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The MONET trial: darunavir/ritonavir The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA standard HAART, for patients with HIV RNA
<50 copies/mL at baseline<50 copies/mL at baselineJR Arribas, A Horban, J Gerstoft, G FJR Arribas, A Horban, J Gerstoft, G Fätkenheuer, M Nelson, N Clumeck, F Pulido, A Hill, tkenheuer, M Nelson, N Clumeck, F Pulido, A Hill, Y van Delft, C Moecklinghoff, T Stark for the MONET Study GroupY van Delft, C Moecklinghoff, T Stark for the MONET Study Group
Oral Late-Breaker presentation at 5th IAS ConferenceOral Late-Breaker presentation at 5th IAS ConferenceCape Town, South Africa, July 2009Cape Town, South Africa, July 2009 #TUAB106-LB#TUAB106-LB
MONET - Trial DesignMONET - 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
4, 12, 24, 36, 48 weeks96 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).
Follow-upphase 96 weeks
256 subjects
DRV/r 800/100 mg OD+ 2 NRTI (re-optimised at baseline)
n = 129
DRV/r 800/100 mg ODn = 127
Follow-upphase 96 weeks
No run-in period
SC
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
30 days BL
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: Study Design and ObjectivesMONET: 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)MONET: Baseline Characteristics (ITT)
57912%
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%)
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 (%)
43 (24-72)83%90%
43 (25-67)78%92%
Age, years (median, range) Male (%) Caucasian (%)
DRV/r + 2NRTI (n=129)
DRV/r (n=127)
0
10
20
30
40
50
60
70
80
90
100
DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT)
MONET: Primary Efficacy Analysis:MONET: Primary Efficacy Analysis:HIV RNA <50 copies/mL at Week 48, TLOVR, S = F HIV RNA <50 copies/mL at Week 48, TLOVR, S = F
Table EFF 4-5
HIV RNA<50 byWeek 48(%)
Per Protocol analysis (PP) Intent to Treat analysis (ITT)Primary analysis
N=123 N=123 N=129 N=127
87.8% 86.2% 85.3% 84.3%
-1.6%; lower limit 95%CI: -10.1% -1%; lower limit 95%CI: -9.9%
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET trial: sensitivity analysesMONET trial: sensitivity analyses
PP, HIV RNA <200, TLOVR, switch equals failure
0%
Difference in 48 week HIV RNA response rate between DRV/r mono and DRV/r + 2NRTI arms (95% confidence intervals)
DRV/r + 2NRTI better
-7.0% -1.8% +3.5%
-12% Analysis
ITT, HIV RNA <50, TLOVR, switch included (S F)
-1.6% +4.2%
Observed HIV RNA <50
Observed HIV RNA <200-0.8% +2.6%-4.2%
-9.5% -3.2% +3.1%
94.8% vs 96.6%
93.5% vs 95.1%
91.3% vs 94.6%
97.6% vs 98.4%
-7.4%
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
DRV/r + 2NRTI: n=129
HIV RNA<50: 110
Baseline
Treatment
period
Last visit
HIV RNA>50
x2: n=7 (TLOVR)
d/c or changed
treatment, n=9
HIV RNA<50: 6
HIV RNA>50: 1
HIV RNA<50: 8
no data: 1
Missing data
n=3
HIV RNA<50: 2
RNA <50 wk36: 1
MONET: Patient outcomes in DRV/r + 2 NRTI (ITT)MONET: Patient outcomes in DRV/r + 2 NRTI (ITT)
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 MONET: Patient outcomes in DRV/r monotherapy (ITT)(ITT)
DRV/r monotherapy: n=127
HIV RNA<50: 107
Baseline
Treatment
period
Last visit
HIV RNA>50
x2: n=11 (TLOVR)
d/c or changed
treatment, n=9
HIV RNA<50: 10
HIV RNA>50: 1
HIV RNA<50: 7
HIV RNA>50: 2
Missing data
n=0
HIV RNA<50: 97.6% 124/127
MONET: Drug resistanceMONET: Drug resistance
1 0DRV mutations
11 Primary IAS-USA PI mutations
01M184V
21/22 (96%) 12/13 (92%)No primary PI, DRV or NRTI mutations
2213 Patients with at least 1 successful genotype
DRV/r mono
N=127
DRV/r + 2NRTI
N=129Genotypic results
1 patient per arm had any evidence of genotypic resistanceNo patients had phenotypic resistance to DRV
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
Median CD4 count:cells/uL
Time - weeks
DRV/r + 2NRTI (n=129)
DRV/r mono (n=127)
MONET: Median CD4 Cell Count (Observed) – ITTMONET: Median CD4 Cell Count (Observed) – ITT
2 (1.6%)
0 (0%)
6 (4.7%)
7 (5.5%)
(N=127)
DRV/r mono
5 (3.9%) GI (all AEs)
2 (1.6%)Diarrhea
(N=129)
2 (1.6%)Rash (all types)
1 (0.8%))Nausea
DRV/r + 2NRTI
Gr 2–4 AEs† ≥2% incidence, n (%)
†At least possibly related to study drug, excluding laboratory-related events
MONET: Grade 2–4 drug related MONET: Grade 2–4 drug related clinical adverse eventsclinical adverse events
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
6 (4.8%)2 (1.6%)Total cholesterol >7.77 mmol/l, sustained
6* (4.0%) 1 (0.8%)AST >5 x ULN
4 (3.2%)3 (2.3%)Lipase >3 x ULN
6* (4.8%)2* (1.6%)ALT >5 x ULN
n = 126n = 129
DRV/r monoDRV/r + 2NRTI
> 2 % Incidence, n (%)*
* 7 of the 8 cases of ALT and AST elevations were associated with Hepatitis A or C co-infection
MONET: Grade 3 / 4 Laboratory abnormalities MONET: Grade 3 / 4 Laboratory abnormalities (Worst values)(Worst values)
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 Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label viral suppression: a randomized open-label
non-inferiority trial, MONOI-ANRS 136non-inferiority trial, MONOI-ANRS 136
C. Katlama et al #WELBB102C. Katlama et al #WELBB102
WEDNESDAY. LATE BREAKERS TRACK B. WEDNESDAY. LATE BREAKERS TRACK B. Session Room 1. 13:10Session Room 1. 13:10
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
Country and Race
Israel3.1%
Hungary4.3%
Germany10.9%
Denmark10.9%
Belgium9.4%
Austria6.3%
UK8.2%
Switzerland0.8%
Spain18.8%
Russia4.3%
Portugal5.5%
Poland11.3% Italy
6.3%
MONET: AcknowledgementsMONET: Acknowledgements
Thanks to all the 256 patients who participated in the MONET trial, plus the investigators and study monitors
J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB
MONET: AcknowledgementsMONET: Acknowledgements
Participating centers:Austria: A. Rieger, N. VetterBelgium: N. Clumeck, E. FlorenceSwitzerland: P. VernazzaGermany: G. Fätkenheuer, A. Stoehr, W. Schmidt, M, Stoll, C. StephanDenmark: J. Gerstoft, C. Pedersen, L. MathiesenSpain: B. Clotet, F. Pulido, J. Arribas, J. Gatell, J. Iribarren, R. Rubio, J. PasquauUnited Kingdom: M. Johnson, B. Peters, M. Nelson, A. Winston, Hungary: D. BanhegyiIsrael: S. MaayanItaly: A. Lazzarin, A. Antinori, F. Suter, A. D‘Arminio Monforte, G. CarosiPoland: A. HorbanPortugal: F. Antunes, R. MarquesRussia: 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.
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