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22848441
Evaluation of persistence of resistant variants with ultra-deep pyrosequencing in chronic hepatitis C patients treated with telaprevir.

PLoS One, 2012;7(7):e41191.

Thomas XV[1], de Bruijne J, Sullivan JC, Kieffer TL, Ho CK, Rebers SP, de Vries M, Reesink HW, Weegink CJ, Molenkamp R, Schinkel J

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PMID: 22848441DOI: 10.1371/journal.pone.0041191

Impact factor: 3.752

Abstract
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±1.2 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.
MeSH terms
Adult; Amino Acid Substitution; DNA Mutational Analysis; Drug Resistance, Viral; Female; Follow-Up Studies; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Mutation, Missense; Oligopeptides; Time Factors; Viral Nonstructural Proteins
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