M Casadellà1, P M van Ham2, M Noguera-Julian3, A van Kessel2, C Pou4, L M Hofstra5, J R Santos6, F Garcia7, D Struck8, I Alexiev9, A M Bakken Kran10, A I Hoepelman2, L G Kostrikis11, S Somogyi12, K Liitsola13, M Linka14, C Nielsen15, D Otelea16, D Paraskevis17, M Poljak18, E Puchhammer-Stöckl19, D Staneková20, M Stanojevic21, K Van Laethem22, S Zidovec Lepej23, B Clotet24, C A B Boucher25, R Paredes24, A M J Wensing2. 1. IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain mcasadella@irsicaixa.es. 2. Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands. 3. IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain Universitat de Vic-Universitat Central de Catalunya, Vic, Spain. 4. IrsiCaixa AIDS Research Institute, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain. 5. Department of Virology, Medical Microbiology, Utrecht Medical Centre, Utrecht, The Netherlands Laboratory of Retrovirology, Luxembourg Institute of Health, Luxembourg. 6. HIV Unit, Hospital Universitari Germans Trias I Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain. 7. Complejo Hospitalario Univeristario de Granada, Instituto de Investigación IBS, Granada, Cohorte de Adultos de la Red de Investigación en SIDA (CoRIS) Spain. 8. Laboratory of Retrovirology, Luxembourg Institute of Health, Luxembourg. 9. National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria. 10. Institute of Clinical Medicine, Oslo, Norway. 11. University of Cyprus, Nicosia, Cyprus. 12. Robert Koch-Institute, Berlin, Germany. 13. National Institute of Health and Welfare, Helsinki, Finland. 14. National Reference Laboratory for HIV/AIDS, National Institute of Public Health, Prague, Czech Republic. 15. Statens Serum Institut, Copenhagen, Denmark. 16. National Institute for Infectious Diseases 'Prof. Dr. Matei Bals', Bucharest, Romania. 17. National Retrovirus Reference Center, University of Athens, Athens, Greece. 18. Slovenian HIV/AIDS Reference Centre, University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia. 19. University of Vienna, Vienna, Austria. 20. Slovak Medical University, Bratislava, Slovakia. 21. Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 22. Clinical and Epidemiological Virology, Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Belgium. 23. University Hospital for Infectious Diseases 'Dr. Fran Mihaljevic', Zagreb, Croatia. 24. 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. 25. Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands.
Abstract
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.
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.
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