Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades
| Autor: | Doyle, Tomas, Dunn, David T., Ceccherini-Silberstein, Francesca, De Mendoza, Carmen, Garcia, Frederico, Smit, Erasmus, Fearnhill, Esther, Marcelin, Anne-Genevieve, Martinez-Picado, Javier, Kaiser, Rolf, Geretti, Anna Maria |
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| Přispěvatelé: | CORONET Study Group, [Doyle,T] Department of Infectious Diseases, King's College London, London, UK. [Dunn,DT, Fearnhill,E] MRC Clinical Trial Unit at UCL, London, UK. [Ceccherini-Silberstein,F] Faculty of Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy. [De Mendoza,C] Research Institute and Hospital Puerta de Hierro, Madrid, Spain. [Garcia,F] HU San Cecilio, Granada, Spain. [Smit,E] Heart of England NHS Foundation Trust, Birmingham, UK. [Marcelin,AG] AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, Paris, France. [Martinez-Picado,J] IrsiCaixa, ICREA and UVic-UCC, Barcelona, Spain. [Kaiser,R] Institute of Virology, University of Cologne, Cologne, Germany. [Geretti,AM] Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK., The study was supported by a research award made by Merck to the Royal Free Charitable Trust. |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Genotype
Anti-HIV Agents Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Integrase Inhibitors [Medical Subject Headings] Estudios de cohortes Mutation Missense HIV Infections Integrase Inhibitors Diseases::Virus Diseases::RNA Virus Infections::Retroviridae Infections::Lentivirus Infections::HIV Infections [Medical Subject Headings] Organisms::Viruses::RNA Viruses::Retroviridae::Lentivirus::Lentiviruses Primate::HIV [Medical Subject Headings] Europa (continente) Cohort Studies Mutación Missense Raltegravir Potassium Inhibidores de integrasa Drug Resistance Viral Humans Original Research Farmacorresistencia viral Geographicals::Geographic Locations::Europe [Medical Subject Headings] Infecciones por VIH Europe Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Mutation Missense [Medical Subject Headings] Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Anti-HIV Agents [Medical Subject Headings] Fármacos anti-VIH Analytical Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings] HIV-1 VIH-1 Phenomena and Processes::Microbiological Phenomena::Drug Resistance Microbial::Drug Resistance Viral [Medical Subject Headings] |
| Zdroj: | Journal of Antimicrobial Chemotherapy |
| Popis: | Journal 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. Yes |
| Databáze: | OpenAIRE |
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