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NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Little real-world cohort data has been reported for Asians who have received interferon-free regimens with sofosbuvir (SOF) for chronic hepatitis C virus (HCV) infection. We evaluated the effectiveness and safety in clinical practice of ledipasvir (LDV) plus SOF for Japanese patients infected with HCV genotype 1.

Methods

This large, multicenter, real-world cohort study consisted of 772 patients treatment-naive or -experienced, with or without compensated cirrhosis, who were treated with LDV (90 mg)/SOF (400 mg) for a fixed 12-week duration. Direct sequence analysis of the NS5A genes (L31 and Y93) was performed at baseline.

Results

Almost all (99.6%) were infected with HCV genotype 1b. The overall sustained virological response 12 weeks after the end of treatment (SVR12) rate was 98.8% (763/772). Multivariable logistic regression analysis extracted male (odds ratio [OR] 6.62, p = 0.024), cirrhosis (OR 20.1, p = 0.0054), and baseline NS5A resistance-associated variants (RAVs) (OR 29.3, p = 0.0018) as independently associated with treatment failure. Notably, the SVR12 rate for cirrhosis patients with baseline NS5A RAVs (87.5%, 49/56) was statistically lower than for the other groups. This tendency was found except for patients with prior daclatasvir/asunaprevir failure. All patients with treatment failure had NS5A Y93H at relapse, whether or not they had NS5A RAVs at baseline. Serious adverse effects were very rare, and discontinuation was required for only five (0.6%) patients.

Conclusions

LDV/SOF for HCV genotype 1b was exceptionally effective, however, NS5A RAVs undermined the virological effect for cirrhosis patients. Moreover, LDV/SOF was shown to be safe, irrespective of age or fibrosis status.

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Abbreviations

HCV:

Hepatitis C virus

PEG-IFNα:

Pegylated interferon alpha

DAAs:

Direct-acting antivirals

SOF:

Sofosbuvir

LDV:

Ledipasvir

SVR:

Sustained virological response

RAVs:

Resistance-associated variants

eGFR:

Estimated glomerular filtration rate

IL28B:

Interleukin-28B

OR:

Odds ratio

CI:

Confidence interval

ASV:

Asunaprevir

DCV:

Daclatasvir

RVR:

Rapid virological response

ALT:

Alanine aminotransferase

PPI:

Proton-pump inhibitor

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Acknowledgements

We are grateful to Drs. Masayuki Murata, Kazuhiro Toyoda, Motohiro Shimizu, Takeo Hayashi, Fujiko Mitsumoto-Kaseida, Koji Takayama, Kazuya Ura, Yoshifumi Kato, Yuuki Tanaka, and Sho Yamasaki from the Department of General Internal Medicine, Kyushu University Hospital for their assistance with data collection for this study. We are also grateful to Yoshitaka Etoh for his excellent lab work on IL28B SNPs and RAVs testing.

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Authors and Affiliations

  1. Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan

    Eiichi Ogawa & Norihiro Furusyo

  2. The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan

    Hideyuki Nomura

  3. Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan

    Kazufumi Dohmen

  4. Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan

    Nobuhiko Higashi

  5. Department of Medicine, Hamanomachi Hospital, Fukuoka, Japan

    Kazuhiro Takahashi

  6. Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan

    Akira Kawano

  7. Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan

    Koichi Azuma

  8. Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan

    Takeaki Satoh

  9. Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan

    Makoto Nakamuta

  10. Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan

    Toshimasa Koyanagi

  11. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masaki Kato

  12. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shinji Shimoda

  13. Kajiwara Clinic, Kitakyushu, Japan

    Eiji Kajiwara

  14. Kyushu General Internal Medicine Center, Haradoi Hospital, Higashi-Ku, Fukuoka, 812-8582, Japan

    Jun Hayashi

Authors
  1. Eiichi Ogawa
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  2. Norihiro Furusyo
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  3. Hideyuki Nomura
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  4. Kazufumi Dohmen
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  7. Akira Kawano
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  8. Koichi Azuma
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  11. Toshimasa Koyanagi
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  12. Masaki Kato
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  13. Shinji Shimoda
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  14. Eiji Kajiwara
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  15. Jun Hayashi
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Consortia

The Kyushu University Liver Disease Study (KULDS) Group

Corresponding author

Correspondence to Jun Hayashi.

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Conflict of interest

Norihiro Furusyo has received grants from Taisho Toyama Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Janssen Pharmaceutical K.K., and Bristol-Myers Squibb. Makoto Nakamuta has received grants from Bristol-Myers Squibb. The other authors declare that they have no conflicts of interest. This study received no specific funding.

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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 52, 845–854 (2017). https://doi.org/10.1007/s00535-016-1290-1

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  • DOI: https://doi.org/10.1007/s00535-016-1290-1

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