DRV/r Monotherapy in PROTEA Study Analysis

Switch to DRV/r monotherapy MONOI MONET PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Design Randomisation* 1 : 1 Open-label W48 W96 282 HIV+ adults 1stline ART 2 NRTIs + (PI or NNRTI) No history of prior virologic failure HIV-1 RNA < 50 c/mL Exclusion if nadir CD4 < 100/mm3or current CD4 < 200/mm3 N = 136 DRV/r 800/100 mg QD + 2 NRTIs (optimisation at D0**) 4-week run-in DRV/r + NRTIs DRV/r 800/100 mg QD N = 137 * Randomisation was stratified on HCV antibody status (+ or -) ** TDF, ABC or ZDV + 3TC or FTC 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 Antinori A. AIDS 2015; 29:1811-20 PROTEA

PROTEA 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 Female Duration of ARV treatment, mean years On first NRTI combination On PI/r / On NNRTI HCV antibody positive Baseline CD4 cell count/mm3 : > 350 / 200-350 Nadir CD4 cell count/mm3 : > 200 / 100-200 Baseline HCV RNA < 50 c/ml AIDS Included in CNS substudy, N Protocol defined treatment failure at W48, n (%) 43 15% 5.3 71% 45 19% 5.7 58% 76% / 23% 10% 93% / 6% 78% / 20% 98% 7% 34 8 (6%) 69% / 26% 9% 90% / 10% 70% / 26% 100% 10% 37 19 (14%) At baseline, 8 patients had a nadir CD4 < 100/mm3(5 in the monotherapy arm and 3 in the triple therapy arm), and were excluded from the Per Protocol population Antinori A. AIDS 2015; 29:1811-20 PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy HIV RNA < 50 c/mL at W48 (FDA snapshot analysis) DRV/r + 2 NRTIs DRV/r qd monotherapy Switch=failure analysis Switch-included analysis ITT ITT (primary endpoint) Per protocol Per protocol 96.7 % 96.3 95.9 100 94.9 92 91.9 89.4 86.1 75 50 25 N= 136 137 123 123 136 137 123 123 0 Difference : - 8.7% (95% CI = - 15.5 ; - 1.8) 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 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) Antinori A. AIDS 2015; 29:1811-20 PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy HIV RNA < 50 c/mL at W48 (FDA snapshot analysis) by baseline nadir CD4 cell count DRV/r + 2 NRTIs DRV/r qd monotherapy ITT, switch=failure analysis Predictors of treatment failure (multiple regression model) : Low nadir CD4 (p = 0.005) Previous use of PI (p = 0.004) CD4 < 200/mm3 CD4 200/mm3 % 96.7 94.8 100 94.3 75 65.9 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 50 25 N= 30 41 106 96 0 Antinori A. AIDS 2015; 29:1811-20 PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Safety 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/mm3 Antinori A. AIDS 2015; 29:1811-20 PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Neurocognitive function and CNS substudy 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 Antinori A. AIDS 2015; 29:1811-20 PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy 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/mm3) was highly predictive of treatment failure in the monotherapy arm. Two patients in the monotherapy arm with CD4 nadir < 200/mm3 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 Antinori A. AIDS 2015; 29:1811-20 PROTEA