We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Protease Inhibitor Resistance Remains Even After Mutant Strains Become Undetectable by Deep Sequencing.
- Authors
Kan, Hiromi; Imamura, Michio; Uchida, Takuro; Hiraga, Nobuhiko; Hayes, C Nelson; Tsuge, Masataka; Abe, Hiromi; Aikata, Hiroshi; Makokha, Grace Naswa; Chowdhury, Sajeda; Miki, Daiki; Ochi, Hidenori; Ishida, Yuji; Tateno, Chise; Chayama, Kazuaki
- Abstract
<bold>Background: </bold> 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.<bold>Methods: </bold> 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.<bold>Results: </bold> 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.<bold>Conclusions: </bold> 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.
- Subjects
PROTEASE inhibitors; NUCLEOTIDE sequence; CHRONIC hepatitis C; DISEASE susceptibility; GENETIC mutation; SOFOSBUVIR
- Publication
Journal of Infectious Diseases, 2016, Vol 214, Issue 11, p1687
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiw437