Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome

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  • Ulrik Fahnøe, Københavns Universitet
  • ,
  • Martin S. Pedersen, Københavns Universitet, Roskilde University
  • ,
  • Christina Sølund, Københavns Universitet
  • ,
  • Anja Ernst, Aalborg Universitet
  • ,
  • Henrik B. Krarup, Aalborg Universitet
  • ,
  • Birgit T. Røge, Lillebaelt Hospital – University Hospital of Southern Denmark
  • ,
  • Peer B. Christensen, Syddansk Universitet
  • ,
  • Alex L. Laursen
  • Jan Gerstoft, Københavns Universitet
  • ,
  • Peter Thielsen, Københavns Universitet
  • ,
  • Lone G. Madsen, Københavns Universitet, Sjællands Universitetshospital
  • ,
  • Anders G. Pedersen, Danmarks Tekniske Universitet
  • ,
  • Kristian Schønning, Københavns Universitet
  • ,
  • Nina Weis, Københavns Universitet
  • ,
  • Jens Bukh, Københavns Universitet

Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p =.0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.

OriginalsprogEngelsk
TidsskriftJournal of Viral Hepatitis
Vol/bind28
Nummer2
Sider (fra-til)302-316
Antal sider15
ISSN1352-0504
DOI
StatusUdgivet - feb. 2021

Bibliografisk note

Funding Information:
We thank the patients who are enrolled in DANHEP for their participation and the staff at the participating clinical departments for their continuous support collecting blood samples and recording data in DANHEP. We thank all members of the DANHEP group for their contributions. Thanks to laboratory technician Anna‐Louise Sørensen, Hvidovre Hospital, for sample collection. We thank Bjarne Ørskov Lindhardt and Christian Østergaard Andersen (Hvidovre Hospital) and Carsten Geisler (University of Copenhagen) for their support of these studies. This work was supported by PhD stipends from Faculty of Health and Medical Sciences, University of Copenhagen [CS and JB], Hvidovre Hospital Research Foundation [CS and MP] and Roskilde University [MP], and by grants from the Weimann Foundation [UF], the Danish Cancer Society [UF], The Capital Region of Denmark's Research Foundation [JB], the Innovation Fund Denmark [JB], the Novo Nordisk Foundation [JB], and the Independent Research Fund Denmark [NW, JB], including an advanced Sapere Aude grant [JB]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2020 John Wiley & Sons Ltd

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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