Transcript The MONET trial 96 week analysis

The MONET trial 96 week analysis: darunavir/r
monotherapy versus darunavir/r + 2NRTIs,
for patients with HIV RNA < 50 copies/mL at
baseline
Armin Rieger, Denes Banhegyi, Wolfgang Schmidt, Jose Arribas, Andrew Hill,
Yvonne Van Delft, Christiane Moecklinghoff
Presented at World AIDS Conference, Vienna, Austria, 22nd July 2010
Abstract TBLBB209
MONET - Trial Design
 Inclusion: Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified)
 HIV RNA <50 copies/mL for at least 6 months, no prior use of darunavir (DRV)
 No history of virological failure
DRV/r 800/100 mg OD
+ 2 NRTI (re-optimised at baseline)
n = 129
256 subjects
DRV/r 800/100 mg OD
n = 127
144 weeks
Primary Endpoint: failure at week 48 (TLOVR). Per Protocol, Switch = Failure
The Week 96 analysis was a secondary endpoint.
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
MONET: statistical methods for HIV RNA
analysis
Main efficacy endpoint: TLOVR, switch equals failure analysis
If a patient shows a confirmed elevation in HIV RNA >50 copies/mL at two visits, this is a
failure, even if the HIV RNA is then suppressed <50 copies/mL at Week 96.Stopping DRV/r
in either arm, or adding NRTIs in the monotherapy arm is also a failure. Missing data is
failure.
Secondary endpoint: Switch included analysis
This analysis only includes the HIV RNA levels at Week 96. If HIV RNA is re-suppressed at
Week 96 following an earlier elevation, this is counted as success. Changes in treatment are
permitted. Missing data is failure.
All results were consistent between the ITT and Per Protocol populations.
ITT analysis is shown here.
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
MONET: Baseline Characteristics (ITT)
DRV/r +2NRTI
(n=129)
Age, years (median, range)
Male (%)
Caucasian (%)
Disease characteristics
CD4 count (median (range), cells/uL)
CD4 <350 cells/uL (%)
Duration of prior ARVs, years (mean, sd)
Use of PI at screening (%)
Use of NNRTI at screening (%)
On their first NRTI combination
PI naïve
Hep B Surface Antigen, positive, n (%)
Hep C Antibody, positive, n (%)
History of IV Drug use
DRV/r
(n=127)
43 (24-72)
83%
90%
43 (25-67)
78%
92%
579
12%
6.4 (4.0)
57%
43%
48%
28%
0
15 (12%)
12 (9%)
571
14%
7.4 (4.2)
56%
44%
35%
23%
0
24 (19%)
20 (16%)
Multivariate analysis at Week 48 showed that HCV co-infection was highly
predictive of response in the primary endpoint.
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
MONET: HIV RNA by study visit (observed data)
>1000 copies/ml
400-1000 copies/ml
50-400 copies/ml
<50 copies/ml
HIV RNA>50 copies/mL
in 47/1051 samples
(4.5%)
DRV/r + 2 NRTIs
DRV/r
100%
100%
80%
80%
60%
60%
40%
40%
20%
20%
0%
0%
n=
129
115
118
115
HIV RNA>50 copies/mL
in 69/1009 samples
(6.9%)
114
127
110
108
108
105
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
MONET: HIV RNA <50 copies/mL at Week 96, TLOVR,
Switch=failure (ITT population)
Switch=failure analysis (TLOVR)
Difference = -5.8% (-16.0%, +4.4%)*
Switch included analysis
Difference = +1.4% (-5.5%, +8.3%)*
100
90
80.6%
80
HIV RNA
<50 by
Week 96
(%)
92.1%
90.7%
74.8%
70
60
50
40
30
20
10
0
DRV/r + 2NRTI
n=129
DRV/r mono
n=127
DRV/r + 2NRTI
DRV/r mono
n=129
n=127
* 95% confidence intervals from univariate analysis
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
MONET: Predictors of 96 week endpoint
HIV RNA <50, TLOVR, Per Protocol, Switch=failure
Odds ratio (95% confidence intervals) for treatment failure (n.s.: not significant)
Univariate analysis
Multivariate analysis
Treatment arm (DRV/r versus DRV/r +2NRTI)
1.31 (0.70 – 2.45),
p=n.s.
1.17 (0.61 – 2.25)
p=n.s.
HCV co-infection
4.25 (1.09 – 9.64),
p<0.0001
4.35 (2.06 – 9.17)
p<0.0001
History of IV Drug use
4.21 (1.90 – 9.32)
p=0.0004
n.s.
Age (>45 years)
0.48 (0.24 – 0.95)
p=0.035
n.s.
Gender (Female)
0.80 (0.38 – 1.72)
p=n.s.
n.s.
Nadir CD4 count (>250 cells/uL)
0.73 (0.39 – 1.39)
p=n.s.
n.s.
Adherence (<95% at any visit)
0.97 (0.51 – 1.83)
p=n.s.
n.s.
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
DRV/r + 2NRTI
Pre-screening genotype shows M184V
+ PI mutations: V82I, L90M
HIV RNA (copies/mL)
MONET trial: one patient in each treatment arm
with genotypic PI mutations during the trial
300
Week 24 genotype shows M184V
+ PI mutations: I54V, V82T, L90M
200
100
HIV RNA (copies/mL)
No pre-screening genotype available
50
<50
<50
<50
<50 <50
0
0
DRV/r mono
78
<50
10
300
20
30
40
50
60
70
80
Time
in MONET
trialDRV
- weeks
Week 12
genotype
shows
RAM: L33F
200
100
<50
63
<50
<50
<50
<50
<50
0
0
10
20
30
40
50
60
70
Time in MONET trial - weeks
Both patient have HIV RNA <50 copies/mL on long-term follow up, with no change in treatment
90
MONET: Clinical Adverse Events
DRV/r + 2NRTI
N=129
DRV/r
N=127
13 (10%)
13 (10%)
0 (0%)
0 (0%)
Grade 1-4 AE
109 (85%)
112 (88%)
Grade 1-4 psychiatric AE, all cause
20 (16%)
15 (12%)
Grade 1-4 nervous system AE, all cause
25 (19%)
27 (21%)
Grade 2-4 psychiatric AE, drug related
0 (0%)
2 (1.6%)
Grade 2-4 nervous system AE, drug related
4 (3.1)
3 (2.4%)
At least one SAE
Deaths
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
MONET Week 96: Conclusions
 In the primary efficacy analysis at Week 96, rates of double HIV RNA blips
and discontinuations were slightly higher in the DRV/r monotherapy arm,
compared with the DRV/r + 2NRTI arm.
 Most elevations in HIV RNA were low level (50-200 copies/mL), and
patients were re-suppressed <50 copies/mL at Week 96, either on the
original randomised treatment or with intensified treatment.
 Non-inferiority was shown in the “Switch Included” analysis.
 HCV co-infection and IV drug use were highly correlated with the primary
endpoint.
 There were no patients with phenotypic resistance to darunavir during
the trial – one patient per arm showed at least one genotypic PI mutation.
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]
Acknowledgments – thanks to the patients and
Country
and Race
investigators who
participated
in the trial
Sw itzerland
0.8%
UK
8.2%
Austria
6.3%
Belgium
9.4%
Spain
18.8%
Denmark
10.9%
Russia
4.3%
Germany
10.9%
Portugal
5.5%
Poland
11.3%
Hungary
4.3%
Italy
6.3%
Israel
3.1%
Rieger et al. WAC July 2010, Vienna [abstr TBLBB209]