Switch to DRV/r monotherapy  MONOI  MONET  PROTEA  DRV600

 Design  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 DRV/r 800/100 mg qd + 2 NRTIs (optimisation at D0**) DRV/r 800/100 mg qd Randomisation* 1 : 1 Open-label 293 HIV+ adults On 2 NRTIs + (PI or NNRTI) Darunavir-naïve No history of prior virologic failure HIV-1 RNA 6 months N = 127 N = 129 W48 * 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% MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Arribas J, AIDS 2010;24: MONET W144

DRV/r qd + 2 NRTIs DRV/r qd monotherapy Mean age, years4443 Female17%22% IV drug user9%16% HCV antibody positive9%17% CD4 cell count, mean/mm Duration of ARV treatment, years PI treatment at screening57%56% NNRTI treatment at screening43%44% Protease inhibitor naïve at screening28%23% Protocol defined treatment failure at W48, n (%)19 (15%)20 (16%) Discontinuation for adverse event04 Confirmed HIV RNA elevation711 Baseline characteristics and patient disposition MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Arribas J, AIDS 2010;24: MONET  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

Results: W48 outcome Arribas J, AIDS 2010;24: MONET DRV/r + 2 NRTIsDRV/r qd monotherapy MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy % 84.3% 123 % 85.3% % Per-protocol (primary endpoint) ITT N= HIV-1 RNA < 50 c/mL (TLOVR, switch = failure) 95% CI for the difference = ; % CI for the difference = ; % CI for the difference = ; % 95.1% ITT, switch-included analysis  Non inferiority of DRV/r monotherapy

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Patient HIV RNA values (c/mL) Change in Treatment Last HIV RNA (c/mL) DRV/r monotherapy arm 1140 ; 133None< ; 214ZDV/3TC + NVP< ; 139LPV/r monotherapy< ; 862TDF/FTC/EFV< ; 810None ; 628None< ; 140ABC/3TC + DRV/r< ; 80None< ; 268TDF/FTC + DRV/r< ; 157TDF/FTC + DRV/r< ; 267ABC/3TC + DRV/r< 50 Triple therapy arm (DRV/r + 2 NRTIs) 1294 ; 116None< ; 3.400None< ; 50None< ; 67None< ; 59None< ; 2.230None ; 548None< 50 Outcomes of confirmed HIV RNA elevations Arribas J, AIDS 2010;24: MONET

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Patient Reason for discontinuation Change in Treatment Last HIV RNA (c/mL) DRV/r monotherapy arm 12History of virologic failureABC/3TC + ATV/r< 50 13Adverse eventTDF + 3TC + EFV< 50 14Investigator decisionTDF/FTC + LPV/r< 50 15Adverse eventABC/3TC + NVP< 50 16Adverse eventABC/3TC + ATV/r< 50 17Withdrew consentZDV/3TC + EFV< 50 18History of virologic failureNone< 50 19Adverse eventOff all ARVs> In prisonNone< 50 8Withdrew consentTDF/FTC + NVP< 50 9Withdrew consentZDV/3TC + NVP< 50 Triple therapy arm (DRV/r + 2 NRTIs) 10PregnancyZDV/3TC + NVP< 50 11Investigator decisionNZDV/3TC + NVP< 50 12Private reasonsTDF + ZDV + 3TC< 50 13PregnancyZDV/3TC + LPV/r< 50 14History of virologic failureNone< 50 15RNA > 50 c/mL at SCR + BLNoneNo data 16Switched to DRV/rDRV/r monotherapy< 50 Outcomes of discontinuations from the trial Arribas J, AIDS 2010;24: MONET

MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy  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 Arribas J, AIDS 2010;24: MONET Other endpoints

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 Arribas J, AIDS 2010;24: MONET

 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%) Rieger A, et al. AIDS Abs. THLBB209 HIV-1 RNA < 50 c/mL at W96, ITT, TLOVR (%) DRV/r monotherapy (N = 127) DRV/r + 2 NRTIs (N = 129) Switch = failure Switch allowed MONET MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy Results: W96 outcome

HIV-1 RNA < 50 c/mL at W144 (ITT-TLOVR)  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 Switch* = failureSwitch* included %- 8.7 % Lower margin of the 95 % CI of the  Non inferiority of DRV/r monotherapy only in the « switch-included » analysis * Change in ARV MONET Study: Switch PI or NNRTI to DRV/r qd monotherapy % 84 % DRV/r + 2 NRTI % 83.5 % DRV/r mono DRV/r + 2 NRTI DRV/r mono 69 % MONET Arribas JR, HIV Medicine 2012;13: