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- Title
Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials.
- Authors
Sullivan, James C.; De Meyer, Sandra; Bartels, Doug J.; Dierynck, Inge; Zhang, Eileen Z.; Spanks, Joan; Tigges, Ann M.; Ghys, Anne; Dorrian, Jennifer; Adda, Nathalie; Martin, Emily C.; Beumont, Maria; Jacobson, Ira M.; Sherman, Kenneth E.; Zeuzem, Stefan; Picchio, Gaston; Kieffer, Tara L.
- Abstract
In phase 3 trials of telaprevir, 77% of patients who did not achieve sustained virologic response had resistant variants. Most populations lost resistance thereafter. For hepatitis C virus genotypes 1a and 1b, median times to wild type were approximately 11 months and 1 month, respectively.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.
- Subjects
HEPATITIS C treatment; TELAPREVIR; DRUG resistance; CLINICAL trials; VIROLOGY; PROTEASE inhibitors; MEDICAL errors
- Publication
Clinical Infectious Diseases, 2013, Vol 57, Issue 2, p221
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1093/cid/cit226