title: Identification of the NS5B S282T resistant variant and two novel amino acid substitutions that affect replication capacity in hepatitis C virus-infected patients treated with mericitabine and danoprevir.
abstract: Baseline and posttreatment samples from hepatitis C virus (HCV) genotype (GT) 1-infected patients who received a combination of danoprevir and mericitabine from a phase II clinical study (INFORM-SVR) were analyzed. In addition to resistance monitoring, sequencing and phenotypic assays were combined with statistical analysis to identify potential novel amino acid substitutions associated with treatment outcome. The NS5B S282T substitution associated with mericitabine resistance was identified in 2/30 viral breakthrough patients and was replaced by wild-type viruses after cessation of drug treatment (during follow-up). The NS3 R155K substitution associated with danoprevir resistance was also observed in these 2 patients. All 69 GT 1a-infected patients who experienced viral breakthrough on treatment or relapsed during follow-up (relapsers) developed NS3 R155K. Among GT 1b-infected patients, substitutions at the danoprevir resistance locus NS3 D168 were observed in 15/20 subjects, whereas substitutions at the danoprevir resistance locus NS3 R155 were observed in 5/20 subjects. Interestingly, the baseline polymorphism NS5B Q47H was more prevalent in GT 1a-infected patients who achieved a sustained virologic response at follow-up week 24 (SVR24) than in non-SVR24 patients (2/13 versus 0/72), and a postbaseline NS3 S122G substitution was more prevalent in GT 1a-infected patients with viral breakthrough than in relapsers (4/22 versus 0/47). Neither substitution conferred resistance to danoprevir or mericitabine, but the substitutions reduced (NS5B Q47H) or improved (NS3 S122G) replication capacity by 2- to 4-fold. The NS5B S282T mericitabine-resistant variant was rare and did not persist once drug was discontinued. NS5B Q47H and NS3 S122G are two newly identified substitutions that affected replication capacity and were enriched in distinct treatment response groups. (This study has been registered at ClinicalTrials.gov under registration no. NCT01278134.).
authors.affiliation: Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.affiliation: Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA.
authors.forename: Lewyn
authors.initials: L
authors.lastname: Li
authors.affiliation: Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Haines
authors.affiliation: Infectious Diseases Discovery, Hoffmann-La Roche, Nutley, New Jersey, USA isabel.najera@roche.com.
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D003521:Cyclopropanes; D004261:DNA Replication / Q000187:drug effects*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C552098:2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine; D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D003841:Deoxycytidine; C553752:danoprevir; D011392:Proline