OBJECTIVES: 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.

Clinical and Epidemiological Virology Rega Institute for Medical Research Department of Microbiology and Immunology KU Leuven Belgium

Complejo Hospitalario Univeristario de Granada Instituto de Investigación IBS Granada Cohorte de Adultos de la Red de Investigación en SIDA Spain

Department of Virology Erasmus Medical Center Rotterdam The Netherlands

Department of Virology Medical Microbiology Utrecht Medical Centre Utrecht The Netherlands

Department of Virology Medical Microbiology Utrecht Medical Centre Utrecht The Netherlands Laboratory of Retrovirology Luxembourg Institute of Health Luxembourg

Faculty of Medicine University of Belgrade Belgrade Serbia

HIV Unit Hospital Universitari Germans Trias 1 Pujol Universitat Autònoma de Barcelona Badalona Catalonia Spain

Institute of Clinical Medicine Oslo Norway

IrsiCaixa AIDS Research Institute Universitat Autònoma de Barcelona Badalona Catalonia Spain

IrsiCaixa AIDS Research Institute Universitat Autònoma de Barcelona Badalona Catalonia Spain Universitat de Vic Universitat Central de Catalunya Vic Spain

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

Laboratory of Retrovirology Luxembourg Institute of Health Luxembourg

National Center of Infectious and Parasitic Diseases Sofia Bulgaria

National Institute for Infectious Diseases 'Prof Dr Matei Bals' Bucharest Romania

National Institute of Health and Welfare Helsinki Finland

National Reference Laboratory for HIV AIDS National Institute of Public Health Prague Czech Republic

National Retrovirus Reference Center University of Athens Athens Greece

Robert Koch Institute Berlin Germany

Slovak Medical University Bratislava Slovakia

Slovenian HIV AIDS Reference Centre University of Ljubljana Faculty of Medicine Ljubljana Slovenia

Statens Serum Institut Copenhagen Denmark

University Hospital for Infectious Diseases 'Dr Fran Mihaljevic' Zagreb Croatia

University of Cyprus Nicosia Cyprus

University of Vienna Vienna Austria

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