In Vivo Emergence of a Novel Mutant L159F/L320F in the NS5B Polymerase Confers Low-Level Resistance to the HCV Polymerase Inhibitors Mericitabine and Sofosbuvir

• Published in: The Journal of infectious diseases 2014-03, Vol.209 (5), p.668-675
• Main Authors: Tong, Xiao, Le Pogam, Sophie, Li, Lewyn, Haines, Kristin, Piso, Katherine, Baronas, Victoria, Yan, Jun-Mei, So, Sung-Sau, Klumpp, Klaus, Nájera, Isabel
• Format: Article
• Language: English
• Subjects: Amino acids; Antiviral Agents - therapeutic use; Antivirals; Biological and medical sciences; Clinical trials; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Drug Resistance, Viral - drug effects; Drug Resistance, Viral - genetics; Drug Therapy, Combination - methods; Fundamental and applied biological sciences. Psychology; Genetic mutation; Genotype; Genotypes; Hepacivirus; Hepacivirus - drug effects; Hepacivirus - genetics; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; Humans; Infections; Infectious diseases; Interferon-alpha - therapeutic use; Medical sciences; Microbiology; Miscellaneous; Mutation - drug effects; Mutation - genetics; Nucleosides; Polyethylene Glycols - therapeutic use; Recombinant Proteins - therapeutic use; Replicon; Replicon - drug effects; Replicon - genetics; Ribavirin - therapeutic use; RNA; RNA, Viral - blood; RNA, Viral - drug effects; RNA, Viral - genetics; Sofosbuvir; Uridine Monophosphate - analogs & derivatives; Uridine Monophosphate - therapeutic use; Viral Nonstructural Proteins - antagonists & inhibitors; Virology; VIRUSES
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit562

Background. Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation. Methods. Serum HCV RNA from patients who experienced viral breakthrough, partial response, or nonresponse in 2 clinical trials in which patients received mericitabine plus peginterferon alfa-2a (40KD)/ribavirin were analyzed by population and donai sequence analysis as well as phenotypic assay for assessment of in vivo mericitabine resistance. Results. Among 405 patients treated with mericitabine plus peginterferon alfa-2a/ribavirin in PROPEL and JUMP-C, virologie breakthrough or nonresponse were not observed; 12 patients experienced a partial response. The NS5B S282T resistance mutation was not observed in any patient. A number of treatment-associated NS5B changes were observed and characterized. A novel double mutant (L159F/L320F) with impaired replication capacity was detected in one HCV genotype 1b-infected patient. Introduction of double mutant L159F/L320F into genotype la (H77) and 1b (Con-1) replicons, respectively, increased the EC₅₀ for mericitabine by 3.1- and 5.5-fold and the EC₉₀ by 3.1-and 8.9-fold. The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and GS-938 but not setrobuvir, relative to wild-type. Conclusions. A novel and replication-deficient double mutation (L159F/L320F) confers low-level resistance to mericitabine and cross-resistance to both sofosbuvir and GS-938.