Details

Autor(en) / Beteiligte

• 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.

Titel

Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials

Ist Teil von

• Clinical infectious diseases, 2013-07, Vol.57 (2), p.221-229

Ort / Verlag

Oxford: Oxford University Press

Erscheinungsjahr

2013

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.