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

2.  Design  Objective –Non inferiority in the proportion of patients with HIV-1 RNA < 50 c/mL at W48 (ITT analysis, missing/discontinuation/switch= failure, snapshot algorithm); lower limit of the 95% CI for the difference= - 12%, 80% power –CNS substudy : CSF HIV RNA at baseline and W48 –Neurocognitive function using a series of neuropsychological tests DRV/r 800/100 mg QD + 2 NRTIs (optimisation at D0**) DRV/r 800/100 mg QD Randomisation* 1 : 1 Open-label 282 HIV+ adults 1 st line ART 2 NRTIs + (PI or NNRTI) No history of prior virologic failure HIV-1 RNA < 50 c/mL Exclusion if nadir CD4 < 100/mm 3 or current CD4 < 200/mm 3 N = 137 N = 136 W48 * Randomisation was stratified on HCV antibody status (+ or -) ** TDF, ABC or ZDV + 3TC or FTC PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print W96 4-week run-in DRV/r + NRTIs PROTEA

3. DRV/r QD + 2 NRTIs DRV/r QD monotherapy Mean age, years4345 Female15%19% Duration of ARV treatment, mean years5.35.7 On first NRTI combination71%58% On PI/r / On NNRTI76% / 23%69% / 26% HCV antibody positive10%9% Baseline CD4 cell count/mm 3 : > 350 / 200-35093% / 6%90% / 10% Nadir CD4 cell count/mm 3 : > 200 / 100-20078% / 20%70% / 26% Baseline HCV RNA < 50 c/ml98%100% AIDS7%10% Included in CNS substudy, N3437 Protocol defined treatment failure at W48, n (%)8 (6%)19 (14%) Baseline characteristics and patient disposition  At baseline, 8 patients had a nadir CD4 < 100/mm 3 (5 in the monotherapy arm and 3 in the triple therapy arm), and were excluded from the Per Protocol population PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA

4. HIV RNA < 50 c/mL at W48 (FDA snapshot analysis) DRV/r + 2 NRTIsDRV/r qd monotherapy 0 25 50 100 75 94.9 89.4 136 % 95.9 137123 86.1 ITT (primary endpoint)Per protocol N= Difference : - 8.7% (95% CI = - 15.5 ; - 1.8) 92 96.3 Switch-included analysis  DRV/r monotherapy is not non inferior to DRV/r + 2 NRTI  Primary analysis adjusting for treatment group, HCV status, nadir CD4 and previous PI use : DRV/r QD mono non inferior to triple therapy (≠ - 5.8%, 95% CI: - 11.51 to - 0.14), but difference still inferior statistically Per protocolITT 91.9 96.7 Difference : - 6.5% (95% CI = - 12.94 ; - 0.04) Difference : - 4.3% (95% CI = - 9.7 ; 1.2) Difference : - 4.7% (95% CI = - 10.5 ; 1) 136137123 Switch=failure analysis PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA

5. HIV RNA < 50 c/mL at W48 (FDA snapshot analysis) by baseline nadir CD4 cell count DRV/r + 2 NRTIsDRV/r qd monotherapy 0 25 50 100 75 96.7 94.8 30 % 94.3 4110696 65.9 CD4 < 200/mm 3 CD4 ≥ 200/mm 3 N=  Predictors of treatment failure (multiple regression model) : Low nadir CD4 (p = 0.005) Previous use of PI (p = 0.004)  Genotype (3 patients with confirmed HIV RNA > 400 c/mL, 2 in monotherapy arm, 1 in triple therapy arm) No emergence of primary PI mutation ITT, switch=failure analysis PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA

6. PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy  Most common adverse events : infections or infestations (32%) and gastrointestinal (16%)  Serious adverse events, N = 14 (5%): 9 in the monotherapy arm and 5 in the triple therapy arm. One unrelated death in the monotherapy arm  Grade 2-4 adverse events considered treatment-related –More common in the monotherapy (N = 12; 9%) than in the triple therapy arm (N = 2; 1%) –In the monotherapy arm, these were mainly gastrointestinal events and rises in cholesterol after discontinuation of TDF  Discontinuation of DRV for adverse event –N = 5 (4%) in the monotherapy arm, N = 1 (1%) in the triple therapy arm  Neurological adverse events, N = 27 (10%) : –13 in the monotherapy arm and 14 in the triple therapy arm –Most common AE = headache (N = 14)  1 case of encephalomyelitis in the monotherapy arm : –required hospitalization; HIV RNA detectable in plasma and CSF; re-suppressed and symptoms resolved after intensification with NRTIs including high-dose ZDV. NB : Nadir CD4 = 17/mm 3 Safety Hill AM. AIDS 2015;29 Epub ahead of print PROTEA

7.  Improvement of all neurocognitive scores at W48 in both groups (learning effect)  No difference between arms in the global score (NPZ-5) over time  W48 NPZ-5 score was very siginificantly associated to sex, race, and baseline NPZ-5 score (p < 0.0001). Alcohol consumption, smoking, history of cardiovascular events and age were also significantly associated. No effect of baseline HIV RNA, baseline CD4 count or nadir CD4.  CNS substudy –At baseline, HIV RNA < 50/mL in the CSF in all patients –At W48 : CSF HIV RNA < 50 c/mL in all except 1 patient in the monotherapy arm : HIV RNA 654 c/mL, no symptoms, nadir CD4 : 166/mm3 –Mean CSF neopterin concentration (nmol/L) Monotherapy: 4.8±2.1 at baseline vs 6.2±4.3 at W48 Triple therapy: 4.8±1.3 at baseline vs 4.1±1.2 at W48 –Mean CSF albumin : normal range at W48 for both arms Neurocognitive function and CNS substudy PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA

8.  Summary –In patients with virologic suppression on standard first-line triple therapy (2 NRTIs + 1 NNRTI or 1 PI), once-daily DRV/r monotherapy did not show non inferior HIV RNA suppression at week 48 compared with a standard therapy of 2 NRTIs + once-daily DRV/r –A low nadir CD4 count (< 200/mm 3 ) was highly predictive of treatment failure in the monotherapy arm. –Two patients in the monotherapy arm with CD4 nadir < 200/mm 3 developed viremia in both CSF and plasma, with one symptomatic case –There was no difference in neurocognitive function or the risk of neuropsychiatric adverse events between DRV/r monotherapy and triple therapy PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Hill AM. AIDS 2015;29 Epub ahead of print PROTEA