Amino acid substitutions associated with treatment failure of hepatitis C virus infection

Soria, M. E.; Garcia-Crespo, C.; Martinez-Gonzalez, B.; Vazquez-Sirvent, L.; Lobo-Vega, R.; de Avila, A. I.; Gallego, I.; Chen, Q.; Garcia-Cehic, D.; Llorens-Revull, M.; Briones, C.; Gomez, J.; Ferrer-Orta, C.; Verdaguer, N.; Gregori, J.; Rodriguez-Frias, F.; Buti, M.; Esteban, J. I.; Domingo, E.; Quer, J.; Perales, C.

doi:10.1101/2020.07.03.180240

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bioRxiv · 10.1101/2020.07.03.180240

Amino acid substitutions associated with treatment failure of hepatitis C virus infection

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Abstract

Despite the high virological response rates achieved with current directly-acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. Identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultra-deep sequencing (UDS) methods for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV from 220 patients who failed therapy, which are not bona fide resistance-associated substitutions (RAS). They were present frequently in basal and post-treatment virus of patients who failed therapy to different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Coherently, their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. Also, they have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value of treatment response are discussed.

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Soria, M. E., Garcia-Crespo, C., Martinez-Gonzalez, B., Vazquez-Sirvent, L., Lobo-Vega, R., de Avila, A. I., Gallego, I., Chen, Q., Garcia-Cehic, D., Llorens-Revull, M., Briones, C., Gomez, J., Ferrer-Orta, C., Verdaguer, N., Gregori, J., Rodriguez-Frias, F., Buti, M., Esteban, J. I., Domingo, E., Quer, J., Perales, C.. 2020-07-03. Amino acid substitutions associated with treatment failure of hepatitis C virus infection. https://doi.org/10.1101/2020.07.03.180240

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