resistance to integrase strand transfer...
TRANSCRIPT
![Page 1: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/1.jpg)
NORTHWEST AIDS EDUCATION AND TRAINING CENTER
Resistance to Integrase Strand Transfer Inhibitors
David Spach, MD Clinical Director, Northwest AETC Professor of Medicine, Division of Infectious Diseases University of Washington
Last Updated: November 1, 2012
![Page 2: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/2.jpg)
Raltegravir Resistance
![Page 3: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/3.jpg)
Virologic Failure on Raltegravir
• A patient on tenofovir-emtricitabine (Truvada) and Raltegravir (Isentress) develops virologic failure with an HIV RNA level of 1,644 copies/ml 18 months after starting this regimen. A baseline genotype showed no mutations and 4 months prior he had an undetectable HIV RNA.
• What type of resistance test should you order?
![Page 4: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/4.jpg)
Commercial Integrase Resistance Testing
• Integrase Genotype - Quest Diagnostics - Lab Corp (Monogram Biosciences) - Virco Lab
• Integrase Phenotype - Lab Corp (Monogram Biosciences) - Virco
![Page 5: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/5.jpg)
HIV Genotypic Resistance Testing that Includes Integrase
LabCorp (Monogram Biosciences)
List Price $890 (as of October 30, 2012)
![Page 6: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/6.jpg)
Virologic Failure on Raltegravir
• A patient on tenofovir-emtricitabine (Truvada) and Raltegravir (Isentress) develops virologic failure with an HIV RNA level of 1,644 copies/ml 18 months after starting this regimen. A baseline genotype showed no mutations and 4 months prior he had an undetectable HIV RNA.
• Genotype Result
RT: M184V Integrase: N155H Protease: No mutations
![Page 7: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/7.jpg)
Genotypic Resistance to Raltegravir
• Primary Mutations - N155H - Q148H/K/R - Y143R/H/C
Source: Fransen S, et al. J Virol. 2009;83:11440-6.
Genotype: Primary Mutations
1 288 Q N
148 155
R H C
Y
143 NTD CTD
CCD 50 212
H K R
H
![Page 8: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/8.jpg)
Source: Metifiot M, et al. Viruses. 2010;2:1347-66.
Major Pathways of Resistance with Raltegravir
Raltegravir Resistance Pathways
Q148H/K/R Primary Mutations N155H Y143R/H/C
L74M, E92Q, T97A, V151I, G163R L74M, G140A/S, E138K E92Q, T97A Secondary
Mutations
![Page 9: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/9.jpg)
Source: Fransen S, et al. J Virol. 2009;83:11440-6.
Major Pathways of Resistance with Raltegravir
Raltegravir
N155H
Q148H/K/R
Secondary Mutations (L74M, E92Q, T97A, V151I, G163R)
Secondary Mutations (L74M, G140A/S, E138K)
Early
Delayed
![Page 10: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/10.jpg)
Evolution of Integrase Resistance During INSTI Failure SCOPE Study
Source: Hatono H, et al. J Acquir Immune Defic Syndr. 2010;54:389-93.
0
20
40
60
80
100
0 1 2 3
Perc
enta
ge o
f Sub
ject
s w
ih
Res
ista
nce
Mut
atio
ns
Visit
0 1 2 3+
Number of Mutations
![Page 11: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/11.jpg)
Virologic Failure on Raltegravir
• A patient on tenofovir-emtricitabine (Truvada) and Raltegravir (Isentress) develops virologic failure with an HIV RNA level of 1,644 copies/ml 18 months after starting this regimen. A baseline genotype showed no mutations and 4 months prior he had an undetectable HIV RNA.
• Genotype Result RT: M184V Integrase: N155H Protease: No mutations
• Do you think the patient would respond to Elvitegravir?
![Page 12: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/12.jpg)
Raltegravir and Elvitegravir: Cross Resistance
Graphical Representation of Mean log10 Fold Change Values for Different Genotype
Source: Van Wesenbeeck L, et al. Antimicrob Agents Chemother. 2011;55:321-5.
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
NPM N155H Q148H Q148K Q148R Y143C Y143R
Log 1
0 FC
Genotype
Raltegravir
Elvitegravir
NPM = no primary mutation
![Page 13: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/13.jpg)
Raltegravir and Elvitegravir: Cross Resistance
Graphical Representation of Mean log10 Fold Change Values for Different Genotype
Source: Van Wesenbeeck L, et al. Antimicrob Agents Chemother. 2011;55:321-5.
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
NPM N155H Q148H Q148K Q148R Y143C Y143R
Log 1
0 FC
Genotype
Raltegravir
Elvitegravir
NPM = no primary mutation
![Page 14: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/14.jpg)
ANRS 138-Easier Trial Low Level Viremia and Raltegravir Resistance
• Background - Analysis of INSTI resistance in 49 patients with HIV RNA 50–500 copies/ml after switch from enfuvirtide to raltegravir
• Results - Significant INSTI resistance mutations in 8% - N155H in two and P145S in one - Mutations not present on baseline proviral DNA analysis
• Conclusion - INSTI resistance mutations can emerge during episodes of low level viremia in patients receiving raltegravir-containing regimens
Source: Gallien S, et al. AIDS 2011;25:665-9.
![Page 15: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/15.jpg)
Elvitegravir Resistance
![Page 16: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/16.jpg)
Virologic Failure on Elvitegravir
• A patient on elvitegravir-cobicistat-tenofovir-emtricitabine (Stribild) develops virologic failure with an HIV RNA level of 3,288 copies/ml 9 months after starting this regimen? A genotype (including integrase) is performed and resistance is identified.
• What resistance pattern would you expect to see? A. M184V, K103N B. M184V, E92Q C. K65R, N155H D. K65R, K103N
![Page 17: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/17.jpg)
Virologic Failure on Elvitegravir
• A patient on elvitegravir-cobicistat-tenofovir-emtricitabine (Stribild) develops virologic failure with an HIV RNA level of 3,288 copies/ml 9 months after starting this regimen? A genotype (including integrase) is performed and resistance is identified.
• What resistance pattern would you expect to see? A. M184V, K103N ✔B. M184V, E92Q C. K65R, N155H D. K65R, K103N
![Page 18: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/18.jpg)
Resistance Data with EVG-Cobi-TDF-FTC Virologic Failures Data from Studies 102 and 103
Source: White KL, et al. IWDR 2012: Abstract 4.
Resistance Data from Studies 102 and 103
Subjects with Virologic Failure (N =13)
NRTI Resistance: Genotype Data N = 12
A62A/V 2 (17%)
K65R 4 (33%)
M184V 12 (100%)
ISTI Resistance Genotype Data: 1° Mutations N = 11
T66I 2 (18%)
E92Q 8 (73%)
Q148R 3 (27%)
N155H 3 (27%)
![Page 19: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/19.jpg)
Resistance Data with EVG-Cobi-TDF-FTC Virologic Failures Genotypic Data from Studies 102 and 103
Source: White KL, et al. IWHHVDR 2012: Abstract 4.
Patient
Genotype Data from Patients with Virologic Failure (N = 13)
NRTI INSTI
Primary Secondary
1 A62V K65R M184V Q148R G140C
2 A62V K65R M184V E92Q H51Y L68V
3 K65R M184V E92Q S153A
4 ND T66A/I E92Q N155H E157Q
5 M184V E92Q Q148R N155H
6 M184V E92Q
7 M184V E92Q
8 M184V N155H
9 M184I E92Q
10 M184V Q148R
11 M184V T66I E92Q
12 K65R M184V/I
13 M184V
Most common pattern of resistance: M184V and E92Q
![Page 20: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/20.jpg)
Source: White KL, et al. IWHHVDR 2012: Abstract 4.
Major Pathways of Resistance with Elvitegravir
Elvitegravir Resistance Pathways
Q148H/K/R Primary Mutations N155H E92Q
? ? ? Secondary Mutations
![Page 21: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/21.jpg)
Virologic Failure on Elvitegravir
• The genotype shows M184V and E92Q. You are going to change the patient’s antiretroviral regimen.
• Do you think the patient will likely respond to raltegravir? A. Yes B. No
![Page 22: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/22.jpg)
Resistance Data with EVG-Cobi-TDF-FTC Virologic Failures Phenotypic Data from Studies 102 and 103
Source: White KL, et al. IWHHVDR 2012: Abstract 4.
Patient Integrase Strand Transfer Inhibitor and Mean Fold Value Change
Elvitegravir (biologic cut-off = 2.5)
Raltegravir (biologic cut-off = 1.5)
1 >198 28 2 149 6.2 3 111 3.3 4 54 6.0 5 51 12 6 44 3.6 7 36 3.0 8 36 11 9 28 3.3
10 23 8.7 11 5.6 1.8
![Page 23: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/23.jpg)
Dolutegravir
Investigational
![Page 24: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/24.jpg)
Dolutegravir-ABC-3TC versus Efavirenz-TDF-FTC SINGLE: 48 Week Virologic Result
Source: Walmsley S, et al. 52nd ICAAC. 2012: Abstract H-556-b.
88 90 83 81 83
76
0
20
40
60
80
100
All ≤ 100,000 copies/ml > 100,000 copies/ml
Patie
nts
(%) w
ith
HIV
RN
A <
50 c
opie
s/m
l
Baseline HIV RNA
Dolutegravir + Abacavir-Lamivudine Efavirenz-Tenofovir-Emtricitabine
Investigational
Dolutegravir-ABC-3TC: No Integrase Resistance with Virologic Failure
![Page 25: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/25.jpg)
Dolutegravir (“572”) in Patients with Raltegravir Resistance VIKING Cohort I: Results
Source: Eron JJ, et al. 18th CROI. 2011:Abstract 151LB.
78
33
100
0
20
40
60
80
100
All Patients Patients with Q148 + Secondary Mutations
Patients with Other Mutations
HIV
RN
A <
400
copi
es/m
l OR
>
0.7
log
Dec
reas
e in
HIV
RN
A
Cohort I
Investigational
![Page 26: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/26.jpg)
Dolutegravir (“572”) in Patients with Raltegravir Resistance VIKING Cohort I and II: Results
Source: Eron JJ, et al. 18th CROI. 2011:Abstract 151LB.
78
33
100 96 100 92
0
20
40
60
80
100
All Patients Patients with Q148 + Secondary Mutations
Patients with Other Mutations
HIV
RN
A <
400
copi
es/m
l OR
>
0.7
log
Dec
reas
e in
HIV
RN
A
Cohort I Cohort II
Investigational
![Page 27: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/27.jpg)
INSTI-Resistance Associated Mutations Major (Black) and High-Level Major (Red) Mutations
Source: Stanford Database
T
H R K
E G
S A
Q N
H G
S
Elvitegravir 66 92 140 147 148 155 IN I AK
Q
Raltegravir
E
Q
92 H R K
Q
148
N
H
155 R C H
Y
143 IN G
S A
140
T
66
A
Dolutegravir
E
Q
92
H R K
Q
148
N
155 IN G
S A
140
![Page 28: Resistance to Integrase Strand Transfer Inhibitorsdepts.washington.edu/nwaetc/presentations/uploads/...- INSTI resistance mutations can emerge during episodes of low level viremia](https://reader034.vdocument.in/reader034/viewer/2022042401/5f0fb74a7e708231d4458849/html5/thumbnails/28.jpg)
Resistance to Integrase Strand Transfer Inhibitors (ISTIs) Key Concepts
• Raltegravir & elvitegravir have low-medium genetic barrier to resistance
• Dolutegravir has medium-high genetic barrier to resistance
• Genotype is appropriate test to evaluate resistance to ISTIs
• Raltegravir & elvitegravir have major cross-resistance
• Dolutegravir likely effective in early virologic failure with ISTI (RAL or EVG)
• Avoid prolonged failure with raltegravir or elvitegravir
• Dolutegravir requires higher dose when used with prior ISTI failure