title: Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials.
abstract: BACKGROUND
  Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A protease inhibitor, has been approved to treat genotype 1 HCV. To understand the clinical impact of TVR-resistant variants, we analyzed samples from patients in phase 3 clinical trials to determine the frequency and retention of TVR-resistant variants in patients who did not achieve sustained virologic response (SVR).
  
  
  METHODS
  A total of 1797 patients were treated with TVR. Resistant variants (V36A/G/I/L/M, T54A/S, I132V [subtype 1a only], R155G/K/T/M, A156F/N/S/T/V, and D168N) were identified after treatment failure and at visits thereafter, by direct (population) sequencing of the NS3/4A region. Kaplan-Meier analysis was used to determine median time to loss of these variants.
  
  
  RESULTS
  Resistant variants were observed in 77% (299/388) of patients who did not achieve SVR. Resistance occurred more commonly in subtype 1a (86%; 232/269) than subtype 1b infections (56%; 67/119). After treatment failure, 355 patients had at least 1 follow-up visit (median follow-up period: 9.6 months). Of patients with resistance at time of failure and at least 1 follow-up visit, 60% (153/254) lost resistance. Kaplan-Meier analysis, including all patients with any sequence data after treatment failure, indicated that median time to wild type was 10.6 months (95% confidence interval [CI], 9.47-12.20) in subtype 1a and 0.9 months (95% CI, 0.00-2.07) in subtype 1b infections.
  
  
  CONCLUSIONS
  After failure to achieve SVR with TVR-based treatment, resistant variants are observed in most patients. However, presumably due to the lower fitness of those variants, they tend to be replaced with wild-type virus over time.
authors.affiliation: Vertex Pharmaceuticals, Cambridge, MA 02139, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bartels
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Joan
authors.initials: J
authors.lastname: Spanks
authors.forename: Ann M
authors.initials: AM
authors.lastname: Tigges
authors.forename: Anne
authors.initials: A
authors.lastname: Ghys
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dorrian
authors.forename: Nathalie
authors.initials: N
authors.lastname: Adda
authors.forename: Emily C
authors.initials: EC
authors.lastname: Martin
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Sherman
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D059645:Mutation Rate; D020125:Mutation, Missense; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; 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; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C486464:telaprevir
keywords: DAA; clinical viral fitness; hepatitis C virus