title: Pre-existence and Persistence of Resistant Minority Hepatitis C Virus Variants in Genotype 1-Infected Patients Treated With Simeprevir/Peginterferon/Ribavirin.
abstract: Background.  The pre-existence of minority hepatitis C virus (HCV) variants and their impact on treatment outcome, as well as the persistence of emerging resistant variants posttreatment in patients failing treatment with simeprevir/peginterferon/ribavirin (SMV/PR), were assessed by deep sequencing (DS). Methods.  Population sequencing (PS) and Illumina DS were performed on HCV genotype 1 isolates from patients treated with SMV/PR in Phase 2b (PILLAR [NCT00882908] and ASPIRE [NCT00980330]) and Phase 3 (QUEST-1 [NCT01289782], QUEST-2 [NCT01290679], and PROMISE [NCT01281839]) trials. Results.  Minority polymorphisms (ie, detected pretreatment by DS only) reducing SMV activity in vitro were uncommon (3.6%, 19 of 534 patients). These SMV-resistant minority polymorphisms were detected in similar proportions of patients achieving (3.7%) and not achieving (3.3%) sustained virologic response with SMV/PR and generally did not emerge as major variants at time of failure. SMV-resistant variants emerging at time of failure were no longer detected at end of study in 69.3% and 52.0% of the patients by PS and DS, respectively. Conclusions.  Minority polymorphisms did not impact outcome of SMV/PR treatment. The majority of emerging variants that became undetectable at end of study by PS were also undetectable by DS. These results suggest no added value of DS for clinical usage of SMV.
authors.affiliation: Janssen Infectious Diseases.
authors.forename: Bart
authors.initials: B
authors.lastname: Fevery
authors.affiliation: Janssen Discovery Sciences, Beerse , Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Thys
authors.affiliation: Janssen Infectious Diseases.
authors.forename: Veerle
authors.initials: V
authors.lastname: Van Eygen
authors.affiliation: Janssen Infectious Diseases.
authors.forename: Thierry
authors.initials: T
authors.lastname: Verbinnen
authors.affiliation: Janssen Discovery Sciences, Beerse , Belgium.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Van Rossem
authors.affiliation: Janssen Infectious Diseases.
authors.forename: Annemie
authors.initials: A
authors.lastname: Buelens
authors.affiliation: Janssen Discovery Sciences, Beerse , Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerssens
authors.affiliation: Janssen Research & Development , LLC , Titusville, New Jersey.
authors.forename: James
authors.initials: J
authors.lastname: Witek
authors.affiliation: Janssen Research & Development , LLC , Titusville, New Jersey.
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.affiliation: Janssen Infectious Diseases.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
authors.affiliation: Janssen Infectious Diseases.
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
keywords: HCV; deep sequencing; minority (viral) variants; resistance; simeprevir