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Unlabelled: In the phase III registration studies conducted in Japan, Japanese HCV gt1 patients administered vaniprevir 300 mg twice daily plus pegylated interferon/ribavirin for 12 or 24 weeks achieved SVR24 rates of 83.7-84.5% among treatment-naïve patients, and 92.0-96.2% and 61.9% among breakthrough/relapsers or null-responders to prior interferon based therapy. As evidenced by direct sequencing, patients who did not achieve SVR24 principally failed due to treatment-emerging mutations at D168 or in a few cases R155. In this work, additional sequence analysis was conducted to address whether there were baseline polymorphisms associated with failure, evaluate the persistence of resistant virus among treatment failures, and assess for evidence of second site co-evolution with R155 or D168 mutations. To accomplish this, clonal sequencing (up to 40 clones per sample) was conducted on baseline, failure, and follow-up samples from all 38 patients among the vaniprevir treatment arms who met virologic failure criteria (37 gt1b, 1 gt1a, herein referred to as virologic failures) and baseline samples from 41 vaniprevir-treated SVR24 patients (all gt1b) selected among the three studies. SVR24 and virologic failure patients showed similar distributions of baseline polymorphisms previously associated with failure to one or more protease inhibitors. Furthermore, there was no evidence for baseline polymorphisms or a genetic signature across the NS3 protease domain specific to virologic failure patients, and which distinguishes them from baseline SVR24 sequences beyond a chance distribution. 24 of 32 virologic failures for whom baseline, failure, and follow-up samples were available showed reduced prevalence of the resistant virus first observed at the time of failure during the protocol-defined follow-up period of 24 weeks. Finally, pairwise analysis using either alignment or phylogenetic based methodologies provided no evidence for second site evolution with either the R155 or D168 mutations attributed to failure. This work supports and extends earlier findings based upon direct sequencing that attributed virologic failure to vaniprevir in the Phase III studies solely to the emergence of R155 or D168 mutations, with no apparent influence by other residues within the NS3 protease domain on treatment outcome. CLINICALTRIALS., Govidentifiers: NCT01370642, NCT01405937, NCT01405560., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The durability of sustained virologic response (SVR) following boceprevir-based therapy in patients with hepatitis C virus (HCV) infection has not been reported. Furthermore, in patients receiving protease inhibitor-based therapies, development of resistance can contribute to treatment failure. The aim of the present study was to follow the clinical progression of patients treated with boceprevir after treatment in phase 2/3 clinical trials. This was a 3-year, long-term follow-up analysis of patients enrolled in boceprevir phase 2/3 studies. No treatment was administered during follow-up. Patients with SVR were assessed for durability of viral eradication. Non-SVR patients with on-treatment resistance-associated variants (RAVs) were assessed for longevity of RAVs. A total of 1148 patients (SVR, n=696; virologic failure, n=452) were enrolled in this follow-up analysis. The median duration of follow-up was approximately 3.4 years (range of 0.0-4.1 years). Overall, 3 of 696 patients with SVR had detectable HCV RNA during the follow-up period (relapse rate of 0.4% or 1.3 relapses/1000 person-years). The majority of patients who developed RAVs during the initial treatment study (228/314, 73%) reverted to wild-type (WT) within 3 years (RAVs persisted in 27% of patients). The median time for all RAVs to become undetectable was 1.11 years (95% confidence interval 1.05-1.20 years). V36M, T54A, A156S, I/V170A and V36M+R155K appeared to have a faster rate of return to WT (median times to return to WT of ⩽0.9 years); whereas, T54S, R155K, V55A and T54S+R155K had a slower rate of return to WT (median times to return to WT of approximately 1.1 years). Return to WT appeared slightly faster in patients with G1b RAVs compared to those with G1a RAVs, and in patients with previous non-response or relapse versus breakthrough or incomplete virologic response. SVR was durable in most patients treated with boceprevir. Furthermore, most RAVs present at the time of virologic failure reverted to WT over time. Time to return to WT was associated with the phenotype of RAV, presumably a reflection of the fitness of the mutant virus, suggesting that HCV RAVs are not permanently archived, but are replaced in the viral population by WT virus., (Copyright © 2014 Elsevier B.V. All rights reserved.)