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J Infect Dis. 2016 Dec 1;214(11):1687-1694. Epub 2016 Sep 20.

Protease Inhibitor Resistance Remains Even After Mutant Strains Become Undetectable by Deep Sequencing.

Author information

1
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences.
2
Liver Research Project Center, Hiroshima University.
3
Laboratory for Digestive Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research, Hiroshima.
4
PhoenixBio, Higashihiroshima, Japan.

Abstract

BACKGROUND:

 Although treatment-emergent NS3/4A protease inhibitor (PI)-resistant variants typically decrease in frequency after cessation of PI therapy in patients with chronic hepatitis C virus (HCV) infection, HCV susceptibility to PIs in patients who have not responded to previous PI therapy has not been addressed.

METHODS:

 Patients with chronic HCV genotype 1 infection were treated either with simeprevir plus interferon or with daclatasvir plus asunaprevir. Frequencies of drug-resistant mutations among patients with treatment failure were analyzed by deep sequencing. Human hepatocyte chimeric mice were injected with serum samples obtained from either treatment-naive patients or nonresponders to treatment with daclatasvir plus asunaprevir and then were treated with simeprevir and sofosbuvir.

RESULTS:

 Virological response to daclatasvir plus asunaprevir treatment was significantly lower in patients with simeprevir treatment failure as compared to those without previous treatment. Deep-sequencing analysis showed that the frequency of PI treatment-emergent NS3-D168 mutations gradually decreased and were completely replaced by wild-type genes after cessation of therapy. However, mice injected with serum obtained from a patient with PI treatment failure rapidly developed NS3-D168 mutations at significantly higher frequencies following either simeprevir or sofosbuvir treatment.

CONCLUSIONS:

 The virological response to daclatasvir plus asunaprevir treatment was low in patients with simeprevir treatment failure. PI resistance remains even after disappearance of mutant strains by deep sequencing.

KEYWORDS:

NS3/4A protease inhibitor; NS5B polymerase inhibitor; chimeric mouse; direct-acting antiviral agent; drug resistance; hepatitis C virus

PMID:
27651415
DOI:
10.1093/infdis/jiw437
[Indexed for MEDLINE]

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