Factors associated with the emergence of integrase resistance mutations in patients failing dual or triple-integrase inhibitors-based regimen in a French national survey

Anne-Genevieve Marcelin (1) , Charlotte Charpentier (2) , Pantxika Bellecave (3) , Basma Abdi (1) , Marie-Laure Chaix (4) , Virginie Ferre (5) , Stephanie Raymond (1) , Djeneba Fofana (1) , Laurence Bocket (6) , Audrey Mirand (7) , Helene Le Guillou-Guillemette (8) , Brigitte Montes (9) , Corinne Amiel (10) , Coralie Pallier (11) , Samira Fafi-Kremer (12) , Anne de Monte (13) , Elodie Alessandri-Gradt (14) , Caroline Scholtes (15) , Anne Maillard (16) , Helene Jeulin (17) , Magali Bouvier-Alias (18) , Catherine Roussel (19) , Georges dos Santos (20) , Anne Signori-Schmuck (21) , Julia Dina (22) , Sophie Vallet (23) , Karl Stefic (24) , Cathia Soulié (1) , Vincent Calvez (1) , Diane Descamps (25) , Philippe Flandre (1)

1 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
2 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
3 CHU Bordeaux
4 GenCellDis (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
5 CHU Nantes - Centre Hospitalier Universitaire de Nantes
6 Laboratoire de Virologie - Laboratoire de Virologie - ULR 3610
7 CHU Clermont-Ferrand
8 CHU Angers - Centre Hospitalier Universitaire d'Angers
9 CHU Montpellier
10 CHU Tenon [AP-HP]
11 Hôpital Paul Brousse
12 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
13 CHU Nice - Centre Hospitalier Universitaire de Nice
14 CHU Rouen
15 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
16 Laboratoire de Virologie [Rennes] = Virology [Rennes]
17 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
18 Service de bactériologie, virologie, hygiène [Mondor]
19 CHU Amiens-Picardie
20 CHU de la Martinique [Fort de France]
21 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
22 UNICAEN - Université de Caen Normandie
23 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
24 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
25 Service de virologie et unité de surveillance biologique [Bordeaux]

Background Successful 2-drug regimens (2DRs) for HIV were made possible by the availability of drugs combining potency and tolerability with a high genetic barrier to resistance. How these deal with resistance development/re-emergence, compared with 3DRs, is thus of paramount importance. Materials and methods A national survey including patients who were either naive or experienced with any 2DR or 3DR but failing integrase strand transfer inhibitor (INSTI)-containing regimens [two consecutive plasma viral load (VL) values >50 copies/mL] was conducted between 2014 and 2019. Genotypic resistance tests were interpreted with the v28 ANRS algorithm. Results Overall, 1104 patients failing any INSTI-containing regimen (2DRs, n = 207; 3DRs, n = 897) were analysed. Five hundred and seventy-seven (52.3%) patients were infected with a B subtype and 527 (47.3%) with non-B subtypes. Overall, 644 (58%) patients showed no known integrase resistance mutations at failure. In multivariate analysis, factors associated with the emergence of at least one integrase mutation were: high VL at failure (OR = 1.24 per 1 log10 copies/mL increase); non-B versus B subtype (OR = 1.75); low genotypic sensitivity score (GSS) (OR = 0.10 for GSS = 2 versus GSS = 0–0.5); and dolutegravir versus raltegravir (OR = 0.46). Although 3DRs versus 2DRs reached statistical significance in univariate analysis (OR = 0.59, P = 0.007), the variable is not retained in the final model. Conclusions This study is one of the largest studies characterizing integrase resistance in patients failing any INSTI-containing 2DR or 3DR in routine clinical care and reveals factors associated with emergence of integrase resistance that should be taken into consideration in clinical management. No difference was evidenced between patients receiving a 2DR or a 3DR.

Mots clés: hiv; mutation; genotype; gerstmann-straussler-scheinker; disease; hiv-1 integrase; integrase inhibitors; plasma; viral load result; genetics raltegravir dolutegravir; univariate analysis; hiv

Domaines: Santé publique et épidémiologie

Anne-Genevieve Marcelin, Charlotte Charpentier, Pantxika Bellecave, Basma Abdi, Marie-Laure Chaix, et al.. Factors associated with the emergence of integrase resistance mutations in patients failing dual or triple-integrase inhibitors-based regimen in a French national survey. Journal of Antimicrobial Chemotherapy, 2021, 76 (9), pp.2400-2406. ⟨10.1093/jac/dkab193⟩. ⟨hal-03388629⟩