Low frequency of drug-resistant virus did not affect the therapeutic eficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV ge notype-1infection

Hideaki Kunugasa, Fusao Ikeda, Kouichi Takaguchi, Chizuru Mori, Takehiro Matsubara, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Shinichi Toyooka, Kazuhide Yamamoto

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Abstract

Background: The eficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood. Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy. Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients. Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically signiicant RAVs for ASV plus DCV therapy.

Original languageEnglish
Pages (from-to)37-44
Number of pages8
JournalAntiviral Therapy
Volume21
Issue number1
DOIs
Publication statusPublished - 2016

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Viruses
Satellite Viruses
Pharmaceutical Preparations
Therapeutics
Drug Resistance
asunaprevir
BMS-790052
High-Throughput Nucleotide Sequencing
Polymerase Chain Reaction
Liver
Serum
Interferons
Antiviral Agents
Genotype
Recurrence

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

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title = "Low frequency of drug-resistant virus did not affect the therapeutic eficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV ge notype-1infection",
abstract = "Background: The eficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood. Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy. Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3{\%}) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88{\%} frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12{\%}) for three of four patients. Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically signiicant RAVs for ASV plus DCV therapy.",
author = "Hideaki Kunugasa and Fusao Ikeda and Kouichi Takaguchi and Chizuru Mori and Takehiro Matsubara and Hidenori Shiraha and Akinobu Takaki and Yoshiaki Iwasaki and Shinichi Toyooka and Kazuhide Yamamoto",
year = "2016",
doi = "10.3851/IMP2976",
language = "English",
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T1 - Low frequency of drug-resistant virus did not affect the therapeutic eficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV ge notype-1infection

AU - Kunugasa, Hideaki

AU - Ikeda, Fusao

AU - Takaguchi, Kouichi

AU - Mori, Chizuru

AU - Matsubara, Takehiro

AU - Shiraha, Hidenori

AU - Takaki, Akinobu

AU - Iwasaki, Yoshiaki

AU - Toyooka, Shinichi

AU - Yamamoto, Kazuhide

PY - 2016

Y1 - 2016

N2 - Background: The eficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood. Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy. Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients. Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically signiicant RAVs for ASV plus DCV therapy.

AB - Background: The eficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood. Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy. Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients. Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically signiicant RAVs for ASV plus DCV therapy.

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U2 - 10.3851/IMP2976

DO - 10.3851/IMP2976

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