title: Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients.
abstract: OBJECTIVE
  The objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir).
  
  
  METHODS
  Data were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23).
  
  
  RESULTS
  Among the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy-one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P < 0.001) and low genotypic sensitivity score of the associated treatment with raltegravir (P < 0.001) were associated with the presence of raltegravir-associated mutations at failure. Q148 mutations were selected more frequently in B subtypes versus non-B subtypes (P = 0.004).
  
  
  CONCLUSIONS
  This study shows that a high proportion of viruses remain susceptible to dolutegravir in the case of failure on a raltegravir-containing regimen.
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France.
authors.forename: Slim
authors.initials: S
authors.lastname: Fourati
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France Université de Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Hôpital Bichat, Laboratoire de Virologie, F-75018 Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.affiliation: AP-HP, CHU Tenon, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Amiel
authors.affiliation: AP-HP, CHU Saint Antoine, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Morand-Joubert
authors.affiliation: CHU de Bordeaux, Laboratoire de Virologie, Université de Bordeaux, CNRS UMR 5234, F-33076 Bordeaux, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Reigadas
authors.affiliation: Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Trabaud
authors.affiliation: CHU Saint Louis, Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaugerre
authors.affiliation: CHU de Toulouse, Hôpital Purpan, Laboratoire de virologie, F-31300 Toulouse, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Nicot
authors.affiliation: CHU Nantes, Nantes, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Rodallec
authors.affiliation: CHU de Rennes, Rennes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Maillard
authors.affiliation: CHU de Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Mirand
authors.affiliation: CHU de Nancy, Nancy, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Jeulin
authors.affiliation: CHU Saint-Eloi, Montpellier, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Montès
authors.affiliation: CHU Tours, Tours, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Barin
authors.affiliation: CHU Saint Jacques, Besançon, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bettinger
authors.affiliation: CHU Angers, Angers, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Le Guillou-Guillemette
authors.affiliation: CHRU La Cavale Blanche, Brest, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vallet
authors.affiliation: CHU Grenoble, Grenoble, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Signori-Schmuck
authors.affiliation: INSERM, IAME, UMR 1137, F-75018 Paris, France Université de Paris Diderot, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Hôpital Bichat, Laboratoire de Virologie, F-75018 Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, INSERM-Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Paris, France anne-genevieve.marcelin@psl.aphp.fr.
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005260:Female; D005602:France; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000494:pharmacology*; D000068898:Raltegravir Potassium / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D019427:HIV Integrase; D016333:HIV Protease; D054303:HIV Reverse Transcriptase; D006575:Heterocyclic Compounds, 3-Ring; D050505:Mutant Proteins; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir; C514824:reverse transcriptase, Human immunodeficiency virus 1
keywords: inhibitors; integrase; mutations; patterns