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Hepatitis C virus (HCV) NS5A replication complex inhibitors (RCIs) have been shown to exhibit picomolar antiviral activity against genotype 1 (GT1) in vitro. This has translated into rapid and robust declines in HCV RNA in GT1 patients. Less is known about the susceptibility of other genotypes such as GT3 to inhibition by NS5A RCIs.
To detect and phenotype naturally occurring HCVGT3 NS5A polymorphisms against two NS5A RCIs (daclatasvir [DCV] and GS-5885) currently in clinical development.
The NS5A region from 96 HCV GT3 treatment-naive patients spanning North America, Europe and Australia was determined.
Phylogenetic analysis revealed a broad distribution with no significant geographic clustering. GT1 DCV resistance-associated variants (RAVs) were observed in GT3 subjects; variants (and their frequencies) included 28M/V (1%), 30A/K/S/T/V (10%), 31L/M (1%), E92A (1%) and Y93H (8.3%). A consensus sequence was used to generate a JFH1/3a-NS5A hybrid replicon and employed to assess susceptibility to NS5A RCIs. Against JFH1/3a-NS5A, DCV was more potent (EC(50)=0.52nM) than GS-5885 (EC(50)=141nM). DCV sensitivity was increased against JFH1/3a-NS5A-M28V (EC(50)=0.006nM), A30V (EC(50)=0.012nM), and E92A (EC(50)=0.004nM) while the NS5A-A30K and -Y93H variants exhibited reduced sensitivity to DCV (EC(50) values of 23nM and 1120nM, respectively) and to GS-5885 (EC(50) values of 1770nM and 4300nM, respectively).
Substitutions conferring resistance to NS5A RCIs pre-existed in treatment-naive patients infected with HCV GT3. The effectiveness of these NS5A RCIs to exert efficacy in the clinic may depend on which inhibitor is used in combination with other antivirals.