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
•
•
•
•
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).
•
•
•
•
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