Switch to DRVr monotherapy MONOI MONET PROTEA PROTEA

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Switch to DRV/r monotherapy § MONOI § MONET § PROTEA

Switch to DRV/r monotherapy § MONOI § MONET § PROTEA

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy § Design 282 HIV+

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy § Design 282 HIV+ adults line ART 2 NRTIs + (PI or NNRTI) No history of prior virologic failure HIV-1 RNA < 50 c/m. L Exclusion if nadir CD 4 < 100/mm 3 or current CD 4 < 200/mm 3 Randomisation* 1: 1 Open-label 1 st N = 136 4 -week run-in DRV/r + NRTIs N = 137 W 48 W 96 DRV/r 800/100 mg QD + 2 NRTIs (optimisation at D 0**) DRV/r 800/100 mg QD * Randomisation was stratified on HCV antibody status (+ or -) ** TDF, ABC or ZDV + 3 TC or FTC § Objective – Non inferiority in the proportion of patients with HIV-1 RNA < 50 c/m. L at W 48 (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 W 48 – Neurocognitive function using a series of neuropsychological tests PROTEA Antinori A. AIDS 2015; 29: 1811 -20

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Baseline characteristics and patient

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 43 45 15% 19% 5. 3 5. 7 71% 58% 76% / 23% 69% / 26% 10% 9% Baseline CD 4 cell count/mm 3 : > 350 / 200 -350 93% / 6% 90% / 10% Nadir CD 4 cell count/mm 3 : > 200 / 100 -200 78% / 20% 70% / 26% Baseline HCV RNA < 50 c/ml 98% 100% AIDS 7% 10% Included in CNS substudy, N 34 37 8 (6%) 19 (14%) Mean age, years Female Duration of ARV treatment, mean years On first NRTI combination On PI/r / On NNRTI HCV antibody positive Protocol defined treatment failure at W 48, n (%) § PROTEA At baseline, 8 patients had a nadir CD 4 < 100/mm 3 (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 Study: Switch PI or NNRTI to DRV/r QD monotherapy HIV RNA < 50

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy HIV RNA < 50 c/m. L at W 48 (FDA snapshot analysis) DRV/r + 2 NRTIs DRV/r qd monotherapy Switch=failure analysis % ITT (primary endpoint) 94. 9 100 86. 1 Switch-included analysis Per protocol 95. 9 89. 4 ITT 96. 3 Per protocol 96. 7 91. 9 92 75 50 25 N= 0 § § PROTEA 136 137 Difference : - 8. 7% (95% CI = - 15. 5 ; - 1. 8) 123 Difference : - 6. 5% (95% CI = - 12. 94 ; - 0. 04) 136 137 123 Difference : - 4. 3% (95% CI = - 9. 7 ; 1. 2) 123 Difference : - 4. 7% (95% CI = - 10. 5 ; 1) DRV/r monotherapy is not non inferior to DRV/r + 2 NRTI Primary analysis adjusting for treatment group, HCV status, nadir CD 4 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 Antinori A. AIDS 2015; 29: 1811 -20

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy HIV RNA < 50

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy HIV RNA < 50 c/m. L at W 48 (FDA snapshot analysis) by baseline nadir CD 4 cell count DRV/r + 2 NRTIs DRV/r qd monotherapy ITT, switch=failure analysis CD 4 < % 200/mm 3 96. 7 100 75 CD 4 ≥ 94. 3 200/mm 3 50 25 0 PROTEA 30 41 106 Predictors of treatment failure (multiple regression model) : • Low nadir CD 4 (p = 0. 005) • Previous use of PI (p = 0. 004) § Genotype (3 patients with confirmed HIV RNA > 400 c/m. L, 2 in monotherapy arm, 1 in triple therapy arm) • No emergence of primary PI mutation 94. 8 65. 9 N= § 96 Antinori A. AIDS 2015; 29: 1811 -20

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Safety § § §

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 CD 4 = 17/mm 3 PROTEA Antinori A. AIDS 2015; 29: 1811 -20

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Neurocognitive function and CNS

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy Neurocognitive function and CNS substudy § Improvement of all neurocognitive scores at W 48 in both groups (learning effect) § No difference between arms in the global score (NPZ-5) over time § W 48 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 CD 4 count or nadir CD 4. § CNS substudy – At baseline, HIV RNA < 50/m. L in the CSF in all patients – At W 48 : CSF HIV RNA < 50 c/m. L in all except 1 patient in the monotherapy arm : HIV RNA 654 c/m. L, no symptoms, nadir CD 4 : 166/mm 3 – Mean CSF neopterin concentration (nmol/L) • Monotherapy: 4. 8± 2. 1 at baseline vs 6. 2± 4. 3 at W 48 • Triple therapy: 4. 8± 1. 3 at baseline vs 4. 1± 1. 2 at W 48 – Mean CSF albumin : normal range at W 48 for both arms PROTEA Antinori A. AIDS 2015; 29: 1811 -20

PROTEA Study: Switch PI or NNRTI to DRV/r QD monotherapy § Summary – In

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 CD 4 count (< 200/mm 3) was highly predictive of treatment failure in the monotherapy arm. – Two patients in the monotherapy arm with CD 4 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 Antinori A. AIDS 2015; 29: 1811 -20