title: Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor.
abstract: Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: de Bruijne
authors.forename: X V
authors.initials: XV
authors.lastname: Thomas
authors.forename: S P
authors.initials: SP
authors.lastname: Rebers
authors.forename: C J
authors.initials: CJ
authors.lastname: Weegink
authors.forename: M A
authors.initials: MA
authors.lastname: Treitel
authors.forename: E
authors.initials: E
authors.lastname: Hughes
authors.forename: J F
authors.initials: JF
authors.lastname: Bergmann
authors.forename: R J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: H L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: H W
authors.initials: HW
authors.lastname: Reesink
authors.forename: R
authors.initials: R
authors.lastname: Molenkamp
authors.forename: J
authors.initials: J
authors.lastname: Schinkel
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D003521:Cyclopropanes; D004151:Dipeptides / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000379:methods; D019143:Evolution, Molecular; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007930:Leucine / Q000031:analogs & derivatives; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D013450:Sulfones / Q000627:therapeutic use*; D014508:Urea; D019562:Viral Load; 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; D003521:Cyclopropanes; D004151:Dipeptides; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007930:Leucine; D011092:Polyethylene Glycols; D011392:Proline; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012254:Ribavirin; D013450:Sulfones; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C552043:narlaprevir; C417083:peginterferon alfa-2b
keywords: HCV viral load; NS3 protease; clonal analysis; mutations; narlaprevir; protease inhibitor