Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir

摘要: Sofosbuvir (Sovaldi, SOF) is a nucleotide analog prodrug that targets the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase and inhibits viral replication. High sustained virological response rates are achieved when SOF used in combination with ribavirin or without pegylated interferon subjects chronic HCV infection. Potential mechanisms of resistance to other nucleos(t)ide NS5B inhibitors not well understood. was first U.S. Food Drug Administration (FDA)-approved antiviral drug for which genotypic analyses were based almost entirely on next-generation sequencing (NGS), an emerging technology lacks standard data analysis pipeline. The FDA Division Antiviral Products developed NGS pipeline performed independent from five clinical trials. Additionally, structural bioinformatics approaches characterize potential resistance-associated substitutions. Using protocols we developed, reproduced results comparable those reported by Gilead Sciences, Inc. Low-frequency, treatment-emergent substitutions occurring at conserved amino acid positions who experienced failure also noted further evaluated. substitutions, L159F (sometimes L320F C316N) V321A, emerged 2.2%-4.4% failed treatment across Moreover, baseline polymorphisms position 316 potentially associated reduced genotype 1b subjects. Analyses these variants modeled crystal structures indicated all four could feasibly affect anti-HCV activity. Conclusion: has high barrier resistance; however, low-frequency identified may contribute this important (Hepatology 2015;61:56–65)