Long term persistence of NS5A inhibitor‐resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy

Publisher： John Wiley & Sons Inc

E-ISSN： 1096-9071|87|11|1913-1920

ISSN： 0146-6615

Source： JOURNAL OF MEDICAL VIROLOGY, Vol.87, Iss.11, 2015-11, pp. : 1913-1920

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Abstract

Although interferon‐free antiviral treatment is expected to improve treatment of hepatitis C, it is unclear to what extent pre‐existing drug‐resistant amino acid substitutions influence response to therapy. The impact of pre‐existing drug‐resistant substitutions on virological response to daclatasvir and asunaprevir combination therapy was studied in genotype 1b hepatitis C virus (HCV)‐infected patients. Thirty‐one patients were treated with daclatasvir and asunaprevir for 24 weeks. Twenty‐six patients achieved sustained virological response (SVR), three patients experienced viral breakthrough, and two patients relapsed. Direct sequencing analysis of HCV showed the existence of daclatasvir‐resistant NS5A‐L31M or ‐Y93H/F variants in nine out of 30 patients (30%) prior to treatment, while asunaprevir‐resistant NS3‐D168 mutations were not detected in any patient. All 21 patients with wild‐type NS5A‐L31 and ‐Y93 achieved SVR, whereas only four out of nine patients (44%) with L31M or Y93F/H substitutions achieved SVR (P = 0.001). Ultra‐deep sequencing analysis showed that treatment failure was associated with the emergence of both NS5A‐L31/Y93 and NS3‐D168 variants. NS5A‐L31/Y93 variants remained at high frequency through post‐treatment weeks 103 through 170, while NS3‐D168 variants were replaced by wild‐type in all patients. In conclusion, pre‐existence of NS5A inhibitor‐resistant substitutions compromised the response to daclatasvir and asunaprevir combination therapy, and treatment failure was associated with the emergence of both NS5A‐L31/Y93 and NS3‐D168 variants. While asunaprevir‐resistant variants that emerged during therapy returned to wild‐type, daclatasvir‐resistant variants tended to persist in the absence of the drug. J. Med. Virol. 87:1913–1920, 2015. © 2015 Wiley Periodicals, Inc.