Transcript Exploring the determinants of antiretroviral treatment failure

Virological predictors of
clinical outcome
Anna Maria Geretti
Royal Free Hampstead NHS
Trust & UCL Medical School
London
Mortality risk with detectable viraemia
during HAART
Cumulative mortality stratified by % VL ≥400 cps/ml recorded
during 18 months after HAART initiation
n=2046 patients who started HAART before 2002
Follow-up: 8898 patient-years after 18 months on HAART
Cumulative mortality
0.25
100%
0.2
51%-75%
76%-99%
0.15
26%-50%
1%-25%
0.1
0%
0.05
0
0
18
36
54
72
Months after starting HAART
Lohse et al, Clin Infect Dis 2006
Determinants of HAART outcomes
Drug exposure
• Adherence
• PK
• Compartments
Host-related factors
• Immune status
• Genetics
• Tolerability
Drug potency
• IC50 value
• Genetic barrier to resistance
Virological factors
• Viral load
• Sequence variability
• Drug-resistance
First-line HAART in the UK
HAART regimen started
 Started HAART in 1996-2006
 82% achieved a VL<50 cps/ml
 At median 3.5 months
 IQR 2.4, 5.5 months
% of patients
 Drug-naïve cohort (n= 1175)
80
70
60
50
40
30
20
10
0
73.2
21.5
1.7
3.6
2 NRTIs 2 NRTIs 2 NRTIs 3 NRTIs
+ NNRTI
+ PI
+ PI/r
Geretti et al, EHDRW 2008
Independent predictors of achieving a VL <50
HR
95% CI
P
Year of
starting
HAART
1999-2001
0.61
0.46, 0.79
0.0002
2002-2003
0.78
0.67, 0.93
0.004
2004-2006
1
-
Age
Per 10 yrs older
1.17
1.06, 1.28
0.001
Baseline VL
Per 1 log 
0.63
0.56, 0.70
<0.0001
Baseline CD4
Per 50 cells 
0.97
0.94, 1.00
0.02
GSS
Per 1 unit 
1.50
1.19, 1.89
0.001
Regimen
NNRTI
1
-
PI/r
0.86
0.70, 1.05
0.13
PI
0.39
0.22, 0.71
0.002
Triple NRTI
0.51
0.35, 0.76
0.001
-
-
No effect of gender, risk group, ethnicity, or B vs non-B subtype
Geretti et al, EHDRW 2008
Exploring the determinants
of HAART failure
 Impact of low-level viraemia
 Impact of HIV-1 subtype
 Impact of transmitted drug resistance
Exploring the determinants
of HAART failure
 Impact of low-level viraemia
 Impact of HIV-1 subtype
 Impact of transmitted drug resistance
Study objectives
 Investigate the long-term virological outcomes
of a large cohort initially showing good responses
to first-line HAART
 Explore the occurrence and impact of low-level
viraemia between 50 and 400 cps/ml
Geretti et al, Antiviral Therapy 2008
Study population
 Drug-naïve cohort (n= 1386)
45
 Started HAART in 1996-2005
40
35
 In the following year:
30
• In follow-up
• On HAART
• No VL >400 cps/mL
% of patients
 Achieved a VL <50 cps/ml
39
HAART regimen
at first VL <50 cps/ml
24
25
20
16
15
10
12
9
5
0
2 NRTIs 2 NRTIs 2 NRTIs 3 NRTIs
+ PI/r
+ PI
+ NNRTI
Other
Note: 320 (23.1%) changed the initial
regimen before achieving <50 cps/ml
due to toxicity (allowed)
Geretti et al, Antiviral Therapy 2008
% of patients
Virological status in the first year after
achieving a VL <50 cps/m
100
90
80
70
60
50
40
30
20
10
0
74.5
19.4
6.1
Consistent
suppression
Transient lowlevel rebound
Persistent lowlevel rebound
Low-level rebound = 50-400 cps/ml
Geretti et al, Antiviral Therapy 2008
% of patients
Virological status in the first year after
achieving a VL <50 cps/m
100
90
80
70
60
50
40
30
20
10
0
74.5
269 patients
Blips per person
1
84.8%
2
13.4%
3
1.5%
4
0.4%
85 patients
Consecutive VL >50
2 in 54.1%
3 in 28.2%
≥4 in 17.6%
19.4
6.1
Consistent
suppression
Transient lowlevel rebound
Persistent lowlevel rebound
Low-level rebound
Low-level
rebound==50-400
50-400copies/ml
cps/ml
Geretti et al, Antiviral Therapy 2008
Predictors of low-level rebound
 Multivariate model
 Factors analysed: age, gender, risk group, ethnicity/country of
birth, baseline CD4 and VL, CD4 at first VL <50 cps/ml, time
from start of HAART to first VL <50 cps/ml, HAART regimen,
year when first achieved a VL <50 cps/ml, HAART changes for
toxicity prior to first VL <50 cps/ml
OR
95% CI
P
2 NRTIs + 1 NNRTI
1.00
-
0.01
2 NRTIs + 1 PI/r
1.39
1.00, 1.94
2 NRTIs + 1 PI
1.48
0.96, 2.26
Triple NRTIs/Other
1.73
1.23, 2.42
Geretti et al, Antiviral Therapy 2008
Virological outcomes
 Follow-up started 1 year after 1st VL <50 cps/m
 Lasted for median 2.2 years (range 0.0–7.4)
 Failure = VL >400 cps/ml
 Failure rate = 86 patients (6.2%)
• Consistent undetectability
5.0%
• Transient low-level rebound
8.2%
• Persistent low-level rebound
14.1%
Low-level rebound = 50-400 cps/ml
Geretti et al, Antiviral Therapy 2008
Predictors of virological failure
 Multivariate model
 Factors analysed: As in previous analysis + VL status in the first year
after achieving a VL <50 cps/m
Predictors
Virological status
in 1st yr after achieving
<50 cps/ml
Gender
HAART regimen
Consistent <50
Transient rebound
Persistent rebound
Male
Female
2 NRTIs + 1 NNRTI
2 NRTIs + 1 PI/r
2 NRTIs + 1PI
3 NRTIs/Other
RR
1.00
1.41
2.18
1.00
1.79
1.00
1.88
1.23
1.87
95% CI
–
0.86, 2.34
1.15, 4.10
–
1.12, 2.85
–
1.02, 3.46
0.66, 2.31
1.04, 3.36
P
0.02
0.02
0.09
Geretti et al, Antiviral Therapy 2008
Effect of VL on the detection of resistance
(multivariate analysis)
VL
N
% RAMs
RR (95% CI)
<300
300-1000
1000-3000
3000-10000
10000-30000
30000-100000
≥100000
449
552
1120
1312
1326
1438
1682
60
72
76
77
67
60
49
0.94 (0.87-1.01)
0.99 (0.94-1.04)
1
1.01 (0.97-1.05)
0.91 (0.87-0.95)
0.84 (0.80-0.88)
0.70 (0.66-0.74)
RAMs: resistance-associated mutations
RR: Relative risk
Geretti et al, IHDRW 2009
Number of mutations detected by VL strata*
*in patients with ≥1 mutation
Median number (IQR)
7
6
5
4
4
3
3
3
3
3
3
300-1000
10003000
300010000
1000030000
30000100000
399
850
1014
888
858
3
2
1
0
<300
N= 270
>100000
809
Geretti et al, IHDRW 2009
Exploring the determinants
of HAART failure
 Impact of low-level viraemia
 Impact of HIV-1 subtype
 Impact of transmitted drug resistance
Study population
 Drug-naïve cohort (n=2116)
Subtype
 Started HAART in 1996-2006
• Most commonly
2 NRTIs + 1 NNRTI
 ≥12 months of follow-up
 Excluded patients with TDR
C, 13%
D, 2%
AG, 3%
Other,
6%
B, 73%
A, 3%
 Ethnicity and risk group strongly
associated with subtype (P<0.001)
Outcomes measured:
 Time to VL suppression <50 cps/ml
 For those who achieved <50, time to rebound >1000 cps/ml
 Median follow-up of 39 months (IQR 23, 67)
Geretti et al, Clin Infect Dis 2009
Responses to first-line HAART by subtype
1906/2116 (90%) achieved VL suppression <50 cps/ml
335/1906 (18%) rebounded >1000 cps/ml
VL suppression
A
VL rebound
B
C
D
255
51
37
7
AG
Other
51
7
118
19
120
100
%
80
60
40
20
0
N=
N=
64
13
1381
238
Geretti et al, Clin Infect Dis 2009
Probability of achieving <50 cps/ml
VL suppression
1.00
Median time to VL suppression
Subtype A
2.6 months
Subtype C
2.8 months
Subtype B
3.1 months
0.80
0.60
A
B
C
0.40
Multivariate analysis*
Time to VL suppression shorter for A
(HR 1.35 [1.04,1.74] P=0.02) and C
(HR 1.16 [1.01,1.33] P=0.04) vs B
0.20
Log-rank
p<0.0005
0.00
0
3
6
9
12
Analysis time (months)
Number at risk
A
66
B
1550
C
272
23
785
10
9
332
41
5
218
23
*adjusted for age, centre, HAART regimen, calendar
year, baseline CD4 and VL
2
169
17
Geretti et al, Clin Infect Dis 2009
Probability of remaining <50 cps/ml
VL rebound
1.00
Multivariate analysis*
Time to VL rebound shorter for C vs
B (HR 1.40 [1.00, 1.95] P=0.05)
0.80
0.60
143 rebounds: virological failure
192 rebounds: non-adherence or
treatment discontinuation
0.40
A
B
C
Log-rank
p=0.09
0.20
Time to virological failure similar
for C vs B
0.00
0
12
24
36
48
60
Analysis time (months)
Number at risk
A
64 49
34
B
1381 1167 830
C
255 197 116
22
630
74
17
454
48
*adjusted for age, centre, HAART regimen, calendar
yr, baseline CD4 and VL, and time to VL suppression
15
317
30
Geretti et al, Clin Infect Dis 2009
CD4 recovery over time
CD4 count (cells/mm3)
500
400
300
A
B
C
200
100
0
6
12
18
24
30
36
28
668
93
20
552
63
Time since ART initiation (months)
Number in analysis
A
66
B
1550
C
272
50
1253
225
57
1174
201
42
970
167
38
796
121
Geretti et al, Clin Infect Dis 2009
Exploring the determinants
of HAART failure
 Impact of low-level viraemia
 Impact of HIV-1 subtype
 Impact of transmitted drug resistance
Detection of TDR
Mutation Frequency
100
10
1
Detected by
routine methods
6-13% of naïve patients
in Europe & N America1-9
Detected by
ultrasensitive
methods
Rates doubled10-16
0.1
0.01
Natural background
0.001
1. Masquelier JAIDS 2005; 2. Wensing JID 2005; 3. Booth JAC 2007; 4. Geretti COID 2007; 5. SPREAD AIDS
2008; 6. Vercauteren AIDS RHR 2008; 7. Peuchant AIDS 2008; 8. Bannister JAIDS 2008; 9. Weinstock JID 2004;
10. Peuchant AIDS 2008; 11. Metzner AIDS 2005; 12. Johnson PLoS ONE 2007; 13. Johnson PLOS Med 2008;
14. Siemen JID 2009; 15. Geretti JAIDS 2009; 16. Goodman IHDRW 2009
The clinical significance of low-frequency TDR
Metzner, Antivir Ther 2007
Peuchant, AIDS 2008
Johnson, PLOS Med 2008
No
Siemens, JID 2009
Impact on
virological
responses
Geretti, JAIDS 2009
Goodman IHDRW 2009
Yes
 Different methods, interpretative cut-offs, populations, HAART regimens
The FIRST study
Mutations
Method
Bulk
UDS
NNRTI
6.6%
15.1%
<0.001
NRTI
6.2%
14.0%
<0.001
PI
2.3%
4.7%
0.03
13.6%
28.3%
<0.001
Any
P
N=258
HR for failure in patients with
NNRTI resistance
 Bulk : 12.4 [3.41-45.1]
 UDS: 2.50 [1.17-5.36]
USD = Ultra deep sequencing
Siemen et al, JID 2009
Impact of NNRTI TDR on responses to first-line
NNRTI-based HAART
 Case control study
 Patients with virological failure (n=18) vs those who
achieved and maintained VL suppression <50 for ≥24
weeks (n=75)
 Pre-HAART sample tested by sensitive PCR
 Targets: K65R, K103N, G190A, Y181C, M184V
 Interpretative cut-off of 0.5-0.9%
Geretti et al, JAIDS 2009
NNRTI TDR reduces responses to first-line
NNRTI-based HAART
Resistance at baseline
 7/18 cases vs 0/75 controls
 2 K103NHIGH 1 G190AHIGH 4 K103NLOW
Odds of virological failure
 Bulk resistance
p=0.006
 4 K103NLOW
p=0.001
 Combined
p <0.0001
HIGH= detected also by bulk genotyping; LOW= detected only by PCR (>0.9%)
Geretti et al, JAIDS 2009
 TDF/FTC/EFV
 ZDV/3TC/EFV
 K103NLOW in 16/476
(3.4%) patients
 6/16 (38%) of patients
with K103NLOW had VF
VF = virological failure
Fit plot for VF (>400 c/mL)
Fit
0.5
99% confidence band
VF
0
Non-VF
-0.5
-1
103.3 = 1995 c/mL
0
1
2
3
4
Log copies of RNA with K103N mutation
Clinical virology VF (>400 c/mL)
GS-01-934 (n=487)
Clinical virology VF (>400 c/mL)
K103N >2% or >2000 cps/ml predicts failure of
first-line NNRTI-based HAART
Fit
1
99% confidence band
VF
0.5
0
Non-VF
-0.5
-1
0
2.5
5
7.5
10
12.5
15
Percent of RNA with K103N mutation
Goodman et al, IHDRW 2009
Conclusions-1
 Low risk of virological failure once suppression is
achieved and maintained for 1 year
 Consistent suppression <50 the optimal target
 NNRTI-based HAART least likely to result in low-level
viraemia and virological failure
 Women at increased risk of virological failure
 Problems with long-term adherence
 Cultural and social-economic factors
 Resistance testing at low VL yields clinically
useful information
Conclusions-2
 Predominantly NNRTI-based HAART achieves
excellent outcomes regardless of the infecting subtype
 Subtype C patients show an increased risk of rebound
possibly related to non-adherence
Conclusions-3
 Low-frequency K103N mutants as prevalent as
bulk-detectable resistant variants
 Significantly associated with virological failure
 Patients infected with single NNRTI mutants
 ? Impact on second generation NNRTIs
Etravirine
Nevirapine
Efavirenz
[email protected]
Thank you