title: Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors.
abstract: Dolutegravir shows a high barrier to resistance with no previously reported cases of acquired integrase mutations during first-line therapy. In this study, rapid development of the G118R mutation arose following a switch from first-line elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine to dolutegravir monotherapy. The G118R mutation also arose in a treatment-experienced patient switched to dolutegravir monotherapy. The genetic basis for G118R selection and potential phenotypic outcome was ascertained.
  
  
  
  Genotypic analysis was performed on patients with virological failure (<1000 copies/mL) on dolutegravir-containing regimens. The Los Alamos database was queried for glycine codon 118 polymorphisms. Cell culture selections and phenotypic drug susceptibility assays assessed resistance via the G118R pathway.
  
  
  
  We report on two patients who developed viral failure while on dolutegravir monotherapy. Both patients had been on a current or previous regimen containing integrase inhibitors. Virological failure (<1000 copies/mL) emerged early within 2 months following the dolutegravir switch. The appearance of G118R in these two cases and subtype C and CRF02_AG in vitro selections were related to a rare GGA natural polymorphism at codon 118 (1.5% prevalence), facilitating a GGA to AGA transition. Cell culture selections were used to assess the in vitro progression of the G118R pathway leading to cross-resistance to all integrase inhibitors.
  
  
  
  Although resistance to dolutegravir is typically rare, genetic polymorphisms and monotherapy can facilitate the acquisition of G118R.
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Bluma G
authors.initials: BG
authors.lastname: Brenner
authors.affiliation: Clinique Médicale l'Actuel, Montreal, Quebec, Canada.
authors.forename: Réjean
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Infectious Disease and AIDS Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Blanco
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Ruxandra-Ilinca
authors.initials: RI
authors.lastname: Ibanescu
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Golubkov
authors.affiliation: Département de Microbiologie et d'Immunologie et Centre de Recherche du Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
authors.affiliation: Microbiology Department, Complejo Hospitalario Universitario Granada, Granada, Spain Hospital Universitario San Cecilio, Instituto de Investigación Ibs, Granada, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Garcia
authors.affiliation: Infectious Disease and AIDS Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Martinez
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada mark.wainberg@mcgill.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D000328:Adult; D024882:Drug Resistance, Viral; D060005:Genotyping Techniques; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D020125:Mutation, Missense; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D017211:Treatment Failure; D000099226:Dolutegravir
chemical_list: D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir; C514801:p31 integrase protein, Human immunodeficiency virus 1