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 Ftkenheuer, M Nelson, N Clumeck, F Pulido, A Hill, Y van Delft, C Moecklinghoff, T Stark for the MONET Study Group 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 #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 4, 12, 24, 36, 48 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). Follow-up phase 96 weeks 256 subjects DRV/r 800/100 mg OD + 2 NRTI (re-optimised at baseline) n = 129 DRV/r 800/100 mg OD n = 127 Follow-up phase 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 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) % 6.4 (4.0) 57% 43% 48% 28% 2 (1.6%) 14 (11.2%) % 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)

DRV/r + 2NRTI (PP)DRV/r mono (PP)DRV/r + 2NRTI (ITT)DRV/r mono (ITT) MONET: Primary Efficacy Analysis: HIV RNA <50 copies/mL at Week 48, TLOVR, S = F Table EFF 4-5 HIV RNA <50 by Week 48 (%) Per Protocol analysis (PP)Intent to Treat analysis (ITT) Primary analysis N=123 N=129 N= % 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

MONET 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 < %+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) 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 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 resistance 10 DRV mutations 11 Primary IAS-USA PI mutations 01 M184V 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=129 Genotypic results 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

Median CD4 count: cells/uL Time - weeks DRV/r + 2NRTI (n=129) DRV/r mono (n=127) MONET: 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 clinical 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 (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 ( 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 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: 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.