Journal article
Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials
Clinical infectious diseases, Vol.57(2), pp.221-229
07/15/2013
DOI: 10.1093/cid/cit226
PMID: 23575197
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.
Details
- Title: Subtitle
- Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials
- Creators
- James C. Sullivan - Vertex Pharmaceuticals (United States)Sandra De Meyer - Janssen (Belgium)Doug J. Bartels - Vertex Pharmaceuticals (United States)Inge Dierynck - Janssen (Belgium)Eileen Z. Zhang - Vertex Pharmaceuticals (United States)Joan Spanks - Vertex Pharmaceuticals (United States)Ann M. Tigges - Vertex Pharmaceuticals (United States)Anne Ghys - Janssen (Belgium)Jennifer Dorrian - Vertex Pharmaceuticals (United States)Nathalie Adda - Vertex Pharmaceuticals (United States)Emily C. Martin - Vertex Pharmaceuticals (United States)Maria Beumont - Janssen (Belgium)Ira M. Jacobson - Cornell UniversityKenneth E. Sherman - University of Cincinnati Medical CenterStefan Zeuzem - Goethe University FrankfurtGaston Picchio - Janssen (United States)Tara L. Kieffer - Vertex Pharmaceuticals (United States)
- Resource Type
- Journal article
- Publication Details
- Clinical infectious diseases, Vol.57(2), pp.221-229
- DOI
- 10.1093/cid/cit226
- PMID
- 23575197
- NLM abbreviation
- Clin Infect Dis
- ISSN
- 1058-4838
- eISSN
- 1537-6591
- Publisher
- Oxford Univ Press
- Number of pages
- 9
- Grant note
- Janssen Pharmaceuticals (Titusville, New Jersey) Vertex Pharmaceuticals Incorporated (Cambridge, Massachusetts); Vertex Pharmaceuticals
- Language
- English
- Date published
- 07/15/2013
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984284343402771
Metrics
8 Record Views