%0 Journal Article
%T Evaluation of Persistence of Resistant Variants with Ultra-Deep Pyrosequencing in Chronic Hepatitis C Patients Treated with Telaprevir
%A Xiomara V. Thomas
%A Joep de Bruijne
%A James C. Sullivan
%A Tara L. Kieffer
%A Cynthia K. Y. Ho
%A Sjoerd P. Rebers
%A Michel de Vries
%A Hendrik W. Reesink
%A Christine J. Weegink
%A Richard Molenkamp
%A Janke Schinkel
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0041191
%X Background & Aims Telaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. It is unclear to what extent these variants persist in untreated patients. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment. Methods Fifteen patients from 2 previous telaprevir phase 1 clinical studies (VX04-950-101 and VX05-950-103) were included. These patients all received telaprevir monotherapy for 14 days, and 2 patients subsequently received standard of care. Variants at previously well-characterized NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4¡À1.2 years by ultra-deep pyrosequencing. The prevalence of resistant variants at follow-up was compared to baseline. Results Resistance associated mutations were detectable at low frequency at baseline. In general, prevalence of resistance mutations at follow-up was not increased compared to baseline. Only one patient had a small, but statistically significant, increase in the number of V36M and T54S variants 4 years after telaprevir-dosing. Conclusion In patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that long-term persistence of resistant variants is rare.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041191