Advertisement

Journal of Gastroenterology

, Volume 53, Issue 4, pp 548–556 | Cite as

Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study

  • Yoshiiku Kawakami
  • Hidenori Ochi
  • Clair Nelson Hayes
  • Michio Imamura
  • Masataka Tsuge
  • Takashi Nakahara
  • Yoshio Katamura
  • Hiroshi Kohno
  • Hirotaka Kohno
  • Keiji Tsuji
  • Shintaro Takaki
  • Nami Mori
  • Yohji Honda
  • Keiko Arataki
  • Shoichi Takahashi
  • Shinsuke Kira
  • Toru Tamura
  • Kazunari Masuda
  • Toshio Nakamura
  • Masaya Kikkawa
  • Kazuaki Chayama
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy.

Methods

Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined.

Results

The overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed.

Conclusion

Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.

Keywords

Daclatasvir Asunaprevir Ledipasvir/sofosbuvir with ribavirin Retreatment Resistance-associated variants NS5A inhibitor NS5B polymerase inhibitor 

Abbreviations

RIKEN

The Institute of Physical and Chemical Research

HCV

Hepatitis C virus

SVR

Sustained virological response

GT1

Genotype 1

IFN

Interferon

RBV

Ribavirin

DAAs

Direct-acting antiviral agents

DCV

Daclatasvir

ASV

Asunaprevir

LDV

Ledipasvir

SOF

Sofosbuvir

OBV

Ombitasvir

PTV

Paritaprevir

r

Ritonavir

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

RAVs

Resistance-associated variants

Hb

Hemoglobin

EOT

End of treatment

SAE

Serious adverse event

AE

Adverse event

Notes

Acknowledgements

We thank Akemi Sada for clerical assistance, and Tsuyoshi Nagata for preparation of the manuscript. Part of this work was carried out at the Analysis Center of Life Science, Hiroshima University. This study was supported by the Research Program on Hepatitis from Japanese Agency for Medical and development (AMED) Japan (Grant Number16fk0210301h0003).

Compliance with ethical standards

Conflict of interest

K. Chayama has received research grants and consulting fees from Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Mitsubishi Tanabe Pharma, Daiichi Sankyo, Toray Industries, Otsuka Pharmaceutical Company, and GlaxoSmithKline KK. All other authors have no conflicts to report.

Financial support

This study was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Labor and Health and Welfare.

References

  1. 1.
    European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol. 2017;66(1):153–94.CrossRefGoogle Scholar
  2. 2.
    Hepatitis C Guidance: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed 16 Sept 2016.
  3. 3.
    JSH guidelines for management of hepatitis C virus infection (ver. 5.2) 2016: http://www.jsh.or.jp/medical/guidelines/jsh_guidlines/hepatitis_c. Accessed Dec 2016.
  4. 4.
    Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55(3):724–8.CrossRefGoogle Scholar
  5. 5.
    Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59(6):2083–91.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol. 2013;58(4):655–62.CrossRefPubMedGoogle Scholar
  7. 7.
    Kanda T, Yasui S, Nakamura M, et al. Daclatasvir plus asunaprevir treatment for real-world HCV genotype 1-infected patients in Japan. Int J Med Sci. 2016;13(6):418–23.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kumada H, Suzuki F, Suzuki Y, et al. Randomized comparison of daclatasvir + asunaprevir versus telaprevir + peginterferon/ribavirin in Japanese hepatitis C virus patients. J Gastroenterol Hepatol. 2016;31(1):14–22.CrossRefPubMedGoogle Scholar
  9. 9.
    Ogawa E, Furusyo N, Yamashita N, et al. Effectiveness and safety of daclatasvir plus asunaprevir for HCV genotype 1b patients aged 75 and over with or without cirrhosis. Hepatol Res. 2017;47(3):E120–31. doi: 10.1111/hepr.12738.CrossRefPubMedGoogle Scholar
  10. 10.
    Morio R, Imamura M, Kawakami Y, et al. Safety and efficacy of dual therapy with daclatasvir and asunaprevir for older patients with chronic hepatitis C. J Gastroenterol. 2017;52(4):504–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Morio K, Imamura M, Kawakami Y, et al. Real-world efficacy and safety of daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients. J Gastroenterol Hepatol. 2017;32(3):645–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Yoshimi S, Imamura M, Murakami E, et al. Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J Med Virol. 2015;87:1913–20.CrossRefPubMedGoogle Scholar
  13. 13.
    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(2):284–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Kobayashi M, Suzuki F, Akuta N, et al. Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus. J Gastroenterol. 2012;47:596–605.CrossRefPubMedGoogle Scholar
  15. 15.
    Fellay J, Thompson AJ, Ge D, et al. ITPA gene variants protect against anemia in patients treated for chronic hepatitis C. Nature. 2010;464:405–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Ochi H, Maekawa T, Abe H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy—a genomewide study of Japanese HCV virus patients. Gastroenterology. 2010;139:1190–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Sterling RK, Lissen E, Clumeck N, Clinical Investigators APRICOT, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;2016(43):1317–25.CrossRefGoogle Scholar
  18. 18.
    Ohara E, Hiraga N, Imamura M, et al. Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice. J Hepatol. 2011;54:872–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Sarrazin C, Dvory-Sobol H, Svarovskaia ES, et al. Prevalence of resistance-associated substitutions in HCV NS5A, NS5B, or NS3 and outcomes of treatment with ledipasvir and sofosbuvir. Gastroenterology. 2016;151(3):501–12.CrossRefPubMedGoogle Scholar
  20. 20.
    Di Maio VC, Cento V, Lenci I, et al. Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. HCV Italian Resistance Network Study Group. Liver Int. 2017;37(4):514–28.CrossRefPubMedGoogle Scholar
  21. 21.
    Gilead Sciences Inc., HARVONI combination tablets® (sofosbuvir + ledipasvir).  US full Prescribing Information. February 2017.Google Scholar
  22. 22.
    Friborg J, Zhou N, Han Z, et al. In vitro assessment of re-treatment options for patients with hepatitis C virus genotype 1b infection resistant to daclatasvir plus asunaprevir. Infect Dis Ther. 2015;4(1):137–44.CrossRefGoogle Scholar
  23. 23.
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483–93.CrossRefPubMedGoogle Scholar
  25. 25.
    Suda G, Ogawa K, Yamamoto Y, et al. Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy. J Gastroenterol. 2017;. doi: 10.1007/s00535-017-1328-z.Google Scholar
  26. 26.
    Lau JY, Tam RC, Liang TJ, et al. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology. 2002;35:1002–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci USA. 2001;98:6895–900.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Dietz J, Schelhorn SE, Fitting D, et al. Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients. J Virol. 2013;87:6172–81.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Akuta N, Sezaki H, Suzuki F, et al. Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens. J Med Virol. 2017;89(7):1248–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Cheng G, Tian Y, Doehle B, et al. In vitro antiviral activity and resistance profile characterization of the hepatitis C virus NS5A inhibitor ledipasvir. Antimicrob Agents Chemother. 2016;60(3):1847–53.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lam AM, Espiritu C, Bansal S, et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother. 2012;56(6):3359–68.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Morio K, Imamura M, Kawakami Y, et al. ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C. J Gastroenterol. 2017;52(6):746–53.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Gastroenterology 2017

Authors and Affiliations

  • Yoshiiku Kawakami
    • 1
    • 2
    • 13
  • Hidenori Ochi
    • 1
    • 13
    • 14
  • Clair Nelson Hayes
    • 1
    • 13
  • Michio Imamura
    • 1
    • 13
  • Masataka Tsuge
    • 1
    • 13
  • Takashi Nakahara
    • 1
    • 13
  • Yoshio Katamura
    • 3
  • Hiroshi Kohno
    • 4
  • Hirotaka Kohno
    • 4
  • Keiji Tsuji
    • 5
  • Shintaro Takaki
    • 5
  • Nami Mori
    • 5
  • Yohji Honda
    • 5
  • Keiko Arataki
    • 6
  • Shoichi Takahashi
    • 7
  • Shinsuke Kira
    • 8
  • Toru Tamura
    • 9
  • Kazunari Masuda
    • 10
  • Toshio Nakamura
    • 11
  • Masaya Kikkawa
    • 12
  • Kazuaki Chayama
    • 1
    • 13
    • 14
  1. 1.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Department of Center for Integrated Medical ResearchHiroshima UniversityHiroshimaJapan
  3. 3.Onomichi General HospitalHiroshimaJapan
  4. 4.Kure Medical CenterHiroshimaJapan
  5. 5.Hiroshima Red Cross Hospital and Atomic-bomb Survivors HospitalHiroshimaJapan
  6. 6.Tsuchiya General HospitalHiroshimaJapan
  7. 7.Koyo New Town HospitalHiroshimaJapan
  8. 8.Saiseikai Hiroshima HospitalHiroshimaJapan
  9. 9.Mazda HospitalHiroshimaJapan
  10. 10.Masuda ClinicHiroshimaJapan
  11. 11.Nakamura ClinicHiroshimaJapan
  12. 12.Kikkawa ClinicHiroshimaJapan
  13. 13.Liver Research Project Center, Hiroshima UniversityHiroshimaJapan
  14. 14.Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical SciencesThe Institute of Physical and Chemical Research (RIKEN)HiroshimaJapan

Personalised recommendations