Advertisement

Journal of Gastroenterology

, Volume 53, Issue 12, pp 1276–1284 | Cite as

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

  • Hidenori ToyodaEmail author
  • 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
Original Article—Liver, Pancreas, and Biliary Tract

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.

Keywords

Chronic hepatitis C Genotype 1 Elbasvir Grazoprevir Efficacy Safety Real world 

References

  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    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.CrossRefGoogle Scholar
  3. 3.
    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.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    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.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    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.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    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).Google Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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.CrossRefGoogle Scholar
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    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.PubMedPubMedCentralGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    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.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    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.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    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.CrossRefGoogle Scholar
  37. 37.
    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.CrossRefGoogle Scholar
  38. 38.
    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.CrossRefGoogle Scholar
  39. 39.
    Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1 infection. Hepatology. 2014;59:2083–91.CrossRefGoogle Scholar
  40. 40.
    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.CrossRefGoogle Scholar
  41. 41.
    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.CrossRefGoogle Scholar
  42. 42.
    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.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Hidenori Toyoda
    • 1
    Email author
  • Masanori Atsukawa
    • 2
  • Koichi Takaguchi
    • 3
  • Tomonori Senoh
    • 3
  • Kojiro Michitaka
    • 4
  • Atsushi Hiraoka
    • 4
  • Shinichi Fujioka
    • 5
  • Chisa Kondo
    • 2
  • Tomomi Okubo
    • 6
  • Haruki Uojima
    • 7
  • Toshifumi Tada
    • 1
  • Hirohito Yoneyama
    • 8
  • Tsunamasa Watanabe
    • 9
  • Toru Asano
    • 10
  • Toru Ishikawa
    • 11
  • Hideyuki Tamai
    • 12
  • Hiroshi Abe
    • 13
  • Keizo Kato
    • 13
  • Kunihiko Tsuji
    • 14
  • Chikara Ogawa
    • 15
  • Noritomo Shimada
    • 16
  • Etsuko Iio
    • 17
  • Akihiro Deguchi
    • 18
  • Ei Itobayashi
    • 19
  • Shigeru Mikami
    • 20
  • Akio Moriya
    • 21
  • Hironao Okubo
    • 22
  • Joji Tani
    • 23
  • Akihito Tsubota
    • 24
  • Yasuhito Tanaka
    • 17
  • Tsutomu Masaki
    • 8
  • Katsuhiko Iwakiri
    • 2
  • Takashi Kumada
    • 1
  1. 1.Department of GastroenterologyOgaki Municipal HospitalOgakiJapan
  2. 2.Division of Gastroenterology and Hepatology, Department of Internal MedicineNippon Medical SchoolTokyoJapan
  3. 3.Department of HepatologyKagawa Prefectural Central HospitalTakamatsuJapan
  4. 4.Gastroenterology CenterEhime Prefectural Central HospitalMatsuyamaJapan
  5. 5.Department of GastroenterologyOkayama Saiseikai General HospitalOkayamaJapan
  6. 6.Division of Gastroenterology, Department of Internal MedicineNippon Medical School Chiba Hokusoh HospitalInzaiJapan
  7. 7.Department of Gastroenterology, Internal MedicineKitasato University School of MedicineSagamiharaJapan
  8. 8.Department of Gastroenterology and NeurologyKagawa University School of MedicineKidaJapan
  9. 9.Department of Internal MedicineSt. Marianna University School of MedicineKawasakiJapan
  10. 10.Division of Gastroenterology and Hepatology, Department of Internal MedicineTokyo Metropolitan Bokutoh HospitalTokyoJapan
  11. 11.Department of HepatologySaiseikai Niigata Daini HospitalNiigataJapan
  12. 12.Department of HepatologyWakayama Rosai HospitalWakayamaJapan
  13. 13.Division of Gastroenterology and Hepatology, Department of Internal MedicineShinmatusdo Central General HospitalMatsudoJapan
  14. 14.Center of GastroenterologyTeine Keijinkai HospitalSapporoJapan
  15. 15.Department of Gastroenterology and HepatologyTakamatsu Red Cross HospitalTakamatsuJapan
  16. 16.Division of Gastroenterology and Hepatology, Department of Internal MedicineOtakanomori HospitalKashiwaJapan
  17. 17.Department of Virology and Liver Unit, Graduate School of Medical SciencesNagoya City UniversityNagoyaJapan
  18. 18.Department of GastroenterologyKagawa Rosai HospitalMarugameJapan
  19. 19.Department of GastroenterologyAsahi General HospitalAsahiJapan
  20. 20.Division of Gastroenterology, Department of Internal MedicineKikkoman General HospitalNodaJapan
  21. 21.Department of GastroenterologyMitoyo General HospitalKannonjiJapan
  22. 22.Department of GastroenterologyJuntendo University Nerima HospitalTokyoJapan
  23. 23.Department of Internal MedicineYashima General HospitalTakamatsuJapan
  24. 24.Core Research Facilities for Basic ScienceThe Jikei University School of MedicineTokyoJapan

Personalised recommendations