title: Long-term follow-up of patients receiving boceprevir for treatment of chronic hepatitis C.
abstract: 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.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: anita.howe@merck.com.
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Howe
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: Jianmin.long@merck.com.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Genetics, Merck Research Laboratories, Whitehouse Station, NJ, USA; Department of Pharmacogenomics, Merck Research Laboratories, Whitehouse Station, NJ, USA. Electronic address: David_nickle@merck.com.
authors.forename: David
authors.initials: D
authors.lastname: Nickle
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: Richard_barnard@merck.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Barnard
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: Seth.thompson@merck.com.
authors.forename: Seth
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: John.howe@merck.com.
authors.forename: John
authors.initials: J
authors.lastname: Howe
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: alveskatia@gmail.com.
authors.forename: Katia
authors.initials: K
authors.lastname: Alves
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address: Janice.wahl@merck.com.
authors.forename: Janice
authors.initials: J
authors.lastname: Wahl
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D018450:Disease Progression; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012008:Recurrence; D017211:Treatment Failure
chemical_list: D000998:Antiviral Agents; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline
keywords: Boceprevir; Hepatitis C; Relapse; Resistance