title: Mutations selected in the hepatitis C virus NS3 protease domain during sequential treatment with boceprevir with and without pegylated interferon alfa-2b.
abstract: Treatment with hepatitis C virus (HCV)-NS3-protease inhibitors lead to the selection of resistant variants. Viral kinetics and resistance profiles in patients who are re-treated with the same protease inhibitor are unknown. Viral kinetics and NS3-resistance mutations obtained by clonal sequencing of the NS3-protease were analyzed in nine HCV-genotype-1-infected nonresponder patients who were sequentially treated with boceprevir (400 mg t.i.d.) for 1 week, peginterferon-alfa-2b for 2 weeks and combination of the two for 2 weeks in varying order. In addition to predominant wild-type isolates, previously described boceprevir-resistant mutations (V36, T54, R155, A156, V170) were observed. Furthermore, two resistant mutations (Q41, F43) were detected for the first time in vivo. In three patients, mutations selected after initial treatment with boceprevir were re-selected during subsequent boceprevir exposure. However, mutational patterns after the first and second exposure to boceprevir were different in five patients. In one patient, a viral variant (V55A) known to reduce susceptibility to boceprevir was the predominant variant observed at baseline and throughout treatment and was associated with a shallow viral decline. Different resistance mutations were selected during treatment with boceprevir ± peginterferon. Sequential short-term dosing of boceprevir was not associated with accumulation of resistant variants but pre-existing variants may impair virologic response.
authors.affiliation: Medizinische Klinik 1, Klinikum der J W Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Vermehren
authors.forename: S
authors.initials: S
authors.lastname: Susser
authors.forename: C M
authors.initials: CM
authors.lastname: Lange
authors.forename: N
authors.initials: N
authors.lastname: Forestier
authors.forename: U
authors.initials: U
authors.lastname: Karey
authors.forename: E
authors.initials: E
authors.lastname: Hughes
authors.forename: R
authors.initials: R
authors.lastname: Ralston
authors.forename: X
authors.initials: X
authors.lastname: Tong
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
authors.forename: C
authors.initials: C
authors.lastname: Sarrazin
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage; D004359:Drug Therapy, Combination / Q000379:methods; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D020125:Mutation, Missense; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011994:Recombinant Proteins / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011392:Proline; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C417083:peginterferon alfa-2b