Doyle, TomasDunn, David TCeccherini-Silberstein, FrancescaDe Mendoza, CarmenGarcia, FredericoSmit, ErasmusFearnhill, EstherMarcelin, Anne-GenevieveMartinez-Picado, JavierKaiser, RolfGeretti, Anna Maria2016-11-092016-11-092015-11Doyle T, Dunn DT, Ceccherini-Silberstein F, De Mendoza C, Garcia F, Smit E, et al. Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades. J Antimicrob Chemother. 2015; 70(11):3080-60305-7453http://hdl.handle.net/10668/2506Journal Article; Research Support, Non-U.S. Gov't;OBJECTIVES The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade. METHODS The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex). RESULTS No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K + G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P = 0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P = 0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P = 0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades. CONCLUSIONS No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K + G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed.enEstudios de cohortesFarmacorresistencia viralFármacos anti-VIHEuropa (continente)Infecciones por VIHVIH-1Inhibidores de integrasaMutación MissenseMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort StudiesMedical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Drug Resistance, Microbial::Drug Resistance, ViralMedical Subject Headings::Geographicals::Geographic Locations::EuropeMedical Subject Headings::Diseases::Virus Diseases::RNA Virus Infections::Retroviridae Infections::Lentivirus Infections::HIV InfectionsMedical Subject Headings::Organisms::Viruses::RNA Viruses::Retroviridae::Lentivirus::Lentiviruses, Primate::HIVMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Integrase InhibitorsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Mutation, MissenseMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Anti-HIV Agentsresearch article26311843open access10.1093/jac/dkv2431460-2091PMC4613743