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Reply:

We enthusiastically agree with the conclusion of Galmozzi et al. that routine direct sequencing of HCV NS5A before starting daclatasvir (DCV) therapy is unnecessary. It is important to note that whereas E62D was detected as a baseline polymorphism in our study,1 we did not detect linkage of Q30R-E62D at baseline as claimed by Galmozzi et al.

In our study, the naturally occurring polymorphisms in the NS5A sequences derived from multiple GT-1a- and -1b-infected patients have no effect on the potency of DCV (Tables 1B, 2B, and 3 of ref. 1). This included the E62D polymorphism in subject P-derived GT-1a NS5A. Therefore, we concluded the following: “This study indicates that the heterogeneity of HCV sequences in infected specimens with no detectable level of previously identified resistant substitutions has a minimal effect on the potency of BMS-790052,…”.1

We also concluded that polymorphisms in the NS5A sequence at baseline can significantly affect which resistance variants emerge. We and others have demonstrated that multiple GT1a NS5A substitutions (Q30E/R, L31M/V, and Y93C/H/N) are selected in vitro and in the clinic with NS5A inhibitors, including DCV.2 In our article, we showed that there are 23 amino acid differences in NS5A derived from the baseline sequence of subject P and the lab strain, H77c. When H77c NS5A was replaced with the corresponding region derived from subject P, the only resistance substitution that emerged with DCV selection was Q30R; other resistance variants previously identified were not detected (Q30E, L31M/V, and Y93C/H/N). Further genetic analysis demonstrated that Q30R-E62D linkage was responsible for the high level of DCV resistance. The conclusion that NS5A baseline polymorphisms affect which resistance variants emerge after selection with DCV was further confirmed in a recent study.3

In summary, our data are in agreement with the recommendation by Galmozzi et al. that routine direct sequencing of HCV NS5A before starting DCV therapy is unnecessary.

References

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  • 1
    Sun J-H, O'Boyle DR, Zhang Y, Wang C, Nower P, Valera L, et al. Impact of a baseline polymorphism on the emergence of resistance to the hepatitis C virus nonstructural protein 5A replication complex inhibitor, BMS-790052. Hepatology 2012; 55: 16921699.
  • 2
    Fridell RA, Wang C, Sun J–H, O'Boyle DR, Nower P, Valera, L, et al. Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS–790052 in humans: in vitro and in vivo correlations. Hepatology 2011; 54: 19241935.
  • 3
    Wang C, Jia L, Huang H, Diu D, Valera L, Huang X, et al. In vitro activity of BMS–790052 on hepatitis C virus genotype 4 NS5A. Antimicrob Agents Chemother 2012; 56: 15881590.

Jin-Hua Sun M.SC.*, Min Gao PH.D.*, Susan Roberts PH.D.*, Robert Fridell PH.D.*, * Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, CT.