Evolution and persistence of resistance‐associated substitutions of hepatitis C virus after direct‐acting antiviral treatment failures

Summary Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all‐oral direct‐acting antiviral (DAA) therapy for the genotype 1b HCV‐infected patients. In this study, we investigated how resistance‐associated substitutions (RASs) evolved after treatment failures and assessed the effect of those sub...

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Bibliographic Details
Published in:Journal of viral hepatitis 2018-11, Vol.25 (11), p.1251-1259
Main Authors: Jeong, Y., Jin, B., Lee, H. W., Park, H. J., Park, J. Y., Kim, D. Y., Han, K.‐H., Ahn, S. H., Kim, S.
Format: Article
Language:English
Subjects:
Amino acids
Antiviral drugs
asunaprevir
Complementation
daclatasvir
Disease resistance
Genotypes
Hepatitis C
hepatitis C virus
Replication
Reproductive fitness
resistance‐associated substitution
Ribonucleic acid
RNA
RNA viruses
Transfection
viral fitness
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Summary:Summary Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all‐oral direct‐acting antiviral (DAA) therapy for the genotype 1b HCV‐infected patients. In this study, we investigated how resistance‐associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild‐type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans‐complementation of NS5A was demonstrated in our co‐transfection experiments and these results suggest that such a trans‐complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs.
ISSN:1352-0504
1365-2893
DOI:10.1111/jvh.12932