Skip to main content
Top
Published in: Journal of Gastroenterology 12/2018

01-12-2018 | Original Article—Liver, Pancreas, and Biliary Tract

Real-world virological efficacy and safety of elbasvir and grazoprevir in patients with chronic hepatitis C virus genotype 1 infection in Japan

Authors: Hidenori Toyoda, Masanori Atsukawa, Koichi Takaguchi, Tomonori Senoh, Kojiro Michitaka, Atsushi Hiraoka, Shinichi Fujioka, Chisa Kondo, Tomomi Okubo, Haruki Uojima, Toshifumi Tada, Hirohito Yoneyama, Tsunamasa Watanabe, Toru Asano, Toru Ishikawa, Hideyuki Tamai, Hiroshi Abe, Keizo Kato, Kunihiko Tsuji, Chikara Ogawa, Noritomo Shimada, Etsuko Iio, Akihiro Deguchi, Ei Itobayashi, Shigeru Mikami, Akio Moriya, Hironao Okubo, Joji Tani, Akihito Tsubota, Yasuhito Tanaka, Tsutomu Masaki, Katsuhiko Iwakiri, Takashi Kumada

Published in: Journal of Gastroenterology | Issue 12/2018

Login to get access

Abstract

Background

The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1.

Methods

The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics.

Results

Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment.

Conclusions

The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.
Literature
1.
go back to reference Bennett H, Waser N, Johnson K, et al. A review of the burden of hepatitis C virus infection in China, Japan, South Korea and Taiwan. Hepatol Int. 2015;9:378–90.CrossRef Bennett H, Waser N, Johnson K, et al. A review of the burden of hepatitis C virus infection in China, Japan, South Korea and Taiwan. Hepatol Int. 2015;9:378–90.CrossRef
2.
go back to reference Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875–81.CrossRef Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127:875–81.CrossRef
3.
go back to reference Shiffman ML, Hofmann CM, Thompson EB, et al. Relationship between biochemical, virological, and histological response during interferon treatment of chronic hepatitis C. Hepatology. 1997;26:780–5.CrossRef Shiffman ML, Hofmann CM, Thompson EB, et al. Relationship between biochemical, virological, and histological response during interferon treatment of chronic hepatitis C. Hepatology. 1997;26:780–5.CrossRef
4.
go back to reference Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med. 2000;132:517–24.CrossRef Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med. 2000;132:517–24.CrossRef
5.
go back to reference Ikeda K, Saitoh S, Arase Y, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29:1124–30.CrossRef Ikeda K, Saitoh S, Arase Y, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29:1124–30.CrossRef
6.
go back to reference Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med. 1998;129:94–9.CrossRef Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med. 1998;129:94–9.CrossRef
7.
go back to reference Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med. 1999;131:174–81.CrossRef Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med. 1999;131:174–81.CrossRef
8.
go back to reference Kasahara A, Hayashi N, Mochizuki K, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Hepatology. 1998;27:1394–402.CrossRef Kasahara A, Hayashi N, Mochizuki K, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Hepatology. 1998;27:1394–402.CrossRef
9.
go back to reference Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective multicenter study. J Hepatol. 2013;58:495–501.CrossRef Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective multicenter study. J Hepatol. 2013;58:495–501.CrossRef
10.
go back to reference van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–93.CrossRef van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–93.CrossRef
11.
go back to reference Tada T, Kumada T, Toyoda H, et al. Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis. Liver Int. 2016;36:817–26.CrossRef Tada T, Kumada T, Toyoda H, et al. Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: a propensity score analysis. Liver Int. 2016;36:817–26.CrossRef
12.
go back to reference Toyoda H, Kumada T, Tada T, et al. Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B. J Hepatol. 2017;66:521–7.CrossRef Toyoda H, Kumada T, Tada T, et al. Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B. J Hepatol. 2017;66:521–7.CrossRef
13.
go back to reference Ogawa E, Furusyo N, Yamashita N, et al. Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis. Hepatol Res. 2017;47:E120–31.CrossRef Ogawa E, Furusyo N, Yamashita N, et al. Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis. Hepatol Res. 2017;47:E120–31.CrossRef
14.
go back to reference Akuta N, Sezaki H, Suzuki F, et al. Favorable efficacy of daclatasvir plus asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older. J Med Virol. 2017;89:91–8.CrossRef Akuta N, Sezaki H, Suzuki F, et al. Favorable efficacy of daclatasvir plus asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older. J Med Virol. 2017;89:91–8.CrossRef
15.
go back to reference Ishigami M, Hayashi K, Honda T, et al. Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by hepatitis C virus genotype 1b infection: real-world data. J Gastroenterol Hepatol. 2017;32:1879–86.CrossRef Ishigami M, Hayashi K, Honda T, et al. Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by hepatitis C virus genotype 1b infection: real-world data. J Gastroenterol Hepatol. 2017;32:1879–86.CrossRef
16.
go back to reference Suda G, Nagasaka A, Yamamoto Y, et al. Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus infected patients with renal impairment. Hepatol Res. 2017;47:1127–36.CrossRef Suda G, Nagasaka A, Yamamoto Y, et al. Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus infected patients with renal impairment. Hepatol Res. 2017;47:1127–36.CrossRef
17.
go back to reference Arai T, Atsukawa M, Tsubota A, et al. Efficacy and safety of ombitasvir/paritaprevir/ritonavir therapy for genotype 1b chronic hepatitis C patients complicated with chronic kidney disease. Hepatol Res (in press). Arai T, Atsukawa M, Tsubota A, et al. Efficacy and safety of ombitasvir/paritaprevir/ritonavir therapy for genotype 1b chronic hepatitis C patients complicated with chronic kidney disease. Hepatol Res (in press).
18.
go back to reference Suda G, Kudo M, Nagasaka A, et al. Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C. J Gastroenterol. 2016;51:733–40.CrossRef Suda G, Kudo M, Nagasaka A, et al. Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C. J Gastroenterol. 2016;51:733–40.CrossRef
19.
go back to reference Toyoda H, Kumada T, Tada T, et al. Safety and efficacy to dual direct-acting antiviral therapy (daclatasvir and asunaprevir) for chronic hepatitis C virus genotype 1 infection in patients on hemodialysis. J Gastroenterol. 2016;51:741–7.CrossRef Toyoda H, Kumada T, Tada T, et al. Safety and efficacy to dual direct-acting antiviral therapy (daclatasvir and asunaprevir) for chronic hepatitis C virus genotype 1 infection in patients on hemodialysis. J Gastroenterol. 2016;51:741–7.CrossRef
20.
go back to reference Kawakami Y, Imamura M, Ikeda H, et al. Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study. J Viral Hepat. 2016;23:850–6.CrossRef Kawakami Y, Imamura M, Ikeda H, et al. Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study. J Viral Hepat. 2016;23:850–6.CrossRef
21.
go back to reference Kumada H, Suzuki Y, Karino Y, et al. The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. J Gastroenterol. 2017;52:520–33.CrossRef Kumada H, Suzuki Y, Karino Y, et al. The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. J Gastroenterol. 2017;52:520–33.CrossRef
22.
go back to reference Ohno O, Mizokami M, Wu RR, et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol. 1997;35:201–7.PubMedPubMedCentral Ohno O, Mizokami M, Wu RR, et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol. 1997;35:201–7.PubMedPubMedCentral
23.
go back to reference Uchida Y, Kouyama J, Naiki K, et al. A novel simple assay system to quantify the percent HCV RNA levels of NS5A Y93H mutant strains and Y93 wild-type strains relative to the total HCV-RNA levels to determine the indication for antiviral therapy with NS5A inhibitors. PLoS One. 2014;9:e112647.CrossRef Uchida Y, Kouyama J, Naiki K, et al. A novel simple assay system to quantify the percent HCV RNA levels of NS5A Y93H mutant strains and Y93 wild-type strains relative to the total HCV-RNA levels to determine the indication for antiviral therapy with NS5A inhibitors. PLoS One. 2014;9:e112647.CrossRef
24.
go back to reference Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.CrossRef Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–25.CrossRef
25.
go back to reference The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology. 1994;20:15–20.CrossRef The French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology. 1994;20:15–20.CrossRef
26.
go back to reference Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology. 2007;46:32–6.CrossRef Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology. 2007;46:32–6.CrossRef
27.
go back to reference Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.CrossRef Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.CrossRef
28.
go back to reference Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Grouop. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3:1–150.CrossRef Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Grouop. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3:1–150.CrossRef
29.
go back to reference Hagiwara S, Nishida N, Watanabe T, et al. Outcome of asunaprevir/daclatasvir combination therapy for chronic liver disease type C. Dig Dis. 2016;34:620–6.CrossRef Hagiwara S, Nishida N, Watanabe T, et al. Outcome of asunaprevir/daclatasvir combination therapy for chronic liver disease type C. Dig Dis. 2016;34:620–6.CrossRef
30.
go back to reference Ide T, Eguchi Y, Harada M, et al. Evaluation of resistance-associated substitutions in NS5A using direct sequence and cycleave method and treatment outcome with daclatasvir and asunaprevir for chronic hepatitis C genotype 1. PLoS One. 2016;11:e0163884.CrossRef Ide T, Eguchi Y, Harada M, et al. Evaluation of resistance-associated substitutions in NS5A using direct sequence and cycleave method and treatment outcome with daclatasvir and asunaprevir for chronic hepatitis C genotype 1. PLoS One. 2016;11:e0163884.CrossRef
31.
go back to reference Iio E, Shimada N, Abe H, et al. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol. 2017;52:94–103.CrossRef Iio E, Shimada N, Abe H, et al. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol. 2017;52:94–103.CrossRef
32.
go back to reference Fujii H, Umemura A, Nishikawa T, et al. Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions. World J Hepatol. 2017;9:1064–72.CrossRef Fujii H, Umemura A, Nishikawa T, et al. Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions. World J Hepatol. 2017;9:1064–72.CrossRef
33.
go back to reference Sezaki H, Suzuki F, Hosaka T, et al. The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int. 2017;37:1325–33.CrossRef Sezaki H, Suzuki F, Hosaka T, et al. The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int. 2017;37:1325–33.CrossRef
34.
go back to reference Akuta N, Sezaki H, Suzuki F, et al. Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan. J Med Virol. 2017;89:284–90.CrossRef Akuta N, Sezaki H, Suzuki F, et al. Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan. J Med Virol. 2017;89:284–90.CrossRef
35.
go back to reference Ogawa E, Furusyo N, Nomura H, et al. NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b. J Gastroenterol. 2017;52:845–54.CrossRef Ogawa E, Furusyo N, Nomura H, et al. NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b. J Gastroenterol. 2017;52:845–54.CrossRef
36.
go back to reference Iio E, Shimada N, Takaguchi K, et al. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res. 2017;47:1308–16.CrossRef Iio E, Shimada N, Takaguchi K, et al. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res. 2017;47:1308–16.CrossRef
37.
go back to reference Backus LI, Belperio PS, Shahoumian TA, et al. Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients. Antiviral Ther. 2017;22:481–93.CrossRef Backus LI, Belperio PS, Shahoumian TA, et al. Real-world effectiveness and predictors of sustained virological response with all-oral therapy in 21,242 hepatitis C genotype-1 patients. Antiviral Ther. 2017;22:481–93.CrossRef
38.
go back to reference Prenner SB, VanWagner LB, Flamm SL, et al. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals. J Hepatol. 2017;66:1173–81.CrossRef Prenner SB, VanWagner LB, Flamm SL, et al. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals. J Hepatol. 2017;66:1173–81.CrossRef
39.
go back to reference Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1 infection. Hepatology. 2014;59:2083–91.CrossRef Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1 infection. Hepatology. 2014;59:2083–91.CrossRef
40.
go back to reference Kumada H, Chayama K, Rodrigues L Jr, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for HCV genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology. 2015;62:1037–46.CrossRef Kumada H, Chayama K, Rodrigues L Jr, et al. Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for HCV genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology. 2015;62:1037–46.CrossRef
41.
go back to reference Kozuka R, Hai H, Motoyama H, et al. The presence of multiple NS5A RASs is associated with the outcome of sofosbuvir and ledipasvir therapy in NS5A inhibitor-naïve patients with chronic HCV genotype 1b infection in a real-world cohort. J Viral Hepat. 2018;25:535–42.CrossRef Kozuka R, Hai H, Motoyama H, et al. The presence of multiple NS5A RASs is associated with the outcome of sofosbuvir and ledipasvir therapy in NS5A inhibitor-naïve patients with chronic HCV genotype 1b infection in a real-world cohort. J Viral Hepat. 2018;25:535–42.CrossRef
42.
go back to reference Kumada H, Watanabe T, Suzuki F, et al. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J Gastroenterol. 2018;53:566–75.CrossRef Kumada H, Watanabe T, Suzuki F, et al. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J Gastroenterol. 2018;53:566–75.CrossRef
Metadata
Title
Real-world virological efficacy and safety of elbasvir and grazoprevir in patients with chronic hepatitis C virus genotype 1 infection in Japan
Authors
Hidenori Toyoda
Masanori Atsukawa
Koichi Takaguchi
Tomonori Senoh
Kojiro Michitaka
Atsushi Hiraoka
Shinichi Fujioka
Chisa Kondo
Tomomi Okubo
Haruki Uojima
Toshifumi Tada
Hirohito Yoneyama
Tsunamasa Watanabe
Toru Asano
Toru Ishikawa
Hideyuki Tamai
Hiroshi Abe
Keizo Kato
Kunihiko Tsuji
Chikara Ogawa
Noritomo Shimada
Etsuko Iio
Akihiro Deguchi
Ei Itobayashi
Shigeru Mikami
Akio Moriya
Hironao Okubo
Joji Tani
Akihito Tsubota
Yasuhito Tanaka
Tsutomu Masaki
Katsuhiko Iwakiri
Takashi Kumada
Publication date
01-12-2018
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 12/2018
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-018-1473-z

Other articles of this Issue 12/2018

Journal of Gastroenterology 12/2018 Go to the issue