Switch to TDFFTCRPV SPIRIT Study SPIRIT study Switch

Switch to TDF/FTC/RPV § SPIRIT Study

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV § Design Randomisation 2: 1 Open-label 476 HIV+ adults Stable PI + RTV + 2 NRTI ≥ 6 months with HIV RNA < 50 c/m. L On 1 st or 2 nd regimen No prior NNRTI use No known resistance to study agents § Objective – – SPIRIT N = 317 N = 159 W 24 W 48 TDF/FTC/RPV STR PI/r + 2 NRTIs TDF/FTC/RPV STR 24 weeks Primary Endpoint 48 weeks Secondary Endpoint Primary Endpoint : Non-inferiority in the proportion of patients with HIV-1 RNA < 50 c/m. L at W 24 (FDA snapshot analysis) ; upper limit of the 95% CI for the difference = 12% Secondary Endpoints: Proportion of HIV 1 RNA < 50 copies/m. L at W 48 ; Change in fasting lipid and CD 4 cell count at W 24 and W 48 ; Safety and tolerability Palella F, AIDS 2014; 28: 335 -44

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV Baseline characteristics and disposition TDF/FTC/RPV N = 159 2 NRTI + PI/r N = 317 Female 14% 9% Baseline CD 4/mm 3 (mean) 576 600 Time since first ART, years (median) 2. 9 2. 6 N = 20 N=7 Adverse event / Lack of efficacy 7/1 0/0 Discontinued between W 24 and W 48 N=7 N=9 Adverse event / Lack of efficacy 0/1 5/1 Discontinued before W 24 ART at screening NRTI SPIRIT PI/r TDF/FTC 81% ATV/r 37% ABC/3 TC 13% DRV/r 20% ZDV/3 TC 3. 4% FPV/r 33% LPV/r 33% Palella F, AIDS 2014; 28: 335 -44

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV HIV RNA < 50 c/m. L at W 24 according to pre-ART HIV RNA < 50 c/m. L at W 24 and W 48 (ITT, snapshot) TDF/FTC/RPV (D 1 to W 24) 2 NRTI + PI/r (D 1 to W 24) TDF/FTC/RPV (delayed switch, W 24 to W 48) 100 TDF/FTC/RPV (immediate switch, D 1 to W 48) % 100 93. 7 89. 9 92. 1 % 95 89. 2 80 60 60 40 40 20 152/ 160 20 ≠ (95%CI) 3. 8 (- 1. 6 ; 9. 1) : non inferiority HIV RNA < 50 c/m. L, ITT, M = excluded RPV = 99. 7% vs PI/r = 94. 7% SPIRIT 92. 3 128/ 134 48/ 52 80 89. 3 0 95. 5 0 % Virologic failure 5 0. 9 3/317 8/159 1. 3 2. 5 2/152 8/317 83/ 93 > 100 000 c/ml < 100 000 c/ml HIV RNA, pre-ART (23 patients TDF/FTC/RPV and 14 PI/r excluded from analysis [data not avalaible]) ≠ (95%CI) : 5. 8 (- 1. 4 ; 12. 9) ≠ (95%CI) : 3. 2 (- 4. 8 ; 11. 3) Non inferiority Palella F, AIDS 2014; 28: 335 -44

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV § Among the 24 patients with the K 103 N mutation on historical genotype – 18 in the immediate switch arm • All maintain HIV RNA < 50 c/m. L at W 24 • 1 virologic failure at W 48 (pre-existing mutations : K 103 N + V 179 I, emergence : M 184 V, E 138 K and V 108 V/I) – 6 in the delayed switch arm • 5 maintain HIV RNA < 50 c/m. L at W 48 (24 weeks after switch) • 1 without data at W 48 (HIV RNA < 50 c/m. L at last study visit) § Virologic failure on TDF/FTC/RPV, N = 7 (1. 5%) – 3 without emergence of resistance mutations – 4 with emergence of resistance mutations • K 103 N + L 100 I + M 184 I • E 138 E/K + M 184 M/V • E 138 K + V 108 V/I + M 184 V SPIRIT Palella F, AIDS 2014; 28: 335 -44

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV Mean change from baseline at W 24 • Discontinuation for adverse event (W 24) – TDF/FTC/RPV, N = 6 • tubulopathy, N = 1 • neuro-psychiatric events, N = 4 (depression, headache, insomnia, psychiatric event) – 2 NRTI + PI/r, N = 0 • Grade 3 -4 Adverse events and laboratory abnormalities to W 48 RPV Immediate switch (at W 48) PI/r (at W 24) Adverse events 5. 7 % 6. 9 % 7. 9% Laboratory abnormalities 8. 8 % 11. 3 % 15. 2% RPV Delayed switch (at W 24) LDL-c (mg/dl) TG (mg/dl) HDL-c Ratio total-c (mg/dl) HDL-c d. L 10 0 -30 -4 -1 -20 0. 08 3 0 -10 GFR decrease significantly more important with RPV SPIRIT Total-chol (mg/dl) -1 -16 - 0. 27 - 25 -40 P < 0. 001 for all comparisons -50 - 53 -60 TDF/FTC/RPV 2 NRTI + PI/r Palella F, AIDS 2014; 28: 335 -44

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV § Conclusion – Switching to the STR TDF/FTC/RPV from a PI/r regimen in virologically suppressed, HIV-1 -infected participants maintained virologic suppression with a low risk of virologic failure, while improving total cholesterol, LDL-cholesterol, and triglycerides • Participants had been virologically suppressed on a PI/r regimen for at least 6 months prior to study entry and had no previous ART failure • Pretreatment HIV-1 RNA levels (while still ARV-naive) did not affect maintenance of viral suppression after switch to TDF/FTC/RPV – Historical K 103 resistance mutation (probably transmitted) did not affect efficacy of switch to TDF/FTC/RPV in participants of the study SPIRIT Palella F, AIDS 2014; 28: 335 -44