Resistance Characteristics of Integrase...
Transcript of Resistance Characteristics of Integrase...
Dr Charlotte CHARPENTIER
Laboratoire de VirologieHôpital Bichat-Claude Bernard
INSERM UMR 1137- IAMEUniversité Paris Diderot
Resistance Characteristicsof Integrase Inhibitors
Plan
• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)
• 2nd generation: Dolutegravir (DTG)
• Epidemiology of resistance to integrase inhibitors
• Ongoing: Bictegravir (BIC) and Cabotegravir (CAB)
Plan
• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)
• 2nd generation: Dolutegravir (DTG)
• Epidemiology of resistance to integrase inhibitors
• Ongoing: Bictegravir (BIC) and Cabotegravir (CAB)
In vitro selection experiments
EVGRAL
RAL and EVG mean FC of single mutation SDMs
• Phase 3 clinical trials conducted in highly-experienced patients with resistant viruses: RAL + Optimized Background Treatment
• VL <400 c/mL in 78 % of patients at W16 (vs 42 % in placebo group)
• Genotypic resistance to RAL in 60 % of patients in VF with available integrase sequence at VF
• Three major resistance mutations: codons 143, 148 and 155
• Emergence of resistance mainly occurred during the first years of the trial, rarely after the third year
RAL: analysis of resistance in the BENCHMRK trials
Cooper et al., NEJM, 2008; Eron et al., Lancet Infect Dis, 2013
Combined analysis of resistance at W96 in the TDF and TAF/FTC/EVG/c trials in ARV-naïve patients
Callebaut et al., IHDRW 2016, Abs. 32; CROI 2016, Abs. 496
E/c/F/TAF
(n = 866)
E/c/F/TDF
(n = 867)
Patients meeting criteria
for resistance analysis19 (2 %) 16 (2 %)
Resistance mutations 10 (1.2 %) 8 (0.9 %)
RT mutations 10 (1.2 %) 7 (0.8 %)
M184I/V 9 6
K65N/R 2 3
K70R 1 1
Integrase mutations 8 (0.9 %) 5 (0.6 %)
T66A/I/V 2 0
E92Q 4 2
Q148R 1 2
N155H/S 2 2
Rare selection of resistance and in similar proportions in the TAF and TDF arms
Distribution of resistance mutations at time of VF
TDF
EVG
FTCTAF
EVG
FTC
0
1
2
3
4
S48 S96 S48 S96
E/C/F/TAF
E/C/F/TDF
Patients with criteria for resistance analysis
Resistance development (%)
Emergence of resistance
16 19 27 28 7 5 10 8
Switch from 155 to 148 resistance profile
1 000
100
10
1
Maximum
Fold Change
Y1
43
R
Y1
43
C
N1
55
H
Q1
48
R
Q1
48
H
+T
97
A
+T
97
A
+E
92
Q
+G
14
0S
+G
14
0S
100
50
0
Y1
43
R
Y1
43
C
N1
55
H
Q1
48
R
Q1
48
H
+T
97
A
+T
97
A
+E
92
Q
+G
14
0S
+G
14
0S
RAL Fold-Change
Viral replicative capacity (%)
Fransen et al., CROI 2009, Abs. 69Fransen et al., Antimicrob Agents Chemother, 2009
Major mutations and secondary mutations
Major mutations Secondary mutations
Q148H/K/R G140A/S, E138K
N155H E92Q, L74M, V151I, G163R
Y143C/H/R T97A, E92Q, E157Q
Secondary mutations: restoration of viral replicative capacity and of resistance level
• Low genetic barrier to resistance
• High level of cross resistance RAL and EVG
Nucleic Acids Research, 2009
Plan
• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)
• 2nd generation: Dolutegravir (DTG)
• Epidemiology of resistance to integrase inhibitors
• Ongoing: Bictegravir (BIC) and Cabotegravir (CAB)
In vitro selection experiments
DTG
DTG, RAL and EVG mean FC against RAL & EVG-relatedsingle mutation SDMs
Resistance Fold-Change to RAL and DTG according to integrase mutations profiles
Underwood et al., IHDRW 2013, Abs. 85
• 143 and 155: most favorable resistance profiles for DTG activity • 148 (specially 140/148 double mutants): worst resistance profile for DTG activity
VIKING-3 trial: virological response at D8 and W24 according to baseline integrase mutations
Day 8 response Week 24 response
IN mutationDecline in VL (log10 c/mL)
Full responsea
< 50 c/mL
n Median n (%) n n (%)
No Q148 122 -1.65 112 (92 %) 72 57 (79 %)
Q148 + 1b 35 -1.10 25 (71 %) 20 9 (45 %)
Q148 + >2b 20 -0.74 9 (45 %) 9 1 (11 %)
a Full response: decline in HIV-1 RNA > 1 log10 c/mL or 50 c/mL at D8b L74I, E138A/K/T and G140A/C/S
Vavro et al., IHVDRW 2013, Abs. 29
• VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg bid while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued
-3.5
0.5 1 2 4 8 16 32
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
Baseline FC IN IC95 relative to wild type virus for DTG
Ch
ange
fro
m b
ase
line
in p
lasm
a H
IV-1
RN
A a
t d
ay 8
(lo
g 10
c/m
L)
Q148 + > 2
Q148 + 1
N155
Y143
> 2 primary mutations
Primary not detected
Baseline INI resistant mutation category
Vavro et al., IHVDRW 2013, Abs. 29
VIKING-3 trial: relationship between baseline integrase mutations and D8 virological response
lemeilleur
…de la CROI 2014
Impact of mutations selected by RAL or EVG on DTG activity
• Assessment of different Q148 mutants on the phenotypic susceptibility to DTG
• Phenotypic assays using clinical isolates and site-directed mutants
10
100
1Mutations 66, 74, 92, 97, 138, 143,
147, 155, and 163 excluded
n = 127
Median fold-change = 4.3
Range = 1.5-22
Susceptibility of clinical isolates
with Q148H + G140S to DTG
(fold-change)
Huang et al., CROI 2014, Abs. 595
Susceptibility of Q148 + E138 mutants
and Q148 + G140 to DTG
(fold-change)
Q148K mutation associated with other integrase
mutations showed a higher of susceptibility to
DTG than Q148H/R viruses
High variability of DTG susceptibility
to G140S + Q148H double mutants
10
100
0.1
0.5 0.4
2.74.0
0.7
2.13.4 3.8
0.7
7.3
58.9
1.81
DTG in ARV-naïve patients
• To date, no INI or NRTI resistance mutations detected at VF in the DTG arms of the phase 3 randomized clinical trials:
- SPRING: 2 NRTI + DTG vs. RAL
- SINGLE: ABC/3TC + DTG vs. EFV
- FLAMINGO: 2 NRTI + DTG vs. DRV/r
• But:
- Very few VF, sequences performed on the first plasma samples at VF, only known INI resistance mutations analyzed
DTG 50 mg qd, n (%) RAL 400 mg bid, n (%)
VF week 24 (VL > 400 c/mL) 14 (4) 34 (9)
BL and VF data 9 (64) 27 (80)
Any emergent IN substitutions 2 (22) 9 (33)
Emergence of IN mutations associated with development of resistance to INI class
L68V, L74M, E92Q, T97A, G140A/S, Y143C/H/R, Q148H/R, V151I, N155H, E157Q, G163K 0 9 (33)
R263K, R263R/K 2 (22) 0
Underwood et al., IHDRW 2013, Abs. 21
SAILING trial: resistance analysis through W24 (1)• Phase 3 randomized clinical trial, ARV-experienced patients but INI-naïve with VL
>400 c/mL (2x) or >1000 c/mL (1x)
Strain IN substitution / FC IC50 DTG RAL EVG
NL432a R263K 1.5 0.8 1.3
HXB2 RVAb
V260I 1.0 0.7 5.3
R263K 2.1 0.6 10.6
V260I/R263K 2.0 0.5 6.3
DTG, RAL and EVG Fold-Change IC50
a HeLa-CD4 cells, 3-day assay, B-gal readout, b MT4 cells, 5-day assay, cell tier glow readout
Underwood et al., IHDRW 2013, Abs. 21
SAILING trial: resistance analysis through W24 (2)
lemeilleur
…de l’IAS-EACS 2015
BL W120 W132
VL (c/mL) 733 622 1 054
IN Mutation WTA49G, S230R,
R263K
A49G, S230R,
R263K
DTG fold change 0.73 3.82 5.77
RAL fold change 0.54 2.39 2.62
RC (% WT) 20 % 7 % 12 %
Patient 1VL (log10 c/mL)
Patient 2VL (log10 c/mL)
• Subtype C
• TDF + DRV/r
• PSS = 2; GSS = 2
BL W72
VL (c/mL) 84 313 27 050
IN Mutation WTI60L, T97A,
N155H
DTG fold change 0.66 2.4
RAL fold change 0.52 113
RC (% WT) ND ND
BL W108
VL (c/mL) 25 105 3 895
IN Mutation WT N155H
DTG fold change 0.97 1.8
RAL fold change 1.18 12
RC (% WT) ND ND
C24h DTG (ng/mL): W4 = 1 780, W48 = 1 230 C24h DTG: W4 = 1 114, W24 <20, W48 = 1 600
SAILING trial: resistance analysis after W48
Underwood et al., EUHHW 2015, Abs. 6
• Subtype A
• ABC + 3TC
• PSS = 2; GSS = 0.5
Patient 3VL (log10 c/mL)
• Subtype B
• TDF + FTC
• PSS = 2; GSS = 2
C24h DTG (ng/mL): W4 = 360, W24 = 220, W48 = 30
622 c/mL1 054 c/mL
386 c/mL
1
2
3
4
0 12 24 36 48 60 72 84 96 108 120 132 144
27 050 c/mL
132 100 c/mL
9 870 c/mL
1
2
3
4
5
6
0 12 24 36 48 60 72 84 96
3 895 c/mL
407 c/mL
0 12 24 36 48 60 72 84 96 108 1201
2
3
4
5
lemeilleur
…de la CROI 2017
• 45 years old man, HIV diagnosis with inaugural pneumocystosis: CD4 = 78/mm3, VL = 1 970 000 c/mL (6.3 log10 c/mL)
• Baseline resistance genotype RT: WT; protease: E35D-L63P-A71T-V77I; integrase not performed
• ARV initiation: TDF/FTC + DTG in the hospital
Follow-up of VL and CD4 Integrase ultra-deep sequencing(codons 142 to 165)
• Emergence of M184V mutation in RT
• Emergence of I151V and G163E mutations in integrase at the second time-point
• Emergence of Q148K viruses: from 0.002 % to 20.9 % between T2 and T3 (< 10 days)
Time 1 Time 2 Time 3
Wild-type
Q148K
I151V-G163E
Silent mutation
I151V
G163E
I151M
Y143L-N144Q-P145S
S147N
I162M
Add DRV/r
RT: M184V
IN: G163E
12
3
107
106
105
104
103
102
101
0 20 40 60 80 100Days
VL (c/mL)
0
400
200
600
800
1 000CD4 (/mm3)
First case report of integrase mutation selection at VF of a DTG-based first-line regimen
Fulcher et al., CROI 2017, Abs. 500LB
DOMONO trial Pooled observational cohorts
French observational cohort
n 104 122 28
Number of VF 8/77 (10 %) 11/122 (9 %) 3/28 (11 %)
Number of IN mutations in VF patients
3/5 (60 %) 9/11 (82 %) 3/3 (100 %)
IN mutations N155HS230RR263K
N155H (n=1)T97A-N155H (n=1)E92Q-N155H (n=1)
Q148H-N155H (n=1)E138K-Q148K (n=1)
G118R (n=2)G140S-Q148H/R (n=2)
N155HL74I-E92Q
E138K-G140A-Q148R
Wijting et al., CROI 2017, Abs. 451LB Blanco et al., CROI 2017, Abs. 42 Katlama et al., EACS 2015, Abs. PS4/4
DTG monotherapy in switch: explored and avoided
High rate of VF and of resistance selection, strategy definitively not recommended
• A Dutch multicenter randomized clinical trial: DOMONO trial• Pooled analysis of 3 observational cohorts (Barcelona, Montréal, Munich)• A monocentric observational cohort in Paris, France
Plan
• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)
• 2nd generation: Dolutegravir (DTG)
• Epidemiology of resistance to integrase inhibitors
• Ongoing: Bictegravir (BIC) and Cabotegravir (CAB)
lemeilleur
…de la CROI 2014
INI resistance profiles in United States: 2009-2012
• HIV integrase sequences issued from 1 677
patients experiencing a VF when receiving a
RAL-based treatment
• INI resistance in 26 % of samples
• Most prevalent resistance profiles:
Q148H/K/R (36 %), N155H (31 %)
Hurt et al., CROI 2013, Abs. 591
R2
63
K
F1
21
Y
S1
47
G
T6
6A
/I/K
E9
2Q
/V
E1
38
A/K
Y1
43
C/H
/R
N1
55
H
Q1
48
H/K
/R
G1
40
A/C
/S
160
140
120
100
80
60
40
20
0
79 % single
Y143C/H/R
(n = 45)
21 %
with other
mutations
(n = 12)
80 % single
N155H
(n = 108)
20 %
with other
mutations
(n = 27)
64 %
Q148H/K/R +
G140A/C/S
(n = 99)
35 %
with other
mutations
(n = 54)
1 %
single Q148H/K/R
(n = 2)
Q148
(n = 155)
N155
(n = 135)
Y143
(n = 57)
INI resistance mutations (n)
Description of major INI resistance mutations
• 12.3 % of high level of resistance to DTG in case of major INI resistance mutations selected at time of VF when receiving a RAL-based treatment
• National multicenter cross-sectional study
• n = 502 patients experiencing a VF when receiving a RAL-based treatment
• 71 % subtype B
• Median VL = 2.9 log10 c/mL
39 % with INI mutation
• Factors associated with presence of INI resistance mutations at VF:- VL at time of VF- GSS <2
13.9 % of resistance to DTG
lemeilleur
…de VIH 2016
3 25
9
35
31
8
15
3
00
10
20
30
40
50
60
Marcelin et al., HIV Glasgow 2016, Abs. O332
INI mutations prevalence at VF (%)
• INI resistance mutation in 36 % of patients
– 22 %: 1 INI resistance mutation
– 8 %: 2 INI resistance mutations
– 6 %: > 2 INI resistance mutations
ANRS study: INI resistance prevalence in patients experiencing a VF with an INI (1)
• National multicenter cross-sectional study
• n = 439 patients experiencing a VF when
receiving an INI-based treatment since
October 2014
• 56 % subtype B
• Median VL = 3.0 log10 c/mL
23 % of resistance to DTG qd and 3.5 % to DTG bid in patients failing RAL or EVG
lemeilleur
…de VIH 2016
DTG bid DTG qd RAL EVG
Susceptible, n (%) 39 (95) 39 (95) 39 (95) 39 (95)
Possible resistance, n (%) 2* (5) 2* (5) - -
Resistance, n (%) 0 0 2* (5) 2* (5)
* 2 patients with single E157Q
– Subtype B (n = 2)
– Present at baseline in 1 case (ongoing BL sequencing for the second patient)
• Subgroup analysis of patients in VF of a DTG first-line regimen (n = 41)
- Treated in median since 0.4 years (IQR = 0.2 - 0.7)
- Median VL at VF: 2.7 log10 c/ml (IQR = 2.1 - 4.4)
- No major INI resistance mutation at VF
- Mutations detected at VF: L74M (n = 1) and E157Q (n = 2)
INI resistance interpretation (%)
ANRS study: INI resistance prevalence in patients experiencing a VF with an INI (2)
Marcelin et al., HIV Glasgow 2016, Abs. O332
• E157Q and L74M are polymorphisms naturally present in some ARV-naïve patients
• Prevalence of 5 % in chronically-infected ARV-naïve patients
• Differential distribution of the E157Q polymorphism among HIV-1 subtypes: Subtype B: 2.3 %, CRF02_AG: 7.5 %
• Selected in vivo in patients failing RAL-based treatment
• Case report of a non virological response to a DTG-based regimen
Malet et al., Antimicrob Agents Chemother, 2008
E157Q mutation: polymorphic and acquired
J Antimicrob Chemother, 2009
Assoumou et al., IAS 2017, Abs. TUPEC0851
Danion et al., J Antimicrob Chemother, 2015
Saladini et al., EHDRW 2017, Abs. 72
E157Q mutation: in vitro analysis
- 3 fold increase of the strand-transfer activity
- 9 fold factor of resistance compared with WT virus
• Virus from the non response to a DTG-based regimen
Danion et al., J Antimicrob Chemother, 2015 Saladini et al., EHDRW 2017, Abs. 72
• Phenotypic analysis of 7 clinical isolates
- 1 virus at the limit of the RAL biological cut-off (FC=1.5)
- All 7 clinical samples susceptible to DTG
Role of the E157Q polymorphism not clearly elucidated
INI acquired drug resistance
• The rate of selection of resistance mutations at time of VF is not so high, between 26 % and 39 % in the US and French studies
• Do we know everything on INI resistance mechanisms ?- Rare resistance profiles ?- Genotypic determinants of resistance outside integrase ?
• These data show that G118R and F121Y represent new RAL resistance pathways that may also be involved in DTG resistance
Fold Change to RAL and DTG
EC50 values were obtained from cell culture assays and IC50 values were obtained from assays using recombinant IN proteins. Each value represents the mean+SD for three independent experiments.
106
105
104
103
102
105 6 9 12 2 2
2016
0
400
200
600
100
700
500
300
120152014
7 8 10 11 1 3 4 5 6 7 8 9 10 11 12
RALTDF/FTC
DRV
VL (c/mL)CD4 (/mm3)
IN: L74FV75I
IN: L74V-V75I I60M-V72I
IN: WT
RAL EVG DTG CAB
L74F 1.5 2.3 0.4 0.7
V75I 0.7 1.2 0.5 0.7
L74F-V75I 4.5 8,1 0.3 1.0
I60M-L74F-V75I 3.7 12 0.5 0.7
V72I-L74F-V75I 11 17 0.5 1.5
I60M-V72I-L74F-V75I 3.9 15 0.3 1.0
Newly described and rare resistance RAL pathways
J Antimicrob Chemother, 2015 Hachiya et al., CROI 2017, Abs. 496
Mutations L74F and V75I: a case report
• Codons that may indirectly affect the Mg2+ coordination position
• The I60M mutation restores the viral RC
lemeilleur
…de la CROI 2017
A high level of resistance to DTG associated with mutations outside integrase
• Objective: in vitro selection experiments but under very high concentrations of DTG ( 500 nM) in order to force the virus to select DTG resistance
• Results– Detection of resistant virus between M2 and M3 of culture
– Integrase sequencing: no emergent mutation
– Whole genome sequencing: mutations in 3’PPT region (nef gene)
Position 9053 // 9068 9069 9070 9071 9072 9073
Reference
sequenceC // G G G G G G
Mutant virus
sequenceT // G C A G T -
Malet et al., CROI 2017, Abs. 499
5’AAAAGAAAAG(G9069C)(G9070A)G(G9072T)(G9073del)0.010
0.1 1 10 100 1 000
50
100 3’ PPT mutated virusWild-type virus
DTG (nM)
• In vitro analysis– High level of resistance to DTG but also RAL and EVG associated with low viral RC (10 %)
– Able to produce newly infections of MT4 cells
• Conclusion: mutations selected in vitro by DTG and located outside the integrase gene can confer
themselves very high-level of resistance to all known INI
Transmitted drug resistance to INI
IN mutations
Assoumou et al., IAS 2017, Abs. TUPEC0851
• National epidemiological survey (ANRS virology network, n = 33 centers, n = 597 patients)
• Chronically-infected ARV-naïve patients diagnosed between October 2015 and March 2016
• Two patients with transmission of major INI resistance mutations (Q148)
• High prevalence of INI transmitted drug resistance mutations
• Pre-therapeutic integrase resistance testing is recommended in France
TDR prevalence by drug class
• : IAS list** : IAS list + E157Q
%
%
Plan
• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)
• 2nd generation: Dolutegravir (DTG)
• Epidemiology of resistance to integrase inhibitors
• Ongoing: Bictegravir (BIC) and Cabotegravir (CAB)
formerly GSK1265744
lemeilleur
…de VIH 2016
In vitro activity of bictegravir (BIC) against INI-resistant viruses
White et al., EWHDR 2016, Abs. O-01
Susceptible Resistance
FC < 2,5 2,5 < FC < 10 FC > 10
+E138K
+G163K
143+E138K
+E138K
+L74M+E138K
+E138K
+T97A
+L74M
+E138A
+T97A
WT
Q148H/R + G140A/C/S + 1Susceptible Reduced susceptibility Resistance
FC < 2,5 2,5 < FC < 10 FC > 10
143143
Q148H/R + G140A/S
WT
Susceptible Resistance
FC < 2,5 2,5 < FC < 10 FC > 10
143 92E92Q
F121Y
Y143R
143Y143R
143N155H
Y143C
143T97A
92E92Q
WT
Single mutantSusceptible Resistance
FC < 2,5 2,5 < FC < 10 FC > 10
143155H+163R
143
92Q+157Q
97A+74M
143C+68V
143R+68,74
155H+74M
155H+157Q
148R+138A
148R+138K
WT
Double mutant
BIC
DTG
EVG
RAL
Reduced susceptibility
Reduced susceptibility
Reduced susceptibility
lemeilleur
…de la CROI 2017
Phase 2 trial comparing BIC versus DTG (+ TAF/FTC) in first-line - Week 48 results
VL < 50 c/mL, ITT snapshot
Sax et al., CROI 2017, Abs. 41 ; Lancet HIV 2017
VL < 50 c/mL; difference, % (95 % CI)
-6 18,8
6,4
-8,5 14,2
2,9
-12 % 12 %
W24
W48
0
Favors
DTG + FTC/TAF
Favors
BIC + FTC/TAF
BIC + FTC/TAF (n = 65)
DTG + FTC/TAF (n = 33)
97
30
97
2 2
94
60
91
63
0
20
40
60
80
100
Virological
success
Virological
failure
No data Virological
success
Virological
failure
No data
W24 W48
• No NRTI or INI resistance detected
• Change in CD4/mm3 at W48: + 258 vs + 192 (p = 0.16)
lemeilleur
…de la CROI 2015
Dudas et al., IHDRW 2015, Abs. 13
• LATTE trial: RCT assessing the efficacy of a dual-therapy in maintenance with RPV + CAB (10 mg,
30 mg or 60 mg) IM
Mutation CAB DTG RAL EVG
Y143C 1.1 0.95 3.2 1.5
Y143H 1.1 0.89 1.8 1.5
Y143R 1.4 1.4 16 1.8
Q148H 0.86 0.97 13 7.3
Q148K 5.6 1.1 83 > 1 700
Q148R 5.1 1.2 47 240
N155H 0.99 1.2 11 25
Phenotypic susceptibility to INI of SDM
(Fold-change)
Highest FC to Q148K/R viruses with CAB than with
DTG (factor 4), suggesting that CAB might be more
impacted by the Q148K/R than DTG
Plasma VL (log10 c/mL)
LATTE trial: resistance analysis of a VF in the CAB 10 mg + RPV arm at W48
481
2
3
4
5CAB +
TDF/FTC
CAB +
RPV
Q148R INT
E138Q RT
Weeks0 12 24 36
Sub-optimal plasma concentrations of CAB and RPV
lemeilleur
…de la CROI 2017
• Objective: modeling in the macaque the risk of emergence of resistance associated with the
initiation of CAB LA during a recent undiagnosed HIV infection
• Methods
– 6 Rhésus macaques
– Infection by intravenous of RT-SHIV virus with SIVmac239 integrase
– 3 monthly IM injections of CAB LA at the dose of 50 mg/kg
ELISA+
RNA RT-SHIV+
CAB LA injectionsRT-SHIV
Infection
M1 M2
Radzio et al., CROI 2017, Abs. 84
Resistance analysis in macaques treated with CAB LA during primary infection (1)
lemeilleur
…de la CROI 2017
Macaque # Integrase mutations1st day of resistance
mutations detectionCompartment
10D181 E92Q-Q124R-G140R 81Blood, rectum,
vagina
35451 E92G 143 Blood
CH54 G118R-A122T 57 Blood, rectum
01D520 None - -
33996 A122T 162 Blood
CJ92 I72T-S135A 32 Blood
E92Q: SIV (EVG: FC ≅ 4; CAB: FC = 2-4); HIV-1 (RAL: FC > 5; DTG: FC > 30)
E92G: SIV (not described); HIV-1 (EVG: FC ≅10)
G118R: SIV (DTG: FC = 11; RAL: FC = 3; EVG: FC = 10); HIV-1 (DTG, RAL and EVG: FC = 5-20)
Phenotypic tests ongoing
• Conclusions
– Frequent selection of resistance
– Presence of resistant viruses in compartments (rectum, vagina) risk of resistance transmission
Resistance analysis by INT sequencing
Resistance analysis in macaques treated with CAB LA during primary infection (2)
Radzio et al., CROI 2017, Abs. 84
To summarize:
• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)
- Low genetic barrier to resistance
- Cross resistance +++
- Selection of mutations in 40 % of VF
• 2nd generation: Dolutegravir (DTG)
- Higher genetic barrier to resistance than RAL/EVG but not a PI (cfmonotherapy strategy)
- bid dosing is required after a VF under INI first generation
- Q148+G140 double mutants, most prevalent mutants at VF, showed an increased phenotypic FC to DTG
VirologyPr Diane Descamps
Dr Charlotte Charpentier
Dr Florence Damond
Dr Nadhira Houhou-Fidouh
Dr Houria Ichou
Dr Lucile Larrouy
Dr Vincent Mackiewicz
Dr Marine Perrier
Dr Benoit Visseaux
Dr Quentin Le Hingrat
Mélanie Bertine
Gilles Collin
Alice Mariaggi
Sarah Peerbaccus
Alexandre Storto
Infectious DiseasesPr Yazdan Yazdanpanah
Pr Elisabeth Bouvet
Pr Sophie Matheron
Pr Patrick Yéni
Dr Véronique Joly
Dr Roland Landman
Dr Sylvie Lariven
Dr Xavier Lescure
Dr Christophe Rioux
Dr Paul Loubet
Clinical PharmacologyDr Gilles Peytavin
Dr Minh Lê
Clinical trials Dr Bao-Chau Phung
Dr Adriana Pinto Dr Ornella Cabras
Cindy GodardDjamila Rahli
Françoise LouniMalikhone Chansombat
Zelie Julia