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

Pr Anne-Geneviève Marcelin

Laboratoire de VirologieHôpital Pitié-SalpêtrièreFrance

Presentation Number: Abst#_O_#03

Presenter Disclosure Information

• AG Marcelin has no commercial interests.

• AG Marcelin has received travel grants, honoraria, and study grantsfrom various pharmaceutical companies including Gilead Sciences,Merck-Sharp & Dohme-Chibret, Janssen-Cilag and ViiV Healthcare.

Background

✓ Integrase inhibitors (INI) are the latest antiretroviralsintroduced in clinical practice and are becoming widelyused.

✓ INI (RAL, EVG and DTG) resistance have been extensivelystudied in vitro and in clinical trials and with limitednumber of failures.

✓ There is a need to get more data about resistance tocompounds of this class in clinical setting.

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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 frenchANRS network

• Secondary objectives:

– To identify factors associated with selection of INI resistance mutations

– To identify new INI associated resistance mutations

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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 (01/01/2014 – 31/12/2017)

– 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 (2nd plasma sample).

– Resistance tests were interpreted according to the last ANRS genotypic algorithm (http://www.hivfrenchresistance.org)

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www.hivfrenchresistance.org

www.hivfrenchresistance.org

Resistance Possible resistance

Population characteristics (n = 513)

8

Variable Median (IQR)

Age, years 48.6 [39.9-55.5]

Sex, male (%) 341 (66)

Naive, n (%) 53 (10.3)

Time since HIV-1 diagnosis, years 16.7 [7.37-22.5]

Duration of current INI regimen, years 0.9 [0.5-2.7]

Nadir CD4 cell count, mm3 128 [33-276]

CD4 cell count at initiation, mm3 365 [156.5-637]

CD4 cell count at failure, mm3 399 [208-659.5]

viral load at initiation (Log10 cp/ml) 3.1 [1.9-4.9]

viral load at failure (Log10 cp/ml) 2.9 [2.3-4]

HIV-1 subtype B (%) 289 (56.3)

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ARV treatment at time of failure (n = 513)

54.19

7.6 7.414.43

4.09 4.87 7.4

0

10

20

30

40

50

60

Pe

rce

nta

ge (

%)

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

% of INIs genotypic resistance at failure

N = 285 N = 106N = 122

Perc

enta

ge(%

)

• High frequency of resistance selected by RAL and EVG with cross resistance• Less resistance selected by DTG

Factors associated with INIs mutations

• 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)

• Frequency of INIs mutations at time of testing significantly associated

with failure VL (Odd Ratio = 1.3 per 1 log10 copies/ml increase)

5.61

35.05

59.35

0

10

20

30

40

50

60

70

<2 LOG 2-3LOG >3 LOG

% o

f IN

I re

sist

ance

mu

tati

on

s

Viral Load Failure (log c/mL)

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, mm3 177.5 [38 ; 303.5]

CD4 cell count at initiation, mm3 246 [77.5 ; 358]

CD4 cell count at failure, mm3 352 [200 ; 620]

viral load at initiation (Log10 cp/ml) 5.1 [3.8 ; 5.5]

viral load at failure (Log10 cp/ml) 3 [2.2 ; 4.2]

HIV-1 subtype B 21 (40)

Patients failing a first line regimen (n = 53)

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)

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

Patients failing a first line regimenDTG (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

• 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

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Conclusions (1)

• 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

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Conclusions (2)

ANRS AC11 Resistance Group

Coordination Comittee

Pr Diane DescampsPr Vincent CalvezDr Marie-Laure ChaixDr Charlotte CharpentierPr Constance DelaugerreDr Philippe Flandre

Pr Jacques IzopetPr Anne-Geneviève MarcelinDr Laurence Morand-JoubertDr Gilles PeytavinPr Jean-Christophe PlantierDr Stéphanie RaymondDr Catherine TamaletPr Sabine Yerly

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