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J Viral Hepat. 2018 Nov;25(11):1251-1259. doi: 10.1111/jvh.12932. Epub 2018 Jun 13.

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

Jeong Y1,2, Jin B1,2, Lee HW2,3, Park HJ2, Park JY2,3, Kim DY2,3, Han KH1,2,3,4, Ahn SH1,2,3, Kim S2,3,4,5.

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Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Yonsei Liver Center, Severance Hospital, Seoul, Korea.
Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, Korea.


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.


asunaprevir; daclatasvir; hepatitis C virus; resistance-associated substitution; viral fitness


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