ArticleInfection and drug resistance2018
Characterization of hepatitis C virus resistance to grazoprevir reveals complex patterns of mutations following on-treatment breakthrough that are not observed at relapse.
Article in Infection and drug resistance, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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Who cites it
5 citing papers in PubMed, 7 citations in OpenAlex.
- Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus.Current medicinal chemistry · 2024Article
- Accelerating antiviral drug discovery: lessons from COVID-19.Nature reviews. Drug discovery · 2023Review
- Viral proteases: Structure, mechanism and inhibition.The Enzymes · 2021Article
- Detection of low-level HCV variants in DAA treated patients: comparison amongst three different NGS data analysis protocols.Virology journal · 2020Article
- Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
purposeA detailed analysis of hepatitis C virus (HCV) resistance-associated substitutions (RASs) is required to understand why people fail direct-acting antiviral therapies. This study was conducted to assess RASs in an analysis of 2 trials evaluating the second-generation NS3/4A protease inhibitor grazoprevir (GZR) in combination with peginterferon/ribavirin. PATIENTS AND
methodsFrom a total of 113 participants with HCV genotype 1 infection, RASs were evaluated in 25 patients who relapsed and 6 patients with on-treatment virologic breakthrough using consensus Sanger and clonal sequence analysis of NS3/NS4a genes, with in vitro testing of replicon mutants. Next-generation sequencing (NGS) was used in a subset of participants to assess minority variants and the evolution of the whole viral genome.
resultsBaseline RASs did not predict treatment failure. Relapse was most commonly associated with RASs at D168, although additional RASs (Y56, R155 and A156) were also detected, particularly in participants with on-treatment breakthrough. Treatment-emergent RASs usually reverted to wild-type (WT), suggesting these mutations were associated with a negative fitness cost (confirmed using in vitro assays). NGS was the most sensitive assay for the detection of minor variants. Significant viral sequence divergence (up to 5.9% codons) was observed across whole genomes in association with the acquisition and reversion of RASs.
conclusionRelapse with GZR and peginterferon/ribavirin is commonly associated with single RASs in NS3 that generally revert to WT, while breakthrough follows more complex patterns of viral resistance. NGS suggests that large diverse pools of viral quasispecies that emerge with RASs facilitate rapid viral evolution.
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