This may explain why, in our analysis, virologic

failure that occurred during triple therapy was predominantly associated with higher-level resistant variants. These higher-level resistant variants were present in a lower proportion of patients with failure during the peginterferon/ribavirin treatment phase and in an even lower proportion of patients with failure during follow-up (i.e., with relapse). These differences could be in part explained by different fitness requirements. In the absence of DAA pressure, higher-level resistance is not necessary and therefore, lower-level variants with improved fitness over those with higher-level resistance may be favored. All patients who received less than 4 weeks of telaprevir had wildtype HCV at the time of failure, suggesting Selleckchem Pirfenidone that a 4-week treatment duration is not sufficient to fully eradicate wildtype virus. Important clinical questions regarding resistance include whether resistant variants that emerge during DAA treatment persist, and if patients with these variants can be retreated in the future with the same DAA class. In our analysis, variants that had developed in non-SVR patients became undetectable MG-132 mw by population sequencing

during the study follow-up period (median 11 months) in the majority (58%) of patients. Some common genotype 1b mutations (positions 54 and 156) became undetectable very quickly after a median of 3-4 months, whereas common genotype 上海皓元医药股份有限公司 1a mutations (positions 36, 155, and 36+155) persisted for longer (up to a median of 15 months). This suggests that the genotype 1b variants are generally less fit than the common genotype 1a variants, and are therefore more rapidly replaced by wildtype. Although the results from our analysis and from a boceprevir study

that also showed a loss of resistant variants in treatment-naïve and treatment-experienced patients posttherapy27 are somewhat reassuring; a limitation is that a relatively small number of patients were included and the analysis was based on population sequencing only. Therefore, it is possible that resistant variants may have persisted at levels below the assay’s sensitivity. However, clonal analysis, which can detect variants at considerably lower levels than population sequencing (5% versus 25%, respectively),28 was used in the EXTEND trial, a multinational, 3-year follow-up study of patients treated with telaprevir-based regimens in Phase 2 and Phase 3 clinical trials (NCT00916474). Interim findings using this approach showed that HCV populations returned to the pretreatment state during long-term follow-up (median 22 months).29 The EXTEND trial is continuing to follow up a subset of non-SVR patients from Phase 2 and 3 telaprevir studies. Additional research is needed to evaluate whether these patients can be successfully retreated with the same DAA class.