Resistance Characteristics of different Integrase...
Transcript of Resistance Characteristics of different Integrase...
![Page 1: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/1.jpg)
Resistance Characteristics of different Integrase Inhibitors
Charles Boucher
![Page 2: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/2.jpg)
Disclosure
Companies/funders
Research grants
Speakers fee
Other
Merck, Gilead, Roche
Viiv, Abvie
Co-owner/scientific director Virology Education
![Page 3: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/3.jpg)
![Page 4: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/4.jpg)
entry
reversetranscription integration
nuclearimport
transcriptionvirusproduction
The HIV life cycle
Hazuda 2012
![Page 5: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/5.jpg)
Integration
• Insertion of the viral DNA into host chromosomal DNA, essential step in cycle
• Point of no return: cell becomes a permanent carrier
• Proviral persistence is the barrier to cure
(eg HCV)
![Page 6: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/6.jpg)
Integration (two reactions)
• 3’ processing: 2/3 nucleotides are removed from the 3’ ends from the DNA strand at both sides of the proviral DNA
• Strand transfer reaction: the processed 3’ ends of viral DNA are covalently bound to the host chromosomal DNA
![Page 7: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/7.jpg)
The mechanics of integration
Craigie and Bushman 2012
![Page 8: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/8.jpg)
strand transfer inhibition
Hazuda 2012
unintegrated linear DNA
Dead end, two LTR circles
![Page 9: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/9.jpg)
Integrase strand-transferinhibitors (INSTIs)
Métifiot, Marchand and Pommier 2013
![Page 10: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/10.jpg)
10
Integrase resistance in Benchmarks (raltegravir) studies
41 failures: 32 integrase mutations following “three patterns”
N155H (E92Q,V151I,T97A,G163R,L74M) Q148K/R/H (G140S,E138K)Y143R (L74A,E92Q,T97A,I203M,S230R)
![Page 11: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/11.jpg)
11
Resistance maps to the catalytic core
D64 D116 E152 SH3H H C C
1 50 212 288
Zinc Finger Catalytic Core DNA Binding
N155HQ148K/R
![Page 12: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/12.jpg)
Key Raltegravir Mutations
Stanford HIV Data Base
![Page 13: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/13.jpg)
Cross resistance elvitegravir and raltegravir
Fold change (IC50))
elvitegravir raltegravir
Q148K/R 67/118 34/30
N155H 38 23
N155H+E92Q 166 135
Q148H+G140S >1000 >1000
![Page 14: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/14.jpg)
14
- The selection of specific mutations is a composite of selection pressure and replication capacity
- Clinical resistance to raltegravir and elvitegravir requires one (to two) mutations (LOW GENETIC BARRIER)
- The resistant viruses selected by one will be resistant to the other inhibitor (cross resistance)
Raltegravir and elvitegravir (First generation)
![Page 15: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/15.jpg)
IN VITRO, MOST RAL- AND EVG-RESISTANT SINGLE MUTANTS ARE SUSCEPTIBLE TO DTG
Mean FC
Viruses DTG RAL EVG
WT1,2 1 1 1
T66A1,2 0.26 0.61 4.1
T66I1,2 0.26 0.51 8.0
T66K1,2 2.3 9.6 84
E92I1,2 1.5 2.1 8.0
E92Q1,2 1.6 3.5 19
E92V1,2 1.3 1.4 8.3
G118S1,2 1.1 1.2 4.9
F121Y1,2 0.81 6.1 36
T124A1,2 0.95 0.82 1.2
E138K1,2 0.97 1 0.93
G140S1,2 0.86 1.1 2.7
Y143C1,2 0.95 3.2 1.5
Y143H1,2 0.89 1.8 1.5
Mean FC
Viruses DTG RAL EVG
Y143R1,2 1.4 16 1.8
P145S1,2 0.49 0.87 >350
Q146R1,2 1.6 1.2 2.8
Q148H1,2 0.97 13 7.3
Q148K1,2 1.1 83 >1700
Q148R1,2 1.2 47 240
I151L1,2 3.6 8.4 29
S153F1,2 1.6 1.3 2.8
S153Y1,2 2.5 1.3 2.3
M154I ,2 0.93 0.82 1.1
N155H1,2 1.2 11 25
N155S1,2 1.4 6.2 68
N155T1,2 1.9 5.2 39
G193E2 1.3 1.3 1.3
3 ≤ FC < 5 5 ≤ FC < 10 10 ≤ FC
RAL and EVG-related single mutation SDMs (site directed mutants)
1. Adapted from Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–212. Adapted from Seki T, et al. CROI 2010. Abstract 555
![Page 16: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/16.jpg)
COMBINATIONS WHICH INCLUDE 148 MUTANTS CAN BE RESISTANT TO DTG
3 ≤ FC < 5 5 ≤ FC < 10 10 ≤ FC
Adapted from Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21
Mean FC
Viruses DTG RAL EVG
WT 1 1 1
T66I/L74M 0.35 2.0 14
T66I/E92Q 1.2 18 190
T66K/L74M 3.5 40 120
L74M/N155H 0.91 28 42
E92Q/N155H 2.5 >130 320
T97A/N155H 1.1 26 37
L101I/S153F 2.0 1.3 2.6
F121Y/T125K 0.98 11 34
E138A/Q148R 2.6 110 260
E138K/Q148H 0.89 17 6.7
E138K/Q148K 19 330 371
E138K/Q148R 4.0 110 460
Mean FC
Viruses DTG RAL EVG
G140C/Q148R 4.9 200 485
G140S/Q148H 2.6 >130 >890
G140S/Q148K 1.5 3.7 94
G140S/Q148R 8.4 200 267
Y143H/N155H 1.7 38 16
Q148R/N155H 10 >140 390
N155H/G163K 1.4 23 35
N155H/G163R 1.1 17 35
N155H/D232N 1.4 20 36
V72I/F121Y/T125K 1.3 13 58
L101I/T124A/S153F 1.9 1.4 2.0
E138A/S147G/Q148R 1.9 27 130
V72I/F121Y/T125K/I151V 1.2 7.0 37
RAL and EVG-related single mutation SDMs (site directed mutants)
![Page 17: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/17.jpg)
Integrase Inhibitor Resistance to Mutations
and Combinations
160
140
120
100
80
60
40
20
RAL
EVG
DTG
BIC
Adapted from White K et al, 14th Euro Workshop, May 2016, Rome
![Page 18: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/18.jpg)
No DTG resistance after 1st-line
DTG VF in RCTs
Study Summary efficacy
PDVF in DTG arm
INSTI resistance
FLAMINGO DTG > DRV/r 2 / 242 0
ARIA DTG > ATV/r 1/ 248 0 (1 K219K/Q + E138E/G)
SINGLE DTG > EFV 18 / 422 1 E157Q/P (no emergent INSTI DR)
SPRING-2 DTG = RAL 16 / 411 0
• DTG better than non-INSTIs, non-inferior to RAL
• No INSTI resistance emergence in ideal conditions
• ART-naive
• WT virus → Active backbone
• Early ART switch after PDFV
![Page 19: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/19.jpg)
00
10
20
30
40
50
60
70
80
90
100
Week
Pro
po
rtio
nw
ith
HIV
-1R
NA
<5
0c
op
ies
/mL
(%)
B/F/TAF
DTG/ABC/3TC
DTG+F/TAF
4 8 12 24 36 48
Rapid Suppression of HIV-1 RNA to < 50 copies/mL through Week 48 (Missing =
Excluded Approach)
White K, CROI, 2018, #532 19AE=adverse event; DC=discontinuation; Other reasons= lost to follow-up, withdrew consent, investigator discretion, noncompliance, etc.)
Week 4
76%
76%
80%
Week 8
91%
92%
90%
Week 12
96%
96%
95%
Week 48
99% B/F/TAF
98% DTG/ABC/3TC
99% DTG+F/TAF
B/F/TAF vs. DTG/ABC/3TC or vs. DTG + F/TAF:
displayed rapid viral suppression and non-inferior efficacy at Week 48
![Page 20: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/20.jpg)
Resistance Analysis Population through Week 48 and Resistance Summary
White K, CROI, 2018, #532 20
Resistance Category
B/F/TAF(N=634)
DTG/ABC/3TC(N=315)
DTG + F/TAF (N=325)
Resistance Analysis Population (RAP)(% of FAS)
8 (1.3%) 4 (1.3%) 5 (1.5%)
Subjects with Data for Any Gene (% of RAP) 8 (100%) 3 (75%) 5 (100%)
Subjects with RT Data 8 (100%) 3 (75%) 5 (100%)
Subjects with IN Data 8 (100%) 2 (50%) 3 (60%)
Developed Resistance Substitutions to Study Drugs
0 0 0
Number of Participants, n (%)
PI = protease inhibitor; PR = protease; R = resistance
![Page 21: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/21.jpg)
Genetic barrier to resistance of DTG
• High genetic barrier to resistance observed in patients
– Clinical studies using DTG containing cART and dual therapy (3TC/rilpivirine)
– Clinical practice
– Only one case report of INSTI naive patient failing on cART containing DTG
• High genetic barrier to resistance observed in vitro
– Classical single INSTI-Resistance Associated Mutations (RAM) confer only small changes changes in IC50
• We performed a randomised clinical study to evaluate the efficacy of DTG monotherapyas maintenance in patients with well controlled HIV infection during previous cARTcomparing efficacy of DTG monotherapy to continuation of cART.
![Page 22: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/22.jpg)
DOMONO study (NTC02401828) –randomized clinical trial on DTG
maintenance monotherapy
• Inclusion criteria:
– CD4 nadir > 200 cells/mm3, and HIV1-RNA zenith < 100.000 copy/mL
– Self reported therapy adherence > 95%
– HIV1-RNA < 50 copy/mL, > 6 months
• Exclusion criteria:
– Documented virological failure on any cART
– Documented RAMs
• Virological failure (VF):
– Defined as 2 consecutive plasma HIV1-RNA > 200 copy/mL
Wijting et al., CROI, 2017. Wijting et al. In press
![Page 23: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/23.jpg)
Results of DOMONO study
• At week 48:
– DTG maintenance monotherapy: viral suppression 87/95 (92%)
– Concurrent control group: viral suppression 149/152 (98%)
– DTG monotherapy inferior
– Premature stop of study
Wijting et al., CROI, 2017. Wijting et al. The lancet HIV 2017
![Page 24: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/24.jpg)
Age (median, Q1 - Q3) 47 years (41 – 53)
HIV1-RNA zenith (median, Q1 - Q3) 56.300 copy/mL (19.300 – 99.635)
CD4 nadir (median, Q1 - Q3) 230 cells/mm3 (85 – 310)
HIV-1 subtype B (12/13), CRF02_AG (1/13)
INST-naive 9/10 (69%)
Time between diagnosis and start cART(median, Q1 - Q3)
47 months (4 – 85)
Time on cART (median, Q1 - Q3) 72 months (39 – 132)
Time suppressed on cART (plasma HIV1 RNA < 50 cop/mL (median, Q1 - Q3)
59 months (21 – 101)
Baseline characteristics of all patients with viral Failure
![Page 25: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/25.jpg)
1 Kobayashi et al., Antimicrob Agents Chemother, 2011. 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune Defic Syndr , 2012. 4 Pham et al., JID in tress
patient 4 6 10 1 2 3 9 8 5 7
HIV-RNA zenith (c/mL) 18.500 7.420 66.500 17.500 99.270 56.300 24.900 67.000 34.600 20.100
DTG plasma level at VF (mg/L)
1.29 (+14h) 2.00 (+19h) 5.31 (+19h) 2.59 (+16h) 2.96 (+22h) 1.00 (+24h) 0.86 (+16) 1.44 (+24h) 0.70 (+13h) 2.15 (+9h)
adherence >95% >95% >95% >95% >95% >95% >95% >95% >95% >95%
INSTI-RAM at VF No - No No S230R - E92Q + N155H No R263K N155H
Fold change IC50 DTG(1-4)
- - - - 4 - 2.5 - 2 - 4 1 - 2
![Page 26: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/26.jpg)
Genetic barrier to DTG resistance
• N155H, E92Q + N155H, R263K, S230R → 1-4 fold change in IC50 of DTG in vitro
• Single INSTI-RAMs conferring low level resistance in vitro are sufficient to cause
virological failure in 50 mg once daily DTG maintenance monotherapy
• Genetic barrier to DTG resistance too low to justify maintenance monotherapy
• Cross resistance with other INSTIs
![Page 27: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/27.jpg)
EXTRA – paper Malet
![Page 28: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/28.jpg)
EXTRA – paper Malet
![Page 29: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/29.jpg)
Large variation in time to virological failure
![Page 30: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/30.jpg)
3' polypurine tract (PPT) LTR
HXB2_ref A A A A G A A A A G G G G G G A C T G
9053 Lai* A A A A G A A A A G C A G T - A C T G
Pat 1 A A A A G A A A A G G G G G G A C T G
Pat 3 A A A A G A A A A G G G G G G A C T G
Pat 4 A A A A G A A A A G G G G G G A C T G
Pat 6 A A A A G A A A A G G G G G G A C T G
Pat 8 A A A A G A A A A G G G G G G A C T G
Pat 10 A A A A G A A A A G G G A G C A C T G
![Page 31: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/31.jpg)
First patient failing on INSTI with emergence of changes in 3’-PPT
![Page 32: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/32.jpg)
The mechanics of integration
Craigie and Bushman 2012
![Page 33: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/33.jpg)
10
100
1000
10000
100000
1000000
0 12 24 36 48 60 72 84 96
SAILING: TREATMENT EXPERIENCED
Day 1 PDVF
HIV-1 RNA 84313 27050
IN mutation - I60L, T97A, N155H
DTG FC 0.66 2.4
RAL FC 0.52 113
IN RC NRb NR
PDVF BR: No emergent resistance, loss of RT M184V and PI L10F, M36I, M46I, I54V, V82A.
Underwood, et al. Abs#85. IDRW June 4-8, 2013. Toronto, Canada
10
100
1000
10000
0 12 24 36 48 60 72 84 96 108 120 132 144
Day 1 PDVF Confirm.
HIV-1 RNA 733 622 1054
IN mutation
- A49G, S230R, R263K
A49G, S230R, R263K
DTG FC 0.73 3.82 5.77
RAL FC 0.54 2.39 2.62
IN RC* 20% 7.1% 12%
PDVF BR: No emergent resistance, and no NRTI resistance at any time points
HIV
-1 R
NA
c/m
L
![Page 34: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/34.jpg)
Conclusions
• Genetic barrier to resistance of DTG with 50 mg dose is too low to justify
maintenance monotherapy. DTG monotherapy failure caused by viruses with
single INSTI-RAMs that confer crossresistance to INSTIs. To rule out INSTI
resistance sequencing outside integrase may be needed
• Second generation has a higher genetic barrier ( cave drug levels!) Selection of
INSTI drug resistance in naive individuals using triple therapy is extremely rare
• Dual therapy (DTG or carbotegravir) with 3TC or rilpivirine trials are underway.
• In patients failing first generation INSTI resistance testing can evaluate the
possibility of switching to second generation.
• Baseline resistance testing is not needed for care, surveillance is warranted
![Page 35: Resistance Characteristics of different Integrase ...regist2.virology-education.com/.../2_Boucher_En.pdf · 2 Wainberg et al., J Virus Erad, 2015. 3 Underwood et al., J Acquir Immune](https://reader031.fdocuments.us/reader031/viewer/2022011914/5fc089a653cc495a364ba606/html5/thumbnails/35.jpg)
• All patients included
• Viroscience, Erasmus MC
• Charles Boucher
• Rob Gruters
• Cynthia Lungu
• David van der Vijver
• Patrick Boers
• Suzan Pas
• Jolanda Voermans
• Internal Medicine, Erasmus MC
• Bart Rijnders
• Ingeborg Wijting
• Ineke van der Ende
Acknowledgements
▪ McGill University AIDS Centre, Canada
▪ Mark Wainberg
▪ Thibault Mesplede
▪ Hanh Pham
▪ Virology, UMC Utrecht
▪ Rob Schuurman