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

The Kyushu University Liver Disease Study (KULDS) Group

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)845-854
Number of pages10
JournalJournal of Gastroenterology
Volume52
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

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Hepacivirus
Genotype
Fibrosis
Odds Ratio
Treatment Failure
Galectin 3
Chronic Hepatitis C
Virus Diseases
sofosbuvir drug combination ledipasvir
Interferons
Sequence Analysis
Cohort Studies
Logistic Models
Regression Analysis
Safety
Recurrence
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b. / The Kyushu University Liver Disease Study (KULDS) Group.

In: Journal of Gastroenterology, Vol. 52, No. 7, 01.07.2017, p. 845-854.

Research output: Contribution to journalArticle

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title = "NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b",
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.",
author = "{The Kyushu University Liver Disease Study (KULDS) Group} and Eiichi Ogawa and Norihiro Furusyo and Hideyuki Nomura and Kazufumi Dohmen and Nobuhiko Higashi and Kazuhiro Takahashi and Akira Kawano and Koichi Azuma and Takeaki Satoh and Makoto Nakamuta and Toshimasa Koyanagi and Masaki Kato and Shinji Shimoda and Eiji Kajiwara and Jun Hayashi",
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T1 - NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b

AU - The Kyushu University Liver Disease Study (KULDS) Group

AU - Ogawa, Eiichi

AU - Furusyo, Norihiro

AU - Nomura, Hideyuki

AU - Dohmen, Kazufumi

AU - Higashi, Nobuhiko

AU - Takahashi, Kazuhiro

AU - Kawano, Akira

AU - Azuma, Koichi

AU - Satoh, Takeaki

AU - Nakamuta, Makoto

AU - Koyanagi, Toshimasa

AU - Kato, Masaki

AU - Shimoda, Shinji

AU - Kajiwara, Eiji

AU - Hayashi, Jun

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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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