title: Primary resistance to integrase strand-transfer inhibitors in Europe.
abstract: OBJECTIVE
  The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance.
  
  
  METHODS
  This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score ≥ 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing.
  
  
  RESULTS
  For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score ≥ 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score ≥ 10 were found in 8 (14.3%) individuals.
  
  
  CONCLUSIONS
  No signature InSTI-resistant variants were circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years.
authors.affiliation: IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain mcasadella@irsicaixa.es.
authors.forename: M
authors.initials: M
authors.lastname: Casadellà
authors.affiliation: Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: van Ham
authors.affiliation: IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain Universitat de Vic-Universitat Central de Catalunya, Vic, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Noguera-Julian
authors.affiliation: Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Kessel
authors.affiliation: IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Pou
authors.affiliation: Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands Laboratory of Retrovirology, Luxembourg Institute of Health, Luxembourg.
authors.forename: L M
authors.initials: LM
authors.lastname: Hofstra
authors.affiliation: HIV Unit, Hospital Universitari Germans Trias I Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: Santos
authors.affiliation: Complejo Hospitalario Univeristario de Granada, Instituto de Investigación IBS, Granada, Cohorte de Adultos de la Red de Investigación en SIDA (CoRIS) Spain.
authors.forename: F
authors.initials: F
authors.lastname: Garcia
authors.affiliation: Laboratory of Retrovirology, Luxembourg Institute of Health, Luxembourg.
authors.forename: D
authors.initials: D
authors.lastname: Struck
authors.affiliation: National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria.
authors.forename: I
authors.initials: I
authors.lastname: Alexiev
authors.affiliation: Institute of Clinical Medicine, Oslo, Norway.
authors.forename: A M
authors.initials: AM
authors.lastname: Bakken Kran
authors.affiliation: Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands.
authors.forename: A I
authors.initials: AI
authors.lastname: Hoepelman
authors.affiliation: University of Cyprus, Nicosia, Cyprus.
authors.forename: L G
authors.initials: LG
authors.lastname: Kostrikis
authors.affiliation: Robert Koch-Institute, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Somogyi
authors.affiliation: National Institute of Health and Welfare, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Liitsola
authors.affiliation: National Reference Laboratory for HIV/AIDS, National Institute of Public Health, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Linka
authors.affiliation: Statens Serum Institut, Copenhagen, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Nielsen
authors.affiliation: National Institute for Infectious Diseases 'Prof. Dr. Matei Bals', Bucharest, Romania.
authors.forename: D
authors.initials: D
authors.lastname: Otelea
authors.affiliation: National Retrovirus Reference Center, University of Athens, Athens, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Paraskevis
authors.affiliation: Slovenian HIV/AIDS Reference Centre, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Poljak
authors.affiliation: University of Vienna, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Puchhammer-Stöckl
authors.affiliation: Slovak Medical University, Bratislava, Slovakia.
authors.forename: D
authors.initials: D
authors.lastname: Staneková
authors.affiliation: Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: M
authors.initials: M
authors.lastname: Stanojevic
authors.affiliation: Clinical and Epidemiological Virology, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Van Laethem
authors.affiliation: University Hospital for Infectious Diseases 'Dr. Fran Mihaljevic', Zagreb, Croatia.
authors.forename: S
authors.initials: S
authors.lastname: Zidovec Lepej
authors.affiliation: IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain Universitat de Vic-Universitat Central de Catalunya, Vic, Spain Laboratory of Retrovirology, Luxembourg Institute of Health, Luxembourg.
authors.forename: B
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: C A B
authors.initials: CA
authors.lastname: Boucher
authors.affiliation: IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain Universitat de Vic-Universitat Central de Catalunya, Vic, Spain Laboratory of Retrovirology, Luxembourg Institute of Health, Luxembourg.
authors.forename: R
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands.
authors.forename: A M J
authors.initials: AM
authors.lastname: Wensing
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D011159:Population Surveillance; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D019562:Viral Load
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1