Authors M. Buti, J. L. Calleja, S. Lens, M. Diago, E. Ortega, J. Crespo, R. Planas, M. Romero-Gómez, F. G. Rodríguez, J. M. Pascasio, B. Fevery, D. Kurland, C. Corbett, R. Kalmeijer, W. Jessner
First published: 29 November 2016
Full publication history DOI: 10.1111/apt.13883
Summary
Background
Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis.
Background
Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis.
Aim
The Phase III, open-label, single-arm PLUTO study evaluated the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis.
The Phase III, open-label, single-arm PLUTO study evaluated the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis.
Methods
Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed.
Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed.
Results
Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91–100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients.
Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91–100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients.
Conclusions
Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807]
Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807]
Discussion Only
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Treatment for 12 weeks with simeprevir in combination with sofosbuvir resulted in an SVR rate of 100% (40/40 patients) in HCV genotype 4-infected treatment-naïve and -experienced patients with and without compensated cirrhosis in the PLUTO study.
Although patient numbers were small for subgroups, all patients achieved SVR12 regardless of fibrosis stage [7/40 (18%) of patients had compensated cirrhosis], IL28B genotype or prior treatment history. It has been previously reported that IL28B genotype is strongly associated with SVR in patients with HCV genotype 4 infection receiving treatment with PR;[14] however, the results of this study demonstrate that simeprevir in combination with sofosbuvir was effective regardless of IL28B genotype. As expected, the NS3 Q80K polymorphism was not observed in this HCV genotype 4-infected population.
The results of this study provide support for the clinical effectiveness of simeprevir in combination with sofosbuvir for the treatment of HCV genotype 4 infection in treatment-naïve and -experienced patients with and without compensated cirrhosis. The 100% SVR12 rate in this study is complemented by the Phase IIa OSIRIS study, which investigated 12 weeks of simeprevir plus sofosbuvir in HCV genotype 4-infected patients in Egypt, and reported an SVR12 rate of 100% (43/43 patients) regardless of prior treatment history or fibrosis stage [23/43 (53%) patients had cirrhosis].[15] In contrast, the PLUTO study investigated simeprevir plus sofosbuvir in a predominantly Caucasian HCV genotype 4-infected population.
The results of this study are comparable with those of the Phase III OPTIMIST-1 study in HCV genotype 1-infected patients without cirrhosis treated with simeprevir plus sofosbuvir for 12 weeks [97% (150/155) achieved SVR12],[12] and improve upon those of the Phase III OPTIMIST-2 study in patients with cirrhosis treated with simeprevir plus sofosbuvir for 12 weeks [83% (86/103) achieved SVR12].[13] Of note, a limited number of patients with cirrhosis were included in the PLUTO study.
Real-world evidence has also highlighted 12 weeks of this treatment combination as a simple, effective and well-tolerated IFN-free regimen. Treatment-naïve and -experienced patients in a study in Egypt that included patients with cirrhosis, reported an SVR4 rate of 96% (207/215 patients).[16] In a study in Qatar, 100% (17/17) of HCV genotype 4-infected patients with cirrhosis achieved SVR12.[17] Similar results have also been reported in a study in Belgium, with 100% (23/23) of HCV genotype 4-infected patients with cirrhosis, treated with or without ribavirin, achieving HCV RNA below the lower limit of quantification at Week 12 of treatment.[18]
Similar results were observed in an open-label study that assessed the combination of sofosbuvir and ledipasvir for 12 weeks in HCV genotype 4-infected patients, reporting an SVR12 rate of 93% (41/44 patients).[19] In contrast, a lower SVR12 rate of 78% (14/18 patients) was reported in HCV genotype 4-infected patients treated with sofosbuvir and ledipasvir plus ribavirin for 12 weeks.[20] Furthermore, the treatment combination of 12 weeks of ritonavir-boosted paritaprevir and ombitasvir (without dasabuvir), with and without ribavirin, resulted in SVR12 rates of 100% (42/42) and 91% (40/44), respectively, for HCV genotype 4-infected treatment-naїve patients without cirrhosis in the Phase IIb PEARL study.[21] Ritonavir-boosted paritaprevir and ombitasvir with ribavirin for 12 weeks has also shown favourable results in HCV genotype 4-infected patients with compensated cirrhosis in the AGATE-1 study, in which SVR12 rates of 97% (57/59 patients) were reported.[22] Another DAA treatment combination, grazoprevir in combination with elbasvir without ribavirin, was studied in the Phase 3 C-EDGE study, in which treatment-naïve and -experienced patients with HCV genotype 4 infection achieved SVR12 rates of 100% (18/18 patients) and 78% (7/9 patients), respectively, with 12 weeks of treatment.[23-25]
The safety and tolerability of DAAs has previously been described in detail. Whilst DAAs have drastically reduced side effects when compared with IFN-containing regimens, subgroup-specific contraindications and safety-related limitations are being studied further.[26] Notably, in this study, the 2-DAA regimen of simeprevir plus sofosbuvir was safe and well-tolerated, with all AEs Grade 1 or 2. Of the treatment-emergent laboratory abnormalities, no Grade 3 or 4 increases in AST, ALT or bilirubin were noted. The safety profile seen in this study is in-line with the OPTIMIST-1 and -2 studies.[12, 13]
Strengths of the PLUTO study included the short 12-week IFN-free treatment regimen without ribavirin. The benefits of ribavirin-free regimens have been further highlighted in a recent article comparing patient-reported outcomes data from multicentre, multinational, Phase 3 studies of sofosbuvir with and without IFN and ribavirin. In a multivariate analysis, the use of ribavirin was independently associated with −9.0% worsening of the patient-reported outcome scores, and ribavirin-free regimens were associated with better patient experience and work productivity during treatment.[27]
Limitations of the PLUTO study included the limited sample size overall and in the subgroups, including patients with cirrhosis, and therefore the results of this study must be interpreted with caution. Due to the small number of patients with cirrhosis, the proportions of patients with albumin <40 g/L and platelets <90 × 109/L were limited and the use of this regimen in patients with advanced liver disease was not investigated. In addition, the patient population was predominantly Caucasian and therefore the results need to be confirmed in the HCV genotype 4-infected populations in many countries. The open-label nature of the study and the lack of a comparator arm could formally be viewed as potential limitations; however, the US Food and Drug Administration draft guidance, and guidance from the European Medicines Agency, include historical-controlled trials as one of the accepted Phase 3 study designs.[28-30]
In conclusion, the combination of simeprevir and sofosbuvir for 12 weeks resulted in a 100% SVR12 rate and was well-tolerated (with no Grade 3/4 AEs or treatment discontinuations reported) by treatment-naïve and treatment-experienced patients with chronic HCV genotype 4 infection, regardless of fibrosis stage or prior treatment history. These data are encouraging with respect to the potential use of this regimen in this patient population
Summary
Introduction
Materials and methods
Results
Discussion
Authorship
Acknowledgements
Treatment for 12 weeks with simeprevir in combination with sofosbuvir resulted in an SVR rate of 100% (40/40 patients) in HCV genotype 4-infected treatment-naïve and -experienced patients with and without compensated cirrhosis in the PLUTO study.
Although patient numbers were small for subgroups, all patients achieved SVR12 regardless of fibrosis stage [7/40 (18%) of patients had compensated cirrhosis], IL28B genotype or prior treatment history. It has been previously reported that IL28B genotype is strongly associated with SVR in patients with HCV genotype 4 infection receiving treatment with PR;[14] however, the results of this study demonstrate that simeprevir in combination with sofosbuvir was effective regardless of IL28B genotype. As expected, the NS3 Q80K polymorphism was not observed in this HCV genotype 4-infected population.
The results of this study provide support for the clinical effectiveness of simeprevir in combination with sofosbuvir for the treatment of HCV genotype 4 infection in treatment-naïve and -experienced patients with and without compensated cirrhosis. The 100% SVR12 rate in this study is complemented by the Phase IIa OSIRIS study, which investigated 12 weeks of simeprevir plus sofosbuvir in HCV genotype 4-infected patients in Egypt, and reported an SVR12 rate of 100% (43/43 patients) regardless of prior treatment history or fibrosis stage [23/43 (53%) patients had cirrhosis].[15] In contrast, the PLUTO study investigated simeprevir plus sofosbuvir in a predominantly Caucasian HCV genotype 4-infected population.
The results of this study are comparable with those of the Phase III OPTIMIST-1 study in HCV genotype 1-infected patients without cirrhosis treated with simeprevir plus sofosbuvir for 12 weeks [97% (150/155) achieved SVR12],[12] and improve upon those of the Phase III OPTIMIST-2 study in patients with cirrhosis treated with simeprevir plus sofosbuvir for 12 weeks [83% (86/103) achieved SVR12].[13] Of note, a limited number of patients with cirrhosis were included in the PLUTO study.
Real-world evidence has also highlighted 12 weeks of this treatment combination as a simple, effective and well-tolerated IFN-free regimen. Treatment-naïve and -experienced patients in a study in Egypt that included patients with cirrhosis, reported an SVR4 rate of 96% (207/215 patients).[16] In a study in Qatar, 100% (17/17) of HCV genotype 4-infected patients with cirrhosis achieved SVR12.[17] Similar results have also been reported in a study in Belgium, with 100% (23/23) of HCV genotype 4-infected patients with cirrhosis, treated with or without ribavirin, achieving HCV RNA below the lower limit of quantification at Week 12 of treatment.[18]
Similar results were observed in an open-label study that assessed the combination of sofosbuvir and ledipasvir for 12 weeks in HCV genotype 4-infected patients, reporting an SVR12 rate of 93% (41/44 patients).[19] In contrast, a lower SVR12 rate of 78% (14/18 patients) was reported in HCV genotype 4-infected patients treated with sofosbuvir and ledipasvir plus ribavirin for 12 weeks.[20] Furthermore, the treatment combination of 12 weeks of ritonavir-boosted paritaprevir and ombitasvir (without dasabuvir), with and without ribavirin, resulted in SVR12 rates of 100% (42/42) and 91% (40/44), respectively, for HCV genotype 4-infected treatment-naїve patients without cirrhosis in the Phase IIb PEARL study.[21] Ritonavir-boosted paritaprevir and ombitasvir with ribavirin for 12 weeks has also shown favourable results in HCV genotype 4-infected patients with compensated cirrhosis in the AGATE-1 study, in which SVR12 rates of 97% (57/59 patients) were reported.[22] Another DAA treatment combination, grazoprevir in combination with elbasvir without ribavirin, was studied in the Phase 3 C-EDGE study, in which treatment-naïve and -experienced patients with HCV genotype 4 infection achieved SVR12 rates of 100% (18/18 patients) and 78% (7/9 patients), respectively, with 12 weeks of treatment.[23-25]
The safety and tolerability of DAAs has previously been described in detail. Whilst DAAs have drastically reduced side effects when compared with IFN-containing regimens, subgroup-specific contraindications and safety-related limitations are being studied further.[26] Notably, in this study, the 2-DAA regimen of simeprevir plus sofosbuvir was safe and well-tolerated, with all AEs Grade 1 or 2. Of the treatment-emergent laboratory abnormalities, no Grade 3 or 4 increases in AST, ALT or bilirubin were noted. The safety profile seen in this study is in-line with the OPTIMIST-1 and -2 studies.[12, 13]
Strengths of the PLUTO study included the short 12-week IFN-free treatment regimen without ribavirin. The benefits of ribavirin-free regimens have been further highlighted in a recent article comparing patient-reported outcomes data from multicentre, multinational, Phase 3 studies of sofosbuvir with and without IFN and ribavirin. In a multivariate analysis, the use of ribavirin was independently associated with −9.0% worsening of the patient-reported outcome scores, and ribavirin-free regimens were associated with better patient experience and work productivity during treatment.[27]
Limitations of the PLUTO study included the limited sample size overall and in the subgroups, including patients with cirrhosis, and therefore the results of this study must be interpreted with caution. Due to the small number of patients with cirrhosis, the proportions of patients with albumin <40 g/L and platelets <90 × 109/L were limited and the use of this regimen in patients with advanced liver disease was not investigated. In addition, the patient population was predominantly Caucasian and therefore the results need to be confirmed in the HCV genotype 4-infected populations in many countries. The open-label nature of the study and the lack of a comparator arm could formally be viewed as potential limitations; however, the US Food and Drug Administration draft guidance, and guidance from the European Medicines Agency, include historical-controlled trials as one of the accepted Phase 3 study designs.[28-30]
In conclusion, the combination of simeprevir and sofosbuvir for 12 weeks resulted in a 100% SVR12 rate and was well-tolerated (with no Grade 3/4 AEs or treatment discontinuations reported) by treatment-naïve and treatment-experienced patients with chronic HCV genotype 4 infection, regardless of fibrosis stage or prior treatment history. These data are encouraging with respect to the potential use of this regimen in this patient population
Summary
Introduction
Materials and methods
Results
Discussion
Authorship
Acknowledgements
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