utilization of genotype and phenotype resistance tests in patient management richard haubrich, md...
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Utilization of Genotype and Phenotype Resistance Tests in
Patient Management
Richard Haubrich, MDProfessor of Medicine
University of California San Diego
To what is Condi referring?
To what is Condi referring?
Case 41 y/o GWM HIV history (all distant)
– zoster– thrush– bacterial pneumonia– cutaneous KS
Medications– azithromycin – fluconazole– oxandralone– sulfamethoxazole./ trimeth
Case
CD4 = 9 (4%)
HIV RNA = 78,900
Current ARV (02- present)
– ABC
– 3TC
– TDF
– SQV
– RTV
Past ARV
– ZDV/ ddC 93-4
– d4T/ 3TC/ IDV 96-01
– ABC/ ddI/ EFV/ APV/r 01-02
NRTI
When considering TDF Susceptibility
1. The current phenotype is important in deciding to use TDF
2. Past treatment history and resistance tests suggests reduced TDF activity
3. The M184V mutation re-sensitizes the virus to TDF
4. All of the above
ZDV Resistance and Resensitization
100I
L74V/I
Model of NRTI Resistance
Parikh et al. JID 2006; 194: 651
215Y/F + other TAMs
Model of NRTI Resistance
Excision
Parikh et al. JID 2006; 194: 651
65R 215Y/F + other TAMs
Model of NRTI Resistance
Decreased Incorporation
Excision
Parikh et al. JID 2006; 194: 651
65R 215Y/F + other TAMs
Model of NRTI Resistance
Decreased Incorporation
Excision
Phenotypic AntagonismCounter selection
Parikh et al. JID 2006; 194: 651
65R 215Y/F + other TAMs
Model of NRTI Resistance
Multi-NRTI Resistance
Decreased Incorporation
Excision
Phenotypic AntagonismCounter selection
Q151M Complex
Parikh et al. JID 2006; 194: 651
NNRTI
V90I A98G L100I K101E K101P K101Q K103H K103N K103S
K103T V106A V106I V106M V108I E138G E138K E138Q V179D
V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H
Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H
F227C F227L M230I M230L P236L K238N K238T Y318F
DUET: Identification of the ETR Resistance Mutations
• Of 44 NNRTI mutations studied, 26 NNRTI mutations were present in 5 patients
• 13 TMC125 RAMs were identified at baseline to have a significant impact on virological response
ETR RAM
RAM Present
0
20
40
60
80
Response according to number of ETR RAMs
0 1No NNRTI mutations (reference)
2 3 4 5
Number of ETR RAMs
52 161 121 64 32 19 9Patients (n)
Data are pooled from DUET-1 and -2; Vingerhoets J, et al. Antiviral Therapy 2007:12:S34;RAMs = resistance-associated mutations
VL
< 5
0
Overall placebo group
414
0
20
40
60
80
Response according to number of ETR RAMs
0 1No NNRTI mutations (reference)
2 3 4 5
Number of TMC125 RAMs
52 161 121 64 32 19 9Patients (n)
Data are pooled from DUET-1 and -2; Vingerhoets J, et al. Antiviral Therapy 2007:12:S34;RAMs = resistance-associated mutations
VL
<50
Overall placebo group
414
0
20
40
60
80
Response according to number of ETR RAMs
0 1No NNRTI mutations (reference)
2 3 4 5
Number of TMC125 RAMs
52 161 121 64 32 19 9Patients (n)
Data are pooled from DUET-1 and -2; Vingerhoets J, et al. Antiviral Therapy 2007:12:S34;RAMs = resistance-associated mutations
VL
<50
Overall placebo group
414
CASE = 100I; 103N
Impact of Specific Mutations
*No detectable baseline NNRTI RAMs from the list of 44
Nomut
(ref)*
G190A+ 0
ETR RAMs
G190A+ 1
G190A+ 2
G190A+ 3
G190A+ 4
52 18 46 25 17 9
G190A1.00.90.80.70.60.50.40.30.20.1
0
Vingerhoets J, et al. 16th IHDRW 2007, #32.
Res
pons
e re
lativ
e to
the
subg
roup
with
no
NN
RT
I RA
Ms
Nomut
(ref)*.
1.00.90.80.70.60.50.40.30.20.1
0Y181C
+ 0
ETR RAMs
Y181C+ 1
Y181C+ 2
Y181C+ 3
Y181C+ 4
52 23 36 26 17 8Patients (n)
Y181C
Impact of Specific Mutations
*No detectable baseline NNRTI RAMs from the list of 44Vingerhoets J, et al. 16th IHDRW 2007, #32.
Res
pons
e re
lativ
e to
the
subg
roup
with
no
NN
RT
I RA
Ms
Nomut
(ref)*.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0Y181C
+ 0
ETR RAMs
Y181C+ 1
Y181C+ 2
Y181C+ 3
Y181C+ 4
52 23 36 26 17 8Patients (n)
Y181C
ETR: Determination of clinical cutoffs
Winters B, et al. 15th CROI, Boston 2008, #873
Cutoffs based on response rates in DUET
Clinical cutoffs (CCOs) for ETR of 1.6 and 27.6 FC defined for the vircoTYPE report (20% and 80% loss of wt ETR response)
ETR: Determination of clinical cutoffs
Winters B, et al. 15th CROI, Boston 2008, #873
Cutoffs based on response rates in DUET
Clinical cutoffs (CCOs) for ETR of 1.6 and 27.6 FC defined for the vircoTYPE report (20% and 80% loss of wt ETR response)
ETR: Determination of clinical cutoffs
Winters B, et al. 15th CROI, Boston 2008, #873
Cutoffs based on response rates in DUET
Clinical cutoffs (CCOs) for ETR of 1.6 and 27.6 FC defined for the vircoTYPE report (20% and 80% loss of wt ETR response)
PI
TPV RESIST: Change in VL at Week 24 According to TPV Score Mutations
Med
ian
log 1
0 H
IV R
NA
cha
nge
from
bas
elin
e
Shapiro. 12th CROI; 2005: 104
21 mutations at 16 amino acid loci identified:10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V
-2.1
-1.4
-0.6 -0.5 -0.4
-0.7-0.5
-0.2-0.4
-0.2 -0.2 -0.3
-2.5
-2
-1.5
-1
-0.5
0
1 2 3 4 5 >=6
Number of TPV score mutations
TPV/r CPI/r
PI Mutations: 10I, 13V, 33F, 46I, 47V, 54M, 63P, 77I, 84V, 90M
TPV RESIST: Change in VL at Week 24 According to TPV Score Mutations
Med
ian
log 1
0 H
IV R
NA
cha
nge
from
bas
elin
e
Shapiro. 12th CROI; 2005: 104
21 mutations at 16 amino acid loci identified:10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V
Our case = 5 TPV Mutation
-2.1
-1.4
-0.6 -0.5 -0.4
-0.7-0.5
-0.2-0.4
-0.2 -0.2 -0.3
-2.5
-2
-1.5
-1
-0.5
0
1 2 3 4 5 >=6
Number of TPV score mutations
TPV/r CPI/r
PI Mutations: 10I, 13V, 33F, 46I, 47V, 54M, 63P, 77I, 84V, 90M
Stanford Algorithm
Protease Inhibitors
ATV High-level resistance
DRV Intermediate resistance
FPV High-level resistance
IDV High-level resistance
LPV High-level resistance
NFV High-level resistance
SQV High-level resistance
TPV High-level resistance
Stanford Algorithm
ATV DRV FPV IDV LPV NFV SQV TPV
M46I 15 6 12 12 12 25 5 8
I47V 5 12 20 5 10 5 5 10
I54M 10 12 20 10 12 15 10 5
I84V 25 12 35 25 12 35 35 25
L90M 20 6 15 20 10 50 35 6
L10I 2 2 2 2 2 2 2 2
L33F 5 5 5 0 5 0 0 8
Total: 82 55 109 74 63 132 92 64
Number of mutations associated with a diminished response to DRV/r and virological response HIV RNA <50
6450
42
2210
42
0
20
40
60
80
100
0(67)
1(94)
2(113)
3(58)
≥4(41)
All (373)
Number of DRV mutations (Number of patients)
Pat
ien
ts w
ith
VL
HIV
RN
A <
50 c
op
ies/
mL
at
Wee
k 24
(%
)
MP de Bethune. 15th DRW 2006, #73
Clinical Cutoffs Applying Breakpoints to a Continuum of SusceptibilityP
rob
ab
ilit
y o
f re
sp
on
se
Fold change at baseline
Clinical Cutoffs Applying Breakpoints to a Continuum of SusceptibilityP
rob
ab
ilit
y o
f re
sp
on
se
Fold change at baseline
“Traditional” lower clinical cutoff…fold change above which the probability of clinical response begins to decrease
Clinical Cutoffs Applying Breakpoints to a Continuum of SusceptibilityP
rob
ab
ilit
y o
f re
sp
on
se
Fold change at baseline
“Traditional” lower clinical cutoff…fold change above which the probability of clinical response begins to decrease
Upper clinical cutoff…fold change beyond which the probability of clinical response is low.
Clinical Cutoffs Applying Breakpoints to a Continuum of SusceptibilityP
rob
ab
ilit
y o
f re
sp
on
se
Fold change at baseline
“Traditional” lower clinical cutoff…fold change above which the probability of clinical response begins to decrease
Upper clinical cutoff…fold change beyond which the probability of clinical response is low. “ Intermediate
Probability of Response”
Pat
ien
ts W
ith
HIV
-1 R
NA
< 5
0 c/
mL
at
Wee
k 24
(%
)
DUET-1 and -2: Response (< 50 c/mL) According to DRV Fold Change
DRV FC 10-40 DRV FC > 40
71
DRV FC < 10
56 57
30
44
2
100
75
50
25
246/345
200/358 73/129 39/132 31/71 1/67
0
Cahn P, et al. ICAAC 2007. Abstract H-717.
Placebo + OBRETR + OBR
Pat
ien
ts W
ith
HIV
-1 R
NA
< 5
0 c/
mL
at
Wee
k 24
(%
)
DUET-1 and -2: Response (< 50 c/mL) According to DRV Fold Change
DRV FC 10-40 DRV FC > 40
71
DRV FC < 10
56 57
30
44
2
100
75
50
25
246/345
200/358 73/129 39/132 31/71 1/67
0
Cahn P, et al. ICAAC 2007. Abstract H-717.
Placebo + OBRETR + OBR
Our case = DRV FC = 42
Continuous Phenotypic Susceptibility Score (cPSS)
• Activity of drug defined by relation to cut-off• Maximum score = 1 for FC < Lower cut off• Minimum = 0 for FC > Upper cut off• For drugs where FC > lower but < upper cut off,
get partial score (between 0 and 1):
Score = Upper CO – patient FC Upper CO – Lower CO
Continuous Phenotypic Susceptibility Score (cPSS)
• Activity of drug defined by relation to cut-off• Maximum score = 1 for FC < Lower cut off• Minimum = 0 for FC > Upper cut off• For drugs where FC > lower but < upper cut off,
get partial score (between 0 and 1):
Score = Upper CO – patient FC Upper CO – Lower CO
LPV 55 – 34 = 0.46 55-9
PI Scoring for the Case
Drug FC Lower CO
Upper CO
cPSS
DRV 42 10 40 0
DRV 42 10 90 0.6
LPV 34 9 55 0.46
TPV 5.75 2 8 0.375
PI Scoring for the Case
Drug FC Lower CO
Upper CO
cPSS
DRV 42 10 40 0
DRV 42 10 90 0.6
LPV 34 9 55 0.46
TPV 5.75 2 8 0.375
CCR5 ANTAGONISTS
R5 Tropism
CD4 + CCR5 CD4 + CXCR4
R5 Tropism
CD4 + CCR5 CD4 + CXCR4
X4 Tropism
CD4 + CCR5 CD4 + CXCR4
X4 Tropism
CD4 + CCR5 CD4 + CXCR4
Dual Co-receptor Tropism
CD4 + CCR5 CD4 + CXCR4
Dual Co-receptor Tropism
CD4 + CCR5 CD4 + CXCR4
R5/X4 (Mixed) Co-receptor Tropism
CD4 + CCR5 CD4 + CXCR4
R5/X4 (Mixed) Co-receptor Tropism
CD4 + CCR5 CD4 + CXCR4
HIV-1 Expression Vector: pHIVlucU3
P A+
HIV envelope
a/b c/d
Indicator Gene
U5gag
pol
Luciferase
P R
envP
RA+
gp120 gp41
U3
Envelope Expression Vector: pHIVenv
Tropism Assay
Transfection
HIV envexpression
vector
++++
HIV genomicluc vector
HIV-1 Expression Vector: pHIVlucU3
P A+
HIV envelope
a/b c/d
Indicator Gene
U5gag
pol
Luciferase
P R
envP
RA+
gp120 gp41
U3
Envelope Expression Vector: pHIVenv
Tropism Assay
Transfection
HIV envexpression
vector
++++
HIV genomicluc vector
HIV-1 Expression Vector: pHIVlucU3
P A+
HIV envelope
a/b c/d
Indicator Gene
U5gag
pol
Luciferase
P R
envP
RA+
gp120 gp41
U3
Envelope Expression Vector: pHIVenv
CD4 +CXCR4 +
X4 Virus
Tropism Assay
Transfection
HIV envexpression
vector
++++
HIV genomicluc vector
CD4 +CCR5 +
HIV-1 Expression Vector: pHIVlucU3
P A+
HIV envelope
a/b c/d
Indicator Gene
U5gag
pol
Luciferase
P R
envP
RA+
gp120 gp41
U3
Envelope Expression Vector: pHIVenv
CD4 +CXCR4 +
X4 Virus
R5 Virus
Tropism Assay
Tropism Assay
Percentage of HIV Co-receptor Usage
Study/Source Population N R5 D/M X4
Homer cohort1 Naive 979 82% 18% <1%
C & W cohort2 Naive 402 81% 19% <1%
Pfizer 10264 Naive142
885% 15% <1
MOTIVATE 1 & 24 Experienced256
056% 41% 3%
TORO 1/25 Experienced 612 50% 46% 4%
ACTG 52116 Experienced 391 49% 47% 4%
1Brumme ZL, et al. J Infect Dis. 2005;192:466-474.2Moyle GJ, et al. J Infect Dis. 2005;191:866-872.
4Coakley E, et al. 2nd Viral Entry Workshop, Abstract 85Melby et al 13th CROI 2006 Abstract 233.&Wilkin T, et al. CROI 2006. Abstract 655.
Percentage of HIV Co-receptor Usage
1Brumme ZL, et al. J Infect Dis. 2005;192:466-474.2Moyle GJ, et al. J Infect Dis. 2005;191:866-872.
4Coakley E, et al. 2nd Viral Entry Workshop, Abstract 85Melby et al 13th CROI 2006 Abstract 233.&Wilkin T, et al. CROI 2006. Abstract 655.
Population CCR5 Only
Naïve ~80%
Experienced ~50%
MERIT: Week 48 virologic response by tropism
MVC (300 mg BID) vs EFV (600 mg QD) + ZDV/3TC in naïve patients (n=721)
All pts screened in as R5 tropic
25 (3.5%) changed from R5 at screening to D/M at baseline
Heera J, et al. 15th CROI, Boston, 2007, #40LB
% Patients with HIV RNA <50 c/mL
n= 339 / 331 11 / 14
%
68.0
7.1
54.6
69.3
0
20
40
60
80
R5 D/M
MVC +ZDV/3TC EFV +ZDV/3TC
MERIT: Week 48 virologic response by tropism
MVC (300 mg BID) vs EFV (600 mg QD) + ZDV/3TC in naïve patients (n=721)
All pts screened in as R5 tropic
25 (3.5%) changed from R5 at screening to D/M at baseline
Heera J, et al. 15th CROI, Boston, 2007, #40LB
% Patients with HIV RNA <50 c/mL
n= 339 / 331 11 / 14
%
68.0
7.1
54.6
69.3
0
20
40
60
80
R5 D/M
MVC +ZDV/3TC EFV +ZDV/3TC
Enhanced Assay Detects CXCR4 Use Enhanced Assay Detects CXCR4 Use Prior to Standard AssayPrior to Standard Assay
Reeves, et al. ICAAC 2007. Abstract H-1026
Possible Mechanisms of MVC ResistancePossible Mechanisms of MVC Resistance
• Emergence of CXCR4 virusEmergence of CXCR4 virus
– Pre-existing low level populationsPre-existing low level populations
– Viral mutation from CCR5 to CXCR4Viral mutation from CCR5 to CXCR4
• Non-competitive resistance through mutationNon-competitive resistance through mutation
• Failure of MVR most likely due emergence to CXCR4 or D/M Failure of MVR most likely due emergence to CXCR4 or D/M
– 60% of MVC60% of MVC
– 6% control6% control
• Origin likely preexisting low frequency CXCR4 virus rather than Origin likely preexisting low frequency CXCR4 virus rather than tropism switch tropism switch
– detailed clonal analysis from 20 (16 MVC, 4 placebo arm) and detailed clonal analysis from 20 (16 MVC, 4 placebo arm) and analysis of amino acid sequence differences and phylogenetic analysis of amino acid sequence differences and phylogenetic data, suggests emergence and not tropism switchdata, suggests emergence and not tropism switch
– Low level CXCR4 not detected by the tropism assay prior to Low level CXCR4 not detected by the tropism assay prior to treatmenttreatment
-100 0 100 200 300
0
100
200
300
400
500
CXCR4-using env Clones Were Detected at Low Frequency in the Baseline Sample
Time Since First Administration (Day)
• CXCR4-using clones detected at baseline (7%)
• No CCR5-tropic clones on treatment
R5 R5 DM DM DM DM DM DM R5 R5
1
2
3
4
5
6
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
CD
4 C
ou
nt
(ce
lls/m
cL)
Patient T6
Lewis M et al. XVI IDRW, 2007, Abstract 56
-100 0 100 200 300
0
100
200
300
400
500
CXCR4-using env Clones Were Detected at Low Frequency in the Baseline Sample
Time Since First Administration (Day)
• CXCR4-using clones detected at baseline (7%)
• No CCR5-tropic clones on treatment
R5 R5 DM DM DM DM DM DM R5 R5
1
2
3
4
5
6
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
CD
4 C
ou
nt
(ce
lls/m
cL)
Patient T6R5 tropic
Dual tropicX4 tropic
Non-functional clone
Lewis M et al. XVI IDRW, 2007, Abstract 56
-100 0 100 200 300
0
100
200
300
400
500
CXCR4-using env Clones Were Detected at Low Frequency in the Baseline Sample
Time Since First Administration (Day)
• CXCR4-using clones detected at baseline (7%)
• No CCR5-tropic clones on treatment
R5 R5 DM DM DM DM DM DM R5 R5
1
2
3
4
5
6
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
CD
4 C
ou
nt
(ce
lls/m
cL)
Patient T6R5 tropic
Dual tropicX4 tropic
Non-functional clone
Lewis M et al. XVI IDRW, 2007, Abstract 56
-100 0 100 200 300
0
100
200
300
400
500
CXCR4-using env Clones Were Detected at Low Frequency in the Baseline Sample
Time Since First Administration (Day)
• CXCR4-using clones detected at baseline (7%)
• No CCR5-tropic clones on treatment
R5 R5 DM DM DM DM DM DM R5 R5
1
2
3
4
5
6
HIV
-1 R
NA
(lo
g10
co
pie
s/m
L)
CD
4 C
ou
nt
(ce
lls/m
cL)
Patient T6R5 tropic
Dual tropicX4 tropic
Non-functional clone
Lewis M et al. XVI IDRW, 2007, Abstract 56
Non-competitive Inhibition & Resistance
CC
R5
CC
R5
resistancenon-comp.inhibition
ENV
virus membraneC
CR
5
cell membrane
Non-competitive Inhibition & Resistance
CC
R5
CC
R5
resistance
ENV
non-comp.inhibition
ENV
virus membraneC
CR
5
cell membrane
Non-competitive Inhibition & Resistance
CC
R5
CC
R5
resistance
ENV
ENV
non-comp.inhibition
ENV
virus membraneC
CR
5
cell membrane
CCR5 Resistance Mutations
• 8 subjects from ACTG 5211 phase IIb study with confirmed virologic failure on VCV analyzed– No tropism shifts observed– Mutations in V3 loop of gp120 identified in all
patients
• 1 patient underwent detailed analysis of viral inhibition at various time points– Progressive susceptibility to VCV until reaching
plateau– When VCV therapy was removed at Week 28,
virus became susceptible to VCV again and plateau effect was reversed
Tsibris AMN, et al. HIV Resistance Workshop 2007. Poster 13.
Clonal 07J SusceptibilitiesClonal 07J Susceptibilities
0 1 2 3
-50
0
50
100Week 0Week 16Week 19Week 28
VCV (log nM)
Per
cen
t In
hib
itio
n (
%)
Following d/c of VCV, phenotypic susceptibility returned by wk 48
Tsibris, Resistance Workshop, 6/07, abstract #13
INTEGRASE INHIBITORS
Partial Analysis of Raltegravir Resistance in BENCHMRK-1 and BENCHMRK-2
• Virologic failure on Raltegravir vs. placebo: 76 (16%) vs. 121 (51%)
• Raltegravir failure was generally associated with one of two genetic pathways: N155H or Q148K/R/H
• Additional mutations were observed with both pathways
N155H + (E92Q,V151I, T97A, G163R, L74M)
Q148K/R/H + (G140S/A, E138K)
• Other pathways? Y143R/C + (L74A/I, E92Q, T97A, I203M, S230R)
• Longitudinal analyses and associations are in progress
Partial analysis based on genotyping 41 Raltegravir failures32 with integrase changes, 9 with no consistent changes from baseline
1. Cooper D, et al. 14th CROI, Los Angeles 2007, #105aLB; 2. Steigbigel R, et al. ibid, #105bLB
Mutation Pathways Leading to Resistance to RAL Identified
RAL failures in a phase II study analyzed Mutations:
– Near active site
– Similar to mutations selected with other integrase inhibitors in cell culture
2 genetic pathways appear to confer resistance to RAL
Hazuda DJ, et al. HIV Resistance Workshop 2007. Abstract 8.
Mutation Pathways Leading to Resistance to RAL Identified
RAL failures in a phase II study analyzed Mutations:
– Near active site
– Similar to mutations selected with other integrase inhibitors in cell culture
2 genetic pathways appear to confer resistance to RAL
Hazuda DJ, et al. HIV Resistance Workshop 2007. Abstract 8.
Path 1
Path 2
Mutation Pathways Leading to Resistance to RAL Identified
RAL failures in a phase II study analyzed Mutations:
– Near active site
– Similar to mutations selected with other integrase inhibitors in cell culture
2 genetic pathways appear to confer resistance to RAL
Hazuda DJ, et al. HIV Resistance Workshop 2007. Abstract 8.
Path 1
Path 2
Catalytic residues
How many new/ active drugs do you need?
• Unanswered question• Multiple new agents from different classes
entering into expanded access• Guidelines suggest addition of at least 2
active agents• cPSS may help to ‘add up’ how many drugs
to include (i.e. include agents until cPSS > 2)
• Perhaps can leave the NRTI out?• A testable hypothesis (ACTG 5241)
MOTIVATE 1 and 2: VL < 50 c/mL at Week 24 by Active Drugs in OBR
No. of active drugs in OBR 0 1 2 ≥ 3
n =
010
2030
4050607080
90100
35 51 56 44 130 134 59 88 104 64 132 121
3
18
29
9
43 43
19
52 53 5561 58
Pat
ien
ts (
%)
Combined Analysis: MOTIVATE 1 & 2
Placebo + OBR MVC QD + OBR MVC BID + OBR
Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.
Regimens with cPSS of >2.0
Resistance test
cPSS >2.0 cPSS ≤2.0
Site selects regimenObservational armRegimen + NRTIs
Virologic failure
RegimenwithoutNRTIs
Regimen+
NRTIs
Virologic failure or permanent discontinuation of NRTI strategy
Randomize
ACTG 5241: OPTIONS
K Tashima, Chair
Regimens with cPSS of >2.0
Resistance test
cPSS >2.0 cPSS ≤2.0
Site selects regimenObservational armRegimen + NRTIs
Virologic failure
RegimenwithoutNRTIs
Regimen+
NRTIs
Virologic failure or permanent discontinuation of NRTI strategy
Randomize
K Tashima, Chair
Regimens with cPSS of >2.0
Resistance test
cPSS >2.0 cPSS ≤2.0
Site selects regimenObservational armRegimen + NRTIs
Panel of agentsT20RAL
DRV/rTPV/rETRMVC
Virologic failure
RegimenwithoutNRTIs
Regimen+
NRTIs
Virologic failure or permanent discontinuation of NRTI strategy
Randomize
K Tashima, Chair
TIME TO GO….