Pre-existing, treatment-specific resistance-associated substitutions in hepatitis C virus genotype 1 and 3 and viral RNA titers during treatment with direct-acting antivirals

Christina Sølund, Martin S. Pedersen, Ulrik Fahnøe, Jonathan Filskov, Håvard Jenssen, Nina Weis, Kristian Schønning, Jens Bukh*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The introduction of direct-acting antiviral (DAA) treatment of hepatitis C virus (HCV) infected patients has greatly increased treatment success rates. However, viral response kinetics to DAA treatment may depend on pre-existing resistance-associated substitutions (RASs) in HCV. The aim of this study was to describe how pre-existing RASs affect DAA treatment-induced reduction in HCV RNA titers in HCV genotypes 1- and 3-infected individuals. Patients with HCV genotype 1 infection (N = 31) treated with either sofosbuvir/ledipasvir/ribavirin or paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin and HCV genotype 3-infected patients (N = 16) treated with either sofosbuvir/daclatasvir/ribavirin or sofosbuvir/ribavirin were analyzed. HCV RNA levels were determined at baseline and frequently during treatment, and RAS profiles were obtained by deep sequencing at baseline. In total, 33/47 (70.2%) of the patients had baseline RASs. However, treatment-specific RASs were detected at baseline only in 12.9% and 18.8% of HCV genotypes 1- and 3-infected patients, respectively. In genotype 1-infected individuals, reduction in HCV RNA titer during the first week of treatment was not affected by evidence of either treatment-specific RASs or cirrhosis or treatment regimen. In genotype 3-infected individuals receiving sofosbuvir/daclatasvir/ribavirin, the presence of daclatasvir-specific NS5A RASs at baseline correlated with a reduced decline of HCV RNA in the first treatment week. For both genotypes 1- and 3-infected individuals, cirrhosis but not treatment-specific RAS were associated with the time of clearance of HCV RNA. It is, however, important to note that this study involves DAA regimens that were used only during the original introduction of interferon-free DAA-based treatments.

Original languageEnglish
Book seriesAPMIS
Volume131
Issue number8
Pages (from-to)426-433
Number of pages8
ISSN0903-4641
DOIs
Publication statusPublished - Aug 2023

Bibliographical note

Funding Information:
This study was supported by a Ph.D. stipend from Roskilde University [M.S.P.], and by grants from The A.P. Møller Foundation for the Advancement of Medical Science [K.S.], The Capital Region of Denmark's Research Foundation [C.S, J.B.], The Innovation Fund Denmark [J.B.], The Novo Nordisk Foundation [N.W., J.B.], and The Independent Research Fund Denmark [J.B.].

Keywords

  • clearance
  • direct-acting antiviral therapy
  • Hepatitis C virus
  • resistance-associated substitutions
  • sofosbuvir
  • viral kinetics

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