title: Two Distinct Hepatitis C Virus Genotype 1a Clades Have Different Geographical Distribution and Association With Natural Resistance to NS3 Protease Inhibitors.
abstract: Background.  Hepatitis C virus (HCV) genotype 1 is the most prevalent worldwide. Subtype 1a, compared with 1b, shows lower response rates and higher propensity to select for drug resistance to NS3 and selected NS5A and nonnucleoside NS5B inhibitors. Two distinct clades of subtype 1a have been described. Methods.  Using Bayesian methodology, we performed a time-scaled phylogeny reconstruction of clade separation and characterized the geographic distribution, phylodynamics, and association with natural resistance variants of NS3 sequences from 362 patients carrying subtype 1a HCV. Results.  All sequences segregated in 2 clearly distinct clades. Clade I showed an earlier origin from the common ancestor compared with clade II. Clade I virus was more prevalent in non-European countries, represented mostly by United States, compared with European (75.7% vs 49.3%; P < .001). The prevalence of the natural NS3 variant Q80K, associated with resistance to the macrocyclic protease inhibitor simeprevir, was detected in 51.6% of clade I and 0% of clade II (P < .001); clade I showed a lower genetic barrier for Q80K, whereas no sign of selective pressure at any protease inhibitor resistance-associated codon was detected. Conclusions.  Hepatitis C virus subtype 1a clades have a clearly different distribution in Europe and the United States, and the natural resistance mutation Q80K is exclusively associated with clade I.
authors.affiliation: Unità Operativa Complessa Malattie Infettive Universitarie , Siena University Hospital , Italy ; Institute of Clinical Infectious Diseases , Catholic University , Roma , Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Institute of Clinical Infectious Diseases , Catholic University , Roma , Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Di Giambenedetto
authors.affiliation: Department of Infectious Diseases , National Institute of Health , Roma , Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lo Presti
authors.affiliation: Partner Site of the German Center for Infection Research Deutsches Zentrum für Infektionsforschung; Institute of Virology , University of Cologne , Germany.
authors.forename: Saleta
authors.initials: S
authors.lastname: Sierra
authors.affiliation: Department of Epidemiology , University of Florida , Gainesville.
authors.forename: Mattia
authors.initials: M
authors.lastname: Prosperi
authors.affiliation: Department of Infectious Diseases , National Institute of Health , Roma , Italy ; Department of Public Health and Infectious Diseases , Sapienza University of Rome , Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cella
authors.affiliation: Department of Infectious Diseases , National Institute of Health , Roma , Italy ; Department of Biology , University of Rome "Tor Vergata" , Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Giovanetti
authors.affiliation: University of Brescia , Italy ; Unit of Infectious Diseases , University "Magna Graecia" , Catanzaro , Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Torti
authors.affiliation: Department of Medical Biotechnologies , University of Siena , Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Caudai
authors.affiliation: Department of Medical Biotechnologies , University of Siena , Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Vicenti
authors.affiliation: Department of Medical Biotechnologies , University of Siena , Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Saladini
authors.affiliation: Unità Operativa Complessa Malattie Infettive ed Epatologia , Siena University Hospital , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Almi
authors.affiliation: Infectious Diseases Unit , S. Caterina Novella Hospital , Galatina, Lecce , Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Grima
authors.affiliation: Unità Operativa Malattie Infettive Ospedale Santa Maria Annunziata Azienda Sanitaria Locale 10 , Firenze , Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Blanc
authors.affiliation: Institute of Clinical Infectious Diseases , Catholic University , Roma , Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fabbiani
authors.affiliation: Unità Operativa Complessa Malattie Infettive Universitarie , Siena University Hospital , Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossetti
authors.affiliation: Institute of Clinical Infectious Diseases , Catholic University , Roma , Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gagliardini
authors.affiliation: Partner Site of the German Center for Infection Research Deutsches Zentrum für Infektionsforschung; Institute of Virology , University of Cologne , Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: Department of Infectious Diseases , National Institute of Health , Roma , Italy ; University Campus-Biomedico , Rome , Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ciccozzi
authors.affiliation: Department of Medical Biotechnologies , University of Siena , Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zazzi
keywords: HCV; Q80K; drug resistance; genotype 1a; protease