1. Pre-existing minor variants with NS5A L31M/V-Y93H double substitution are closely linked to virologic failure with asunaprevir plus daclatasvir treatment for genotype 1b hepatitis C virus infection.
- Author
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Morishita N, Sakamori R, Yamada T, Kai Y, Tahata Y, Urabe A, Yamada R, Kodama T, Hikita H, Doi Y, Tamura S, Hagiwara H, Imai Y, Iio S, Tatsumi T, and Takehara T
- Subjects
- Aged, Carbamates, Case-Control Studies, Drug Resistance, Viral genetics, Drug Therapy, Combination, Female, Genotype, Hepacivirus isolation & purification, Hepatitis C virology, Humans, Male, Mutation, Pyrrolidines, Sustained Virologic Response, Treatment Failure, Valine analogs & derivatives, Antiviral Agents therapeutic use, Hepacivirus genetics, Hepatitis C drug therapy, Imidazoles therapeutic use, Isoquinolines therapeutic use, Sulfonamides therapeutic use, Viral Nonstructural Proteins genetics
- Abstract
Background: L31 and Y93 in the NS5A region of the hepatitis C virus (HCV) are the most important substitution positions associated with resistance to direct-acting antiviral (DAA) treatment., Methods: We analyzed the frequency of NS5A L31M/V and Y93/H in NS5A inhibitor-naive HCV genotype 1 patients who received asunaprevir plus daclatasvir combination treatment using a conventional sequencing method and a deep sequencing method that can distinguish a single substitution at either position and a double substitution at both positions with a 0.1% detection threshold., Results: The frequency of substitutions at both sites using the conventional method was very low, with 1 in 14 non-responders and 0 in 42 randomly selected responder patients. On the other hand, for the deep sequencing method, cases with double substitutions in the tandem sequence were detected in 8/14 non-responders and 1/42 responders (p<0.0001). For the conventional method, substitutions were detected at any position in 6/14 non-responders and 2/42 responders (p = 0.0019), with a clear difference between the two groups. The difference was also clear with the deep sequencing method, with 11/14 non-responders and 8/42 responders. Interestingly, for the deep sequencing method, the single substitution of L31 was found in 6/14 non-responders and 7/42 responders, whereas single substitutions of Y93 or double substitutions were found in 7/14 vs. 1/42 and 8/14 vs. 1/42 patients, respectively., Conclusions: NS5A L31 and Y93 substitutions were detected in tandem by the deep sequencing methods in several genotype 1 patients, who may be more resistant to DAA treatment containing an NS5A inhibitor., Competing Interests: This study is partially supported by grants from Gilead Sciences, Inc., Janssen Pharmaceutical K. K., and a Grant-in-Aid for Research on Hepatitis from the Ministry of Health, Labour and Welfare of Japan and the Japan Agency for Medical Research and Development (JP18fk0210021, T.T., R.S. and H.H.; JP18fk0210025, R.S.). Gilead Sciences, Inc. does not alter our adherence to PLOS ONE policies on sharing data and materials. Professor Tetsuo Takehara received grants from Bristol-Myers Squibb and is on the speakers’ bureau for Bristol-Myers Squibb. All other authors declare that they have no conflicts of interest to disclose. Bristol-Myers Squibb does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2020
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