine E Macbrayne, Diana M Brainard, Kristen M Marks, Daniel S Fierer, Susanna Naggie, Raymond T Chung, Michael Hughes, Arthur Y Kim, Marion G Peters, Sharon M SeifertAbstract:Background The nucleotide analogues tenofovir and Sofosbuvir are considered to have low potential for drug interactions. Objectives To determine the effect of Sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate. Methods HIV-infected participants with acute HCV were treated for 12 weeks with Sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/Sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS. Results Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of Sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/Sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment. Conclusions These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and Sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.
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drug drug interaction profile of the fixed dose combination tablet regimen ledipasvir Sofosbuvir
Clinical Pharmacokinectics, 2018Co-Authors: Polina German, Diana M Brainard, Anita Mathias, Brian P. KearneyAbstract:Ledipasvir/Sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor ledipasvir and an NS5B polymerase inhibitor Sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/Sofosbuvir exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/Sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug-drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, ledipasvir/Sofosbuvir is not expected to act as a victim of clinically relevant drug-drug interactions. As a perpetrator of pharmacokinetic drug-drug interactions via P-glycoprotein/BCRP, ledipasvir/Sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of ledipasvir/Sofosbuvir.
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resistance analysis in patients with genotype 1 6 hcv infection treated with Sofosbuvir velpatasvir in the phase iii studies
Journal of Hepatology, 2017Co-Authors: Christophe Hezode, John Mcnally, Hadas Dvorysobol, Anu Osinusi, Evguenia S. Svarovskaia, Ragavi Shanmugam, Charlotte Hedskog, Nancy Reau, Brian P. Doehle, Diana M BrainardAbstract:Background & Aims The fixed-dose combination of Sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1–6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with Sofosbuvir/velpatasvir. Methods Non-structural protein 5A and 5B (NS5A and NS5B ) deep sequencing was performed at baseline and at the time of relapse for all patients treated with Sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1–3, ASTRAL-5 and POLARIS-2–3 studies. Results Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with Sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4–6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1%) in patients treated with Sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. Conclusions Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1–6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not Sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. Lay summary Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not Sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.
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Sofosbuvir velpatasvir voxilaprevir with or without ribavirin in direct acting antiviral experienced patients with genotype 1 hepatitis c virus
Hepatology, 2017Co-Authors: Eric Lawitz, Diana M Brainard, Robert H Hyland, Hadas Dvorysobol, Luisa M Stamm, Jennifer Wells, Fred Poordad, Yin Yang, Carmen LandaverdeAbstract:: The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1-infected patients who fail direct-acting antiviral (DAA)-based regimens remains unknown. In this phase 2, open-label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA-based regimen were randomized to receive treatment with a fixed-dose combination tablet of Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86-100) receiving Sofosbuvir-velpatasvir-voxilaprevir alone and 24 of 25 (96%; 95% CI, 80-100) receiving the same treatment with RBV. None of the patients discontinued Sofosbuvir-velpatasvir-voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with Sofosbuvir-velpatasvir-voxilaprevir alone were diarrhea and bronchitis; and with Sofosbuvir-velpatasvir-voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. CONCLUSION: A fixed-dose combination of Sofosbuvir-velpatasvir-voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803-1809).
Eric Lawitz - One of the best experts on this subject based on the ideXlab platform.
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efficacy of 8 weeks of Sofosbuvir velpatasvir and voxilaprevir in patients with chronic hcv infection 2 phase 3 randomized trials
Gastroenterology, 2017Co-Authors: Ronald Nahass, Ira M Jacobson, Sergio Borgia, Peter Ruane, Eric Lawitz, Edward Gane, Stephen D. Shafran, Bernard Willems, Kimberly A. WorkowskiAbstract:Background & Aims Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor Sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with Sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (Sofosbuvir-velpatasvir-voxilaprevir). Methods In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given Sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or Sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of Sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of Sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. Results In POLARIS-2, 95% (95% confidence interval [CI], 93%–97%) of patients had an SVR to 8 weeks of Sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of Sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%–99%; difference in the stratum-adjusted Mantel–Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of Sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%–99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%–1%). Conclusions In phase 3 trials of patients with HCV infection, we did not establish that Sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to Sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.
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Sofosbuvir velpatasvir voxilaprevir with or without ribavirin in direct acting antiviral experienced patients with genotype 1 hepatitis c virus
Hepatology, 2017Co-Authors: Eric Lawitz, Diana M Brainard, Robert H Hyland, Hadas Dvorysobol, Luisa M Stamm, Jennifer Wells, Fred Poordad, Yin Yang, Carmen LandaverdeAbstract:: The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1-infected patients who fail direct-acting antiviral (DAA)-based regimens remains unknown. In this phase 2, open-label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA-based regimen were randomized to receive treatment with a fixed-dose combination tablet of Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86-100) receiving Sofosbuvir-velpatasvir-voxilaprevir alone and 24 of 25 (96%; 95% CI, 80-100) receiving the same treatment with RBV. None of the patients discontinued Sofosbuvir-velpatasvir-voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with Sofosbuvir-velpatasvir-voxilaprevir alone were diarrhea and bronchitis; and with Sofosbuvir-velpatasvir-voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. CONCLUSION: A fixed-dose combination of Sofosbuvir-velpatasvir-voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803-1809).
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post treatment resistance analysis of hepatitis c virus from phase ii and iii clinical trials of ledipasvir Sofosbuvir
Journal of Hepatology, 2017Co-Authors: David L Wyles, Diana M Brainard, Hadas Dvorysobol, Evguenia S. Svarovskaia, Eric Lawitz, Brian P. Doehle, Nezam H Afdhal, Kris V Kowdley, Ross Martin, Michael D MillerAbstract:Background & Aims Ledipasvir/Sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in ledipasvir/Sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to ledipasvir. One patient in a phase II study with a known ledipasvir RAS at baseline (L31M) developed the S282T Sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with ledipasvir/Sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to Sofosbuvir. Lay summary Clinical studies have shown that combination treatment with ledipasvir/Sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to Sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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Sofosbuvir and velpatasvir for hcv genotype 2 and 3 infection
The New England Journal of Medicine, 2015Co-Authors: Graham R. Foster, Stephen Pianko, Eric Lawitz, Stuart K. Roberts, Norbert Bräu, Alexander J Thompson, Nezam H Afdhal, Edward Gane, Curtis CooperAbstract:BackgroundIn phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor Sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. MethodsWe conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive Sofosbuvir–velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or Sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive Sofosbuvir–velpatasvir for 12 weeks (277 patients) or Sofosbuvir–ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustai...
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ledipasvir and Sofosbuvir for 8 or 12 weeks for chronic hcv without cirrhosis
The New England Journal of Medicine, 2014Co-Authors: Kris V Kowdley, Eric Lawitz, Stuart C. Gordon, Rajender K Reddy, Lorenzo Rossaro, David Bernstein, Mitchell L Shiffman, Eugene R Schiff, Reem Ghalib, Michael J RyanAbstract:BACKGROUND High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor Sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and Sofosbuvir (ledipasvir–Sofosbuvir) for 8 weeks, ledipasvir–Sofosbuvir plus ribavirin for 8 weeks, or ledipasvir–Sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir–Sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir–Sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir–Sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir–Sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, −4 to 6) and the rate in the group that received 8 weeks of ledipasvir–Sofosbuvir with ribavirin was 1 percentage point lower (95% CI, −6 to 4); these results indicated noninferiority of the 8-week ledipas vir–Sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir–Sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS Ledipasvir–Sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.)
Edward Gane - One of the best experts on this subject based on the ideXlab platform.
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Sofosbuvir velpatasvir voxilaprevir for patients with hcv who previously received a Sofosbuvir velpatasvir containing regimen results from a retreatment study
Journal of Viral Hepatitis, 2019Co-Authors: Peter Ruane, Diana M Brainard, Robert H Hyland, Hadas Dvorysobol, Tram Tran, Luisa M Stamm, Simone I Strasser, Jiang Shao, Edward Gane, L. NybergAbstract:This study evaluated 12-week retreatment with Sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a Sofosbuvir- and velpatasvir-containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last Sofosbuvir/velpatasvir/voxilaprevir dose.
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efficacy of 8 weeks of Sofosbuvir velpatasvir and voxilaprevir in patients with chronic hcv infection 2 phase 3 randomized trials
Gastroenterology, 2017Co-Authors: Ronald Nahass, Ira M Jacobson, Sergio Borgia, Peter Ruane, Eric Lawitz, Edward Gane, Stephen D. Shafran, Bernard Willems, Kimberly A. WorkowskiAbstract:Background & Aims Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor Sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with Sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (Sofosbuvir-velpatasvir-voxilaprevir). Methods In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given Sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or Sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of Sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of Sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. Results In POLARIS-2, 95% (95% confidence interval [CI], 93%–97%) of patients had an SVR to 8 weeks of Sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of Sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%–99%; difference in the stratum-adjusted Mantel–Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of Sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%–99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%–1%). Conclusions In phase 3 trials of patients with HCV infection, we did not establish that Sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to Sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.
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Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection.
Gastroenterology, 2017Co-Authors: Edward Gane, Diana M Brainard, Robert H Hyland, Luisa M Stamm, Evguenia S. Svarovskaia, Yin Yang, John G. Mchutchison, Catherine A M StedmanAbstract:Background & Aims Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with Sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of Sofosbuvir and ledipasvir in treatment-naive and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment. Methods This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of ledipasvir–Sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of ledipasvir–Sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA Results SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of ledipasvir–Sofosbuvir. The single patient receiving 12 weeks of ledipasvir–Sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event. Conclusions For treatment-naive and -experienced patients, ledipasvir–Sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).
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prevalence of resistance associated substitutions in hcv ns5a ns5b or ns3 and outcomes of treatment with ledipasvir and Sofosbuvir
Gastroenterology, 2016Co-Authors: Christoph Sarrazin, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H Afdhal, Kris V Kowdley, Phillip S Pang, Shu Min Chuang, Xiao Ding, Edward GaneAbstract:Background & Aims We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and Sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. Methods We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and Sofosbuvir (400 mg) (ledipasvir/Sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. Results Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/Sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/Sofosbuvir for 8 weeks ( P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/Sofosbuvir ( P Conclusions Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/Sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.
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Sofosbuvir and velpatasvir for hcv genotype 2 and 3 infection
The New England Journal of Medicine, 2015Co-Authors: Graham R. Foster, Stephen Pianko, Eric Lawitz, Stuart K. Roberts, Norbert Bräu, Alexander J Thompson, Nezam H Afdhal, Edward Gane, Curtis CooperAbstract:BackgroundIn phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor Sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. MethodsWe conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive Sofosbuvir–velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or Sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive Sofosbuvir–velpatasvir for 12 weeks (277 patients) or Sofosbuvir–ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustai...
Robert H Hyland - One of the best experts on this subject based on the ideXlab platform.
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Sofosbuvir velpatasvir voxilaprevir for patients with hcv who previously received a Sofosbuvir velpatasvir containing regimen results from a retreatment study
Journal of Viral Hepatitis, 2019Co-Authors: Peter Ruane, Diana M Brainard, Robert H Hyland, Hadas Dvorysobol, Tram Tran, Luisa M Stamm, Simone I Strasser, Jiang Shao, Edward Gane, L. NybergAbstract:This study evaluated 12-week retreatment with Sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a Sofosbuvir- and velpatasvir-containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last Sofosbuvir/velpatasvir/voxilaprevir dose.
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Sofosbuvir based direct acting antiviral therapies for hcv in people receiving opioid substitution therapy an analysis of phase 3 studies
Open Forum Infectious Diseases, 2018Co-Authors: Jason Grebely, Robert H Hyland, Luisa M Stamm, Mark S Sulkowski, David L Wyles, Jordan J Feld, Joe Llewellyn, Heshaam M Mir, Nika Sajed, John McnallyAbstract:Background Hepatitis C virus (HCV) direct-acting antiviral therapy is effective among people receiving opioid substitution therapy (OST), but studies are limited by small numbers of nongenotype 1 (GT1) patients. The aim of this study was to evaluate the treatment completion, adherence, SVR12, and safety of Sofosbuvir-based therapies in HCV patients receiving and not receiving OST. Methods Ten phase 3 studies of Sofosbuvir-based regimens included ION (ledipasvir/Sofosbuvir ± ribavirin for 8, 12, or 24 weeks in GT1), ASTRAL (Sofosbuvir/velpatasvir for 12 weeks in GT1-6), and POLARIS (Sofosbuvir/velpatasvir and Sofosbuvir/velpatasvir/voxilaprevir in GT1-6). Patients with clinically significant drug use (last 12 months) or noncannabinoids detected at screening were ineligible. Results Among 4743 patients, 4% (n = 194) were receiving OST (methadone; n = 113; buprenorphine, n = 75; other, n = 6). Compared with those not receiving OST (n = 4549), those receiving OST (n = 194) were younger (mean age, 48 vs 54), more often male (73% vs 61%), GT3 (38% vs 17%), treatment-naive (78% vs 65%), and cirrhotic (36% vs 23%). Among those receiving and not receiving OST, there was no significant difference in treatment completion (97% vs 99%, P = .06), SVR12 (94% vs 97%, P = .06), relapse (0.5% vs 2.1%, P = .19), adverse events (78% vs 77%, P = .79), or serious adverse events (3.6% vs 2.4%, P = .24). There was no difference in SVR12 in patients with cirrhosis (99% vs 95%, P = .25) or those with G3 (95% vs 95%, P = .77) in those receiving OST. Among patients receiving OST, SVR12 was high among those receiving methadone (95%) and buprenorphine (96%). Conclusion Sofosbuvir-based therapies are effective and safe in patients receiving OST.
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Sofosbuvir velpatasvir voxilaprevir with or without ribavirin in direct acting antiviral experienced patients with genotype 1 hepatitis c virus
Hepatology, 2017Co-Authors: Eric Lawitz, Diana M Brainard, Robert H Hyland, Hadas Dvorysobol, Luisa M Stamm, Jennifer Wells, Fred Poordad, Yin Yang, Carmen LandaverdeAbstract:: The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1-infected patients who fail direct-acting antiviral (DAA)-based regimens remains unknown. In this phase 2, open-label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA-based regimen were randomized to receive treatment with a fixed-dose combination tablet of Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86-100) receiving Sofosbuvir-velpatasvir-voxilaprevir alone and 24 of 25 (96%; 95% CI, 80-100) receiving the same treatment with RBV. None of the patients discontinued Sofosbuvir-velpatasvir-voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with Sofosbuvir-velpatasvir-voxilaprevir alone were diarrhea and bronchitis; and with Sofosbuvir-velpatasvir-voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. CONCLUSION: A fixed-dose combination of Sofosbuvir-velpatasvir-voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803-1809).
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ledipasvir Sofosbuvir and Sofosbuvir plus ribavirin in patients with chronic hepatitis c and bleeding disorders
Haemophilia, 2017Co-Authors: Christopher E Walsh, Robert H Hyland, Kimberly A. Workowski, Arthur Y Kim, Norah A Terrault, Paul E Sax, Alice J Cohen, Christopher L Bowlus, B Han, Jing WangAbstract:Introduction Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. Aim We evaluated the efficacy and safety of ledipasvir–Sofosbuvir and Sofosbuvir plus ribavirin in patients with chronic HCV genotype 1–4 infection and an inherited bleeding disorder. Methods Ledipasvir–Sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received Sofosbuvir plus ribavirin for 12 and 24 weeks respectively. Results The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. Conclusion Treatment with ledipasvir–Sofosbuvir for patients with HCV genotype 1 or 4 infection or Sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.
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Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection.
Gastroenterology, 2017Co-Authors: Edward Gane, Diana M Brainard, Robert H Hyland, Luisa M Stamm, Evguenia S. Svarovskaia, Yin Yang, John G. Mchutchison, Catherine A M StedmanAbstract:Background & Aims Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with Sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of Sofosbuvir and ledipasvir in treatment-naive and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment. Methods This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of ledipasvir–Sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of ledipasvir–Sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA Results SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of ledipasvir–Sofosbuvir. The single patient receiving 12 weeks of ledipasvir–Sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event. Conclusions For treatment-naive and -experienced patients, ledipasvir–Sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).
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post treatment resistance analysis of hepatitis c virus from phase ii and iii clinical trials of ledipasvir Sofosbuvir
Journal of Hepatology, 2017Co-Authors: David L Wyles, Diana M Brainard, Hadas Dvorysobol, Evguenia S. Svarovskaia, Eric Lawitz, Brian P. Doehle, Nezam H Afdhal, Kris V Kowdley, Ross Martin, Michael D MillerAbstract:Background & Aims Ledipasvir/Sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in ledipasvir/Sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to ledipasvir. One patient in a phase II study with a known ledipasvir RAS at baseline (L31M) developed the S282T Sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with ledipasvir/Sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to Sofosbuvir. Lay summary Clinical studies have shown that combination treatment with ledipasvir/Sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to Sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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prevalence of resistance associated substitutions in hcv ns5a ns5b or ns3 and outcomes of treatment with ledipasvir and Sofosbuvir
Gastroenterology, 2016Co-Authors: Christoph Sarrazin, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H Afdhal, Kris V Kowdley, Phillip S Pang, Shu Min Chuang, Xiao Ding, Edward GaneAbstract:Background & Aims We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and Sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. Methods We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and Sofosbuvir (400 mg) (ledipasvir/Sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. Results Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/Sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/Sofosbuvir for 8 weeks ( P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/Sofosbuvir ( P Conclusions Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/Sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.
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Sofosbuvir and velpatasvir for hcv genotype 2 and 3 infection
The New England Journal of Medicine, 2015Co-Authors: Graham R. Foster, Stephen Pianko, Eric Lawitz, Stuart K. Roberts, Norbert Bräu, Alexander J Thompson, Nezam H Afdhal, Edward Gane, Curtis CooperAbstract:BackgroundIn phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor Sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. MethodsWe conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive Sofosbuvir–velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or Sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive Sofosbuvir–velpatasvir for 12 weeks (277 patients) or Sofosbuvir–ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustai...
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ledipasvir and Sofosbuvir for untreated hcv genotype 1 infection
The New England Journal of Medicine, 2014Co-Authors: Nezam H Afdhal, S Zeuzem, Mario Chojkier, Norman Gitlin, Massimo Puoti, Jean-pierre Zarski, Kosh Agarwal, Paul Y Kwo, Manuel Romerogomez, Peter BuggischAbstract:Background In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor Sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. Methods We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and Sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir–Sofosbuvir plus ribavirin for 12 weeks, ledipasvir–Sofosbuvir for 24 weeks, or ledipasvir–Sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confide...
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ledipasvir and Sofosbuvir for previously treated hcv genotype 1 infection
The New England Journal of Medicine, 2014Co-Authors: Nezam H Afdhal, Ronald Nahass, Eric Lawitz, Stuart C. Gordon, Norman Gitlin, Rajender K Reddy, Eugene R Schiff, Reem Ghalib, David R Nelson, Robert HerringAbstract:Background Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. Methods We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor Sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir–Sofosbuvir plus ribavirin for 12 weeks, ledipasvir–Sofosbuvir for 24 weeks, or ledipasvir–Sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of ...
