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Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir‐containing regimens without sofosbuvir
Author(s) -
Kitrinos K. M.,
Corsa A. C.,
Worth A.,
Hedskog C.,
Brainard D. M.,
Miller M. D.,
Mo H.
Publication year - 2018
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12783
Subject(s) - ledipasvir , sofosbuvir , ribavirin , ns5a , medicine , hepatitis c virus , gastroenterology , pegylated interferon , virology , hepatitis c , population , genotype , hepacivirus , virus , biology , gene , environmental health , biochemistry
Summary The study aimed to evaluate the effects of baseline hepatitis C virus ( HCV ) nonstructural protein 5A (NS5A) resistance‐associated substitutions ( RAS s) on sustained virologic response to ledipasvir ( LDV )‐containing regimens in the absence of sofosbuvir ( SOF ) in patients with HCV genotype ( GT ) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir ( NS 3 protease inhibitor ) + tegobuvir ( NS 5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS 5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT 1a, and 298 (26.9%) had GT 1b infection. The overall prevalence of NS 5A RAS s at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT 1a and GT 1b infection, respectively. The majority of GT 1a‐infected patients with NS 5A RAS s at baseline had a single NS 5A RAS (78.9%) at NS 5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS 5A RAS s detected in GT 1b patients was much less diverse compared to GT 1a patients, with all patients harbouring a single NS 5A RAS either L31M or Y93H/C. For patients treated with LDV ‐containing regimens in the absence of SOF , the presence of baseline NS 5A RAS s was associated with low SVR rates. In patients with virologic failure, nearly all had either pre‐existing and/or emergent NS 5A RAS s: 287/287 (100%) and 40/42 (95.2%) patients with GT 1a and GT 1b infection, respectively. Three novel NS 5A substitutions were identified as emergent NS 5A RAS s: K26E and S38F in GT 1a; and L31I in GT 1b. In conclusion, the presence of NS 5A RAS s at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS 5A RAS s in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAA s.