Data suggests that Sofosbuvir (SOF) has a high barrier to resistance; however, low frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic hepatitis C virus (HCV) infection.
Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for Sofosbuvir
Eric F. Donaldson*, Patrick R. Harrington, Julian J. O’Rear andLisa K. Naeger
Eric F. Donaldson*, Patrick R. Harrington, Julian J. O’Rear andLisa K. Naeger
DOI: 10.1002/hep.27375
Sofosbuvir (Sovaldi™, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) NS5B polymerase and inhibits viral replication. High sustained virologic response rates are achieved when SOF is used in combination with ribavirin with or without pegylated interferon in subjects with chronic HCV infection. Potential mechanisms of HCV resistance to SOF and other nucleos(t)ide analog NS5B polymerase inhibitors are not well understood. SOF was the first FDA-approved antiviral drug for which genotypic resistance analyses were based almost entirely on next generation sequencing (NGS), an emerging technology that lacks a standard data analysis pipeline. The FDA Division of Antiviral Products developed an NGS analysis pipeline and performed independent analyses of NGS data from 5 SOF clinical trials.
Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low frequency treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virologic failure were also noted and further evaluated.
The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modelled in NS5B crystal structures indicated that all 4 substitutions could feasibly impact SOF anti-HCV activity.
Conclusion: SOF has a high barrier to resistance; however, low frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection. (Hepatology 2014;)
Additionally, structural bioinformatics approaches were used to characterize potential resistance-associated substitutions. Using protocols we developed, independent analyses of the NGS data reproduced results that were comparable to those reported by Gilead Sciences, Inc. Low frequency treatment-emergent substitutions occurring at conserved NS5B amino acid positions in subjects who experienced virologic failure were also noted and further evaluated.
The NS5B substitutions, L159F (sometimes in combination with L320F or C316N) and V321A, emerged in 2.2-4.4% of subjects who failed SOF treatment across clinical trials. Moreover, baseline polymorphisms at position 316 were potentially associated with reduced response rates in HCV genotype 1b subjects. Analyses of these variants modelled in NS5B crystal structures indicated that all 4 substitutions could feasibly impact SOF anti-HCV activity.
Conclusion: SOF has a high barrier to resistance; however, low frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection. (Hepatology 2014;)
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