A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir.

Guilherme Rodrigues Fernandes Campos,Cintia Bittar,Paula Rahal,Shucheng Chen,Ana De Lourdes Candolo Martinelli,Leonardo Régis Leira Pereira,Mark Harris,Fernanda Fernandes Souza,Joseph Ward,João Paulo Vilela Rodrigues

doi:10.1099/jgv.0.001496

Abstract

Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.

Highlights

Hepatitis C virus (HCV) currently infects an estimated total of 70 million individuals worldwide
This study focused on resistance to the NS5A-targeting direct-acting antivirals (DAAs) daclatasvir (DCV) with a view to characterizing the substitutions associated with treatment failure in GT3-infected patients
Identification of a novel substitution in NS5A from patients who relapsed after DAA therapy his study analysed a cohort of 82 patients infected with HCV genotype 3 who were treated with a combination of sofosbuvir (SOF: NS5B inhibitor) and daclatasvir (DCV: NS5A inhibitor) for a period of 12 weeks

Summary

Introduction

Hepatitis C virus (HCV) currently infects an estimated total of 70 million individuals worldwide. He variability of the virus results from a lack of proofreading activity of the viral RNA-dependent RNA polymerase (NS5B) and importantly enables the emergence of mutations that can lead to evasion of both the immune response and antiviral treatments. He development of direct-acting antivirals (DAAs) has revolutionized the treatment of HCV infection. Resistance is invariably linked to the presence of resistance-associated substitutions (RASs) These substitutions can be found and in high frequency ater treatment failure, but in some cases they can be detected pre-treatment and rapidly increase in frequency due to the selective pressure of DAAs. Since the circulation of these pre-existing substitutions can impact on the eicacy of antiviral treatment, studying the phenotype of these substitutions with regard to DAA resistance and viral itness is important to understand DAA failure

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Conclusion