Switch to DRV/r monotherapy ARV-trial.com Switch to DRV/r monotherapy MONOI MONET PROTEA 1

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Design Randomisation* 1 : 1 Open-label W48 W144 N = 129 293 HIV+ adults On 2 NRTIs + (PI or NNRTI) Darunavir-naïve No history of prior virologic failure HIV-1 RNA < 50 c/mL > 6 months DRV/r 800/100 mg qd + 2 NRTIs (optimisation at D0**) N = 127 DRV/r 800/100 mg qd * Randomisation was stratified on the use of PI or NNRTI (57% patients on PI, 43% on NNRTI) ** NRTI used at baseline: TDF + FTC = 46% ; ABC + 3TC: 31% ; ZDV + 3TC = 10% ; TDF + 3TC = 7% ; other combinations: 6% Objective Non inferiority in the proportion of patients with HIV-1 RNA < 50 c/mL at W48 (per-protocol analysis, switch= failure, TLOVR algorithm) ; lower limit of the 95% CI for the difference= - 12%, 80% power MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy ARV-trial.com MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Baseline characteristics and patient disposition DRV/r qd + 2 NRTIs DRV/r qd monotherapy Mean age, years 44 43 Female 17% 22% IV drug user 9% 16% HCV antibody positive CD4 cell count, mean/mm3 579 571 Duration of ARV treatment, years 5.9 7.4 PI treatment at screening 57% 56% NNRTI treatment at screening 43% 44% Protease inhibitor naïve at screening 28% 23% Protocol defined treatment failure at W48, n (%) 19 (15%) 20 (16%) Discontinuation for adverse event 4 Confirmed HIV RNA elevation 7 11 At baseline, 13 patients had HIV-1 RNA levels > 50 c/mL (9 in the monotherapy arm and 4 in the triple therapy arm) despite having results < 50 c/ml at screening MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Results: W48 outcome 25 50 100 75 87.8% 84.3% 123 % 85.3% 129 127 86.2% Per-protocol (primary endpoint) ITT N= HIV-1 RNA < 50 c/mL (TLOVR, switch = failure) 95% CI for the difference = - 10.1 ; 6.8 95% CI for the difference = - 9.9 ; 8.8 95% CI for the difference = - 7.4 ; 4.2 93.5% 95.1% ITT, switch-included analysis DRV/r + 2 NRTIs DRV/r qd monotherapy Non inferiority of DRV/r monotherapy MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Outcomes of confirmed HIV RNA elevations Patient HIV RNA values (c/mL) Change in Treatment Last HIV RNA (c/mL) DRV/r monotherapy arm 1 140 ; 133 None < 50 2 59 ; 214 ZDV/3TC + NVP 3 132 ; 139 LPV/r monotherapy 4 539 ; 862 TDF/FTC/EFV 5 67 ; 810 810 6 40.500 ; 628 7 158 ; 140 ABC/3TC + DRV/r 8 51 ; 80 9 106 ; 268 TDF/FTC + DRV/r 10 722 ; 157 11 779 ; 267 Triple therapy arm (DRV/r + 2 NRTIs) 294 ; 116 54.000 ; 3.400 78 ; 50 164 ; 67 989 ; 59 746 ; 2.230 2.230 128 ; 548 MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Outcomes of discontinuations from the trial Patient Reason for discontinuation Change in Treatment Last HIV RNA (c/mL) DRV/r monotherapy arm 12 History of virologic failure ABC/3TC + ATV/r < 50 13 Adverse event TDF + 3TC + EFV 14 Investigator decision TDF/FTC + LPV/r 15 ABC/3TC + NVP 16 17 Withdrew consent ZDV/3TC + EFV 18 None 19 Off all ARVs > 75 000 20 In prison 8 TDF/FTC + NVP 9 ZDV/3TC + NVP Triple therapy arm (DRV/r + 2 NRTIs) 10 Pregnancy 11 NZDV/3TC + NVP Private reasons TDF + ZDV + 3TC ZDV/3TC + LPV/r RNA > 50 c/mL at SCR + BL No data Switched to DRV/r DRV/r monotherapy MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Other endpoints In multivariate analysis, hepatitis C co-infection was a significant predictor of confirmed HIV RNA elevations (p < 0.01) Resistance data: Genotype was available for 35/61 patients with HIV RNA > 50 c/mL (22 in the monotherapy group and 13 in the triple therapy group) Resistance mutations to PI in 1 one patient in each arm, with no phenotypic resistance to DRV. HIV-1 RNA returned to < 50 c/mL without changing therapy in both patients Most common grade 2 to 4 adverse events (AE) were gastrointestinal Serious AE were seen in 9 patients in each group Discontinuation for AE by W48 occurred in 8 patients in the monotherapy group and 3 in the triple therapy group Grade 1 to 4 nervous system AE were seen in 16% of patients in each group, and Grade 1 to 4 psychiatric AE in 9% of patients in each group There were more haematological abnormalities in the triple therapy arm, related to zidovudine MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Conclusions from W48 data In patients with virologic suppression on standard triple therapy (2 NRTIs + 1 NNRTI or 1 PI), once-daily DRV/r monotherapy has shown non inferior HIV RNA suppression at week 48 compared with a standard therapy of 2 NRTIs + once-daily DRV/r A switch to once-daily DRV/r monotherapy can be considered in patients who have HIV RNA < 50 c/mL for more than 6 months on other treatments and no history of virologic failure, but wish to avoid toxicities related to other ARVs MONET Arribas J, AIDS 2010;24:223-230

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Results: W96 outcome HIV-1 RNA < 50 c/mL at W96, ITT, TLOVR (%) Monotherapy is not noninferior with switch = failure analysis at W96 Δ -5.8% (95% CI: -16.0% to +4.4%) If resuppression with intensification included as success, then monotherapy is noninferior at W96 Δ +1.4% (95% CI: -5.5% to +8.3%) 40 100 20 80 60 DRV/r monotherapy (N = 127) DRV/r + 2 NRTIs (N = 129) 80.6 74.8 Switch = failure 92.1 90.7 Switch allowed MONET Rieger A, et al. AIDS 2010. Abs. THLBB209

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy HIV-1 RNA < 50 c/mL at W144 (ITT-TLOVR) Switch* = failure Switch* included 2 consecutive HIV-1 RNA > 50 c/mL: DRV/r monotherapy, N = 21 DRV/r + 2 NRTI, N = 13 18/21 and 10/13 had HIV-1 RNA < 50 c/mL at W144 Level of HIV-1 RNA at baseline and HCV co-infection were significantly associated with transient viremia during the 144 weeks (p < 0.05) Resistance emergence to PI (IAS-USA): 1 in each arm, both before W24 Lower margin of the 95 % CI of the  - 16.9 % - 8.7 % 25 50 100 75 75 % 84 % DRV/r + 2 NRTI % 83.5 % DRV/r mono 69 % Non inferiority of DRV/r monotherapy only in the « switch-included » analysis * Change in ARV MONET Arribas JR, HIV Medicine 2012;13:398-405