French National survey of resistance to integrase inhibitors in a context of routine hospital care (ANRS AC11 virology network)

Transcription

1 French National survey of resistance to integrase inhibitors in a context of routine hospital care (ANRS AC11 virology network) Marcelin AG ; Grude M; Charpentier C; Bellecave, P; Le Guen, L; Pallier, C; Raymond, S; Mirand, A ; Bocket, L; Morand-Joubert, L; Delaugerre, C ; Montes, B; Jeulin, H; Mourez, T; Fafi-Kremer, S; Amiel, C ; Roussel, C ; Dina, J; Trabaud, MA ; Le Guillou-Guillemette, H ; Valet, S ; Signori-Schmuck, A ; Maillard, A; Krivine, A; Flandre, P; Descamps, D; Calvez, V Presentation Number: Abst#_O_#03 Pr Anne-Geneviève Marcelin Laboratoire de Virologie Hôpital Pitié-Salpêtrière France

2 Presenter Disclosure Information AG Marcelin has no commercial interests. AG Marcelin has received travel grants, honoraria, and study grants from various pharmaceutical companies including Gilead Sciences, Merck-Sharp & Dohme-Chibret, Janssen-Cilag and ViiV Healthcare.

3 Background Integrase inhibitors (INI) are the latest antiretrovirals introduced in clinical practice and are becoming widely used. INI (RAL, EVG and DTG) resistance have been extensively studied in vitro and in clinical trials and with limited number of failures. There is a need to get more data about resistance to compounds of this class in clinical setting. 3

4 Objectives of the study Multicenter, observational study Primary objective: To characterize resistance patterns in case of virological failure to integrase inhibitor-based regimen in clinical setting from the french ANRS network Secondary objectives: To identify factors associated with selection of INI resistance mutations To identify new INI associated resistance mutations 4

5 Patients and methods Inclusion criteria HIV-1 infected patient Failing an integrase inhibitor-based regimen (RAL, EVG, DTG) Virological failure confirmed if 2 consecutive plasma VL 50 cp/ml (01/01/ /12/2017) Patients followed in clinical sites within the ANRS AC11 resistance sentinel network Genotypic resistance The sequences of the protease, reverse transcriptase (RT) and integrase genes were performed in each Virology laboratory, using the ANRS consensus technique (2 nd plasma sample). Resistance tests were interpreted according to the last ANRS genotypic algorithm ( 5

6

7 Resistance Possible resistance

8 Population characteristics (n = 513) Variable Median (IQR) Age, years 48.6 [ ] Sex, male (%) 341 (66) Naive, n (%) 53 (10.3) Time since HIV-1 diagnosis, years 16.7 [ ] Duration of current INI regimen, years 0.9 [ ] Nadir CD4 cell count, mm [33-276] CD4 cell count at initiation, mm [ ] CD4 cell count at failure, mm [ ] viral load at initiation (Log 10 cp/ml) 3.1 [ ] viral load at failure (Log 10 cp/ml) 2.9 [2.3-4] HIV-1 subtype B (%) 289 (56.3) 8

9 Percentage (%) ARV treatment at time of failure (n = 513)

10 INIs resistance-associated mutations at failure 58 % of virological failures: no INIs resistance mutations 42 % of virological failures: presence of at least 1 INI mutation 25 % with 1 mutation 10 % with 2 mutations 7 % of with >2 mutations

11 Percentage (%) % of INIs genotypic resistance at failure N = 285 N = 122 N = 106 High frequency of resistance selected by RAL and EVG with cross resistance Less resistance selected by DTG

12 % of INI resistance mutations Factors associated with INIs mutations Frequency of INIs mutations at time of testing significantly associated with failure VL (Odd Ratio = 1.3 per 1 log 10 copies/ml increase) <2 LOG 2-3LOG >3 LOG Viral Load Failure (log c/ml) Patients failing DTG had significantly less INI resistance mutations at failure than patients failing RAL (p = 0.003) and patients failing EVG (p=0.001)

13 Patients failing a first line regimen (n = 53) Variable Median (IQR) Age, years 43.3 [32.2 ; 52.6] Sex, male (%) 35 (66) Time since HIV-1 diagnosis, years 2.2 [0.6 ; 8.0] Duration of current INI regimen, years 0.9 [0.5 ; 2.7] Nadir CD4 cell count, mm [38 ; 303.5] CD4 cell count at initiation, mm [77.5 ; 358] CD4 cell count at failure, mm [200 ; 620] viral load at initiation (Log 10 cp/ml) 5.1 [3.8 ; 5.5] viral load at failure (Log 10 cp/ml) 3 [2.2 ; 4.2] HIV-1 subtype B 21 (40)

14 Patients failing a first line regimen (RAL, n = 31) At failure 8/31 (26%) patients had INI resistance mutations - 1 with emergent mutations: 1 T97A - 7 with no baseline genotype: 3 L74I, 1 92Q + 1 N155H, 1 T97A + 1 N155H + 1 E157Q, 1 E138K, 1 N155H 5/31 (16%) had M184V (4 alone and 1 with INI mutation)

15 Patients failing a first line regimen (EVG, n = 16) At failure 6/16 (37.5%) patients had INI resistance mutations : - 5 with emergent mutations: 1 T66I ; 1 E92Q + 1 S153Y + 1 N155H ; 2 N155H, 1 E92Q + 1 E157Q - 1 with no baseline genotype: L74I + P145S 5/16 (31%) had M184V always with INI mutations

16 Patients failing a first line regimen DTG (n = 6) At failure: 0/6 patients had INI emergent resistance mutations at failure - 2/6 patients had INI mutations at baseline: 1 L74I, 1 E157Q 0/6 patients had M184V

17 Conclusions (1) Large cohort of patients (n = 513) failing INI-based regimens (RAL, EVG, DTG) followed in hospital clinical care Among patients failing an INI-based regimen, 42% harbored viruses with at least 1 INI resistance mutation Close to 39% in 502 patients failing RAL-based regimen (Fourati et al. JAC 2015) RAM profiles: - N155H = 16%, L74I/M = 12%, Q148HR = 8% and T97A = 7% - Y143HRC and E138AK = 3% - No R263K Among patients failing to RAL, 34% harboured a virus resistant to RAL Among patients failing to EVG, 43% harboured a virus resistant to EVG High level of cross resistance between RAL and EVG 17

18 Conclusions (2) Among all patients failing to DTG (as the first INI or in patients previously exposed to RAL or EVG) 15% harboured a virus resistant to DTG QD and 6% to DTG BID However, in patients failing to DTG when used as the first line regimen (ARV naïve patients), neither major resistance to INI, nor NRTI resistance was detected at failure. Confirm resistance robustness of DTG Ongoing studies Plasma drug levels at failure (Dr Gilles Peytavin, Bichat Claude Bernard hospital) Ultradeep sequencing at failure 18

19 ANRS AC11 Resistance Group Coordination Comittee Pr Diane Descamps Pr Vincent Calvez Dr Marie-Laure Chaix Dr Charlotte Charpentier Pr Constance Delaugerre Dr Philippe Flandre Pr Jacques Izopet Pr Anne-Geneviève Marcelin Dr Laurence Morand-Joubert Dr Gilles Peytavin Pr Jean-Christophe Plantier Dr Stéphanie Raymond Dr Catherine Tamalet Pr Sabine Yerly

20 ANRS AC11 Resistance Group Dr Evelyne Lagier Dr Catherine Roussel Dr Hélène Le Guillou Dr Dominique Bettinger Pr Hervé Fleury Dr Sandrine Reigadas Dr Pantxika Bellecave Dr Patricia Recordon-Pinson Pr Christopher Payan Dr Sophie Vallet Pr Astrid Vabret Dr Cécile Henquell Dr Audrey Mirand Dr Alexis de Rougemont Pr Francis Barin Dr Antoine Chaillon Pr Virginie Ferre Dr Elisabeth André-Garnier Pr Jacques Izopet Dr Stéphanie Raymond Dr Georges Dos Santos Pr Patrice Morand Dr Anne Signori-Schmuck Dr Laurence Bocket Dr Sylvie Ranger-Rogez Pr Patrice André Dr Jean-Claude Tardy Dr Mary-Anne Trabaud Dr Catherine Tamalet Dr Catherine Delamare Dr Brigitte Montes Pr Evelyne Schvoerer Dr Jacqueline Cottalorda Dr Jérôme Guinard Dr Aurélie Guiguon Dr Geneviève Giraudeau Dr Véronique Brodard Dr Anne Maillard Pr Jean-Christophe Plantier Dr Chantal Chaplain Pr Thomas Bourlet Dr Stéphanie Marque-Juillet Dr Chakib Alloui Dr Samira Fafi-Kremer Dr Marie-Paule Schmitt Dr Heidi Barth Pr Francoise Stoll-Keller Dr Cécile Poggi Pr Françoise Brun-Vézinet Pr Diane Descamps Dr Charlotte Charpentier Dr Benoit Visseaux Dr Lucile Larouy Gilles Collin Mélanie Bertine Dr Gilles Peytavin Dr Anne Krivine Dr Magali Bouvier Dr Marie-Laure Chaix Pr Vincent Calvez Pr Anne-Geneviève Marcelin Dr Marc Wirden Dr Cathia Soulié Dr Sidonie Lambert-Niclot Dr Isabelle Malet Dr Stéphanie Haim-Boukobza Pr Anne-Marie Roque Dr Corinne Amiel Dr Véronique Schneider Dr Coralie Pallier Dr Ali Si-Mohamed Dr Laurence Morand-Joubert Dr Constance Delaugerre Dr Véronique Avettand-Fenoel Dr Jean-Dominique Poveda Dr Sabine Yerly Dr Dominique Costagliola Dr Philippe Flandre Dr Lambert Assoumou Dr Karine Grenet Dr Frédérique Moreau