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HCV NS5A resistance-associated variants in a group of real-world Japanese patients chronically infected with HCV genotype 1b

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Abstract

Background

Recent advances in interferon-free treatment could lead to the eradication of hepatitis C virus (HCV) from patients infected with HCV. One of the direct-acting anti-viral agents, HCV NS5A inhibitor, is available for these combination therapies. However, naturally occurring resistance-associated variants (RAVs) to HCV NS5A inhibitors in treatment-naïve patients chronically infected with HCV genotype 1b are still unknown.

Methods

We performed ultra-deep sequencing and analysed previously reported RAVs in a total 132 HCV genotype 1b-infected Japanese patients who had never used HCV NS5A inhibitors. We also performed direct-sequencing by Sanger method in consecutively selected 50 of the total 132 samples, and the differences between the results of the two methods were compared.

Results

In the comparison of the variant frequencies of ultra-deep sequencing with RAVs of direct-sequencing by Sanger method in 50 patients, we identified 32 RAVs by direct-sequencing with the Sanger method; minimum variant frequency was shown by ultra-deep sequencing to be 9 %. A total of 110 RAVs were identified only by ultra-deep sequencing. In the samples from all 132 patients, L31W (2.3 %), L31V (49.2 %), L31F (41.7 %), L31M (1.5 %), L31I (5.3 %), L31S (2.0 %), L31P (3.0 %) and L31R (0.8 %), and Y93N (2.3 %), Y93H (25 %), Y93C (0.8 %), Y93P (2.3 %) and Y93D (0.8 %) were identified.

Conclusions

We demonstrated naturally-occurring RAVs of HCV NS5A inhibitors by ultra-deep sequencing and that several mutations including Y93H are common in HCV NS5A inhibitor-treatment-naïve patients with chronic HCV genotype 1b. Careful attention should be paid to these RAVs, and further improvement of treatment options might be needed.

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Acknowledgements

We are all thankful to our colleagues at the liver units of each hospital who cared for the patients described herein. This study was supported by a Grant-in-Aid for the Genome Research Project from Yamanashi Prefecture (to Yosuke Hirotsu and Masao Omata).

Compliance with ethical requirements and Conflict of interest

All procedures followed were in accordance with ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for participation in the study. Yosuke Hirotsu, Hiroshi Matsumura, Mitsuhiko Moriyama and Masao Omata declare that they have no conflicts of interest. Tatsuo Kanda reports receiving lecture fees from Chugai Pharmaceutical, MSD, Tanabe-Mitsubishi, Daiichi-Sankyo, and Bristol-Myers Squibb, and Osamu Yokosuka reports receiving grant support from Chugai Pharmaceutical, Bayer, MSD, Daiichi-Sankyo, Tanabe-Mitsubishi, and Bristol-Myers Squibb. Written informed consent was obtained from all patients, and this study was approved by the respective Institutional Ethics Committees (Yamanashi Prefectural Central Hospital GS-US-337-0113; Chiba University School of Medicine, No.1462, No. 502; and Nihon University School of Medicine RK-100910-14).

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Authors and Affiliations

  1. Genome Analysis Center, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan

    Yosuke Hirotsu & Masao Omata

  2. Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan

    Tatsuo Kanda & Osamu Yokosuka

  3. Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, 173-8610, Japan

    Hiroshi Matsumura & Mitsuhiko Moriyama

  4. University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Masao Omata

Authors
  1. Yosuke Hirotsu
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  2. Tatsuo Kanda
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  3. Hiroshi Matsumura
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  4. Mitsuhiko Moriyama
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  5. Osamu Yokosuka
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  6. Masao Omata
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Corresponding author

Correspondence to Tatsuo Kanda.

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Hirotsu, Y., Kanda, T., Matsumura, H. et al. HCV NS5A resistance-associated variants in a group of real-world Japanese patients chronically infected with HCV genotype 1b. Hepatol Int 9, 424–430 (2015). https://doi.org/10.1007/s12072-015-9624-2

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  • DOI: https://doi.org/10.1007/s12072-015-9624-2

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