Transcript Title
The MONET trial: darunavir/ritonavir
monotherapy shows non-inferior efficacy to
standard HAART, for patients with HIV RNA
<50 copies/mL at baseline
JR Arribas, A Horban, J Gerstoft, G Fätkenheuer, M Nelson, N Clumeck, F Pulido, A Hill,
Y van Delft, C Moecklinghoff, T Stark for the MONET Study Group
Oral Late-Breaker presentation at 5th IAS Conference
Cape Town, South Africa, July 2009
#TUAB106-LB
MONET - Trial Design
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Taking 2 NRTI + either NNRTI or boosted PI at screening (stratified)
No prior use of darunavir (DRV)
HIV RNA <50 copies/mL for at least 6 months,
No history of virological failure
DRV/r 800/100 mg OD
+ 2 NRTI (re-optimised at baseline)
n = 129
256 subjects
No run-in period
DRV/r 800/100 mg OD
n = 127
SC
30 days
Follow-up
phase 96 weeks
BL
4, 12, 24, 36, 48 weeks
Follow-up
phase 96 weeks
96
wks
Primary Endpoint: HIV RNA< 50 at week 48 (TLOVR). Per Protocol, Switch = Failure
2 consecutive HIV RNA > 50 copies/mL (Roche Amplicor HIV-1 Monitor assay 1.5)
Stopping DRV/r
Starting NRTIs in the monotherapy arm
Stopping NRTIs in the triple therapy arm (switches in NRTIs were permitted at any time).
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J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Study Design and Objectives
• Primary objective: to show non-inferior efficacy for DRV/r
monotherapy (800/100 mg OD dose) versus standard HAART
(DRV/r + 2 NRTI).
• Study power: 80% to show non-inferiority for DRV/r vs DRV/r + 2
NRTIs, with a sample size of 125 patients per arm (delta = -12%).
• Analysis:
− Per protocol (PP): excluded patients with major protocol
violations such as a history of virological failure, or patients
randomised incorrectly (n = 10).
Time to loss of virolgical response (TLOVR)
− Observed: only virological endpoints.
− Intent To Treat (ITT) – all randomised patients
▫ Switch = Failure (S = F)
▫ Switch Included (S F)
• All patients were followed up to Week 48
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Baseline Characteristics (ITT)
DRV/r + 2NRTI
(n=129)
Age, years (median, range)
Male (%)
Caucasian (%)
Disease characteristics
CD4 count (median, 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 (%)
DRV/r
(n=127)
43 (24-72)
83%
90%
43 (25-67)
78%
92%
579
12%
6.4 (4.0)
57%
43%
48%
28%
2 (1.6%)
14 (11.2%)
571
14%
7.4 (4.2)
56%
44%
35%
23%
1 (0.8%)
24 (19.0%)
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Primary Efficacy Analysis:
HIV RNA <50 copies/mL at Week 48, TLOVR, S = F
Per Protocol analysis (PP)
Intent to Treat analysis (ITT)
Primary analysis
100
90
-1.6%; lower limit 95%CI: -10.1%
-1%; lower limit 95%CI: -9.9%
87.8%
86.2%
85.3%
DRV/r + 2NRTI (PP)
DRV/r mono (PP)
DRV/r + 2NRTI (ITT)
84.3%
80
HIV RNA
<50 by
Week 48
(%)
70
60
50
40
30
20
10
0
Table EFF 4-5
N=123
N=123
N=129
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
DRV/r mono (ITT)
N=127
MONET trial: sensitivity analyses
Difference in 48 week HIV RNA response rate between
DRV/r mono and DRV/r + 2NRTI arms (95% confidence intervals)
-12%
-1.8%
-7.0%
94.8% vs 96.6%
-1.6%
-7.4%
93.5% vs 95.1%
Analysis
0%
-9.5%
-3.2%
+3.5%
+4.2%
ITT, HIV RNA <50,
TLOVR, switch included (S F)
+3.1%
91.3% vs 94.6%
97.6% vs 98.4%
PP, HIV RNA <200,
TLOVR, switch equals failure
Observed HIV RNA <50
-4.2%
-0.8%
+2.6%
Observed HIV RNA <200
DRV/r + 2NRTI better
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Patient outcomes in DRV/r + 2 NRTI (ITT)
Baseline
DRV/r + 2NRTI: n=129
Treatment
HIV RNA>50
d/c or changed
Missing data
x2: n=7 (TLOVR)
treatment, n=9
n=3
HIV RNA<50: 6
HIV RNA<50: 8
HIV RNA<50: 2
HIV RNA>50: 1
no data: 1
RNA <50 wk36: 1
period
HIV RNA<50: 110
Last
visit
HIV RNA<50: 97.7% 126/129
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Patient outcomes in DRV/r monotherapy (ITT)
DRV/r monotherapy: n=127
Baseline
Treatment
HIV RNA>50
d/c or changed
Missing data
x2: n=11 (TLOVR)
treatment, n=9
n=0
period
Last
visit
HIV RNA<50: 107
HIV RNA<50: 10
HIV RNA<50: 7
HIV RNA>50: 1
HIV RNA>50: 2
HIV RNA<50: 97.6% 124/127
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Drug resistance
DRV/r + 2NRTI
Genotypic results
DRV/r mono
N=129
N=127
13
22
12/13 (92%)
21/22 (96%)
M184V
1
0
Primary IAS-USA PI mutations
1
1
DRV mutations
0
1
Patients with at least 1 successful genotype
No primary PI, DRV or NRTI mutations
1 patient per arm had any evidence of genotypic resistance
No patients had phenotypic resistance to DRV
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Median CD4 Cell Count (Observed) – ITT
Median
CD4
count:
cells/uL
DRV/r + 2NRTI (n=129)
DRV/r mono (n=127)
Time - weeks
MONET: Grade 2–4 drug related
clinical adverse events
DRV/r + 2NRTI
DRV/r mono
Gr 2–4 AEs† ≥2% incidence, n (%)
(N=129)
(N=127)
GI (all AEs)
5 (3.9%)
7 (5.5%)
Diarrhea
2 (1.6%)
6 (4.7%)
Nausea
1 (0.8%))
0 (0%)
Rash (all types)
2 (1.6%)
2 (1.6%)
†At
least possibly related to study drug, excluding laboratory-related events
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Grade 3 / 4 Laboratory abnormalities
(Worst values)
DRV/r + 2NRTI
DRV/r mono
n = 129
n = 126
ALT >5 x ULN
2* (1.6%)
6* (4.8%)
AST >5 x ULN
1 (0.8%)
6* (4.0%)
Lipase >3 x ULN
3 (2.3%)
4 (3.2%)
Total cholesterol >7.77 mmol/l, sustained
2 (1.6%)
6 (4.8%)
> 2 % Incidence, n (%)*
* 7 of the 8 cases of ALT and AST elevations were associated with Hepatitis A or C
co-infection
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
Conclusions
Darunavir/ritonavir monotherapy showed consistently
non-inferior efficacy versus triple antiretroviral drug
treatment at Week 48.
Most elevations in HIV RNA were low level (50-400
copies/mL), and patients were re-suppressed <50
copies/mL at last visit, either on the original randomised
treatment or with intensified treatment.
There were no patients with phenotypic resistance to
darunavir during the trial – one patient per arm showed
at least one genotypic PI mutation.
No new or unexpected safety signals were detected
(details submitted to EACS and AELD conferences).
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
Efficacy of darunavir/ritonavir as single-drug
maintenance therapy in patients with HIV-1
viral suppression: a randomized open-label
non-inferiority trial, MONOI-ANRS 136
C. Katlama et al #WELBB102
WEDNESDAY. LATE BREAKERS TRACK B.
Session Room 1. 13:10
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Acknowledgements
Country and Race
Thanks to all the 256 patients who participated in the MONET trial, plus the investigators and
study monitors
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%
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Acknowledgements
Participating centers:
Austria: A. Rieger, N. Vetter
Belgium: N. Clumeck, E. Florence
Switzerland: P. Vernazza
Germany: G. Fätkenheuer, A. Stoehr, W. Schmidt, M, Stoll, C. Stephan
Denmark: J. Gerstoft, C. Pedersen, L. Mathiesen
Spain: B. Clotet, F. Pulido, J. Arribas, J. Gatell, J. Iribarren, R. Rubio, J. Pasquau
United Kingdom: M. Johnson, B. Peters, M. Nelson, A. Winston,
Hungary: D. Banhegyi
Israel: S. Maayan
Italy: A. Lazzarin, A. Antinori, F. Suter, A. D‘Arminio Monforte, G. Carosi
Poland: A. Horban
Portugal: F. Antunes, R. Marques
Russia: N Zakharova, V. Pokrovsky
The authors would like to thank the patients and their families for their participation and support
during the study, and the MONET study team and co-investigators for their collaboration.
This study was sponsored by Tibotec, a division of Janssen-Cilag.
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB