Switch to TDF/FTC/RPV  SPIRIT Study

SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV TDF/FTC/RPV STR 24 weeks 48 weeks Primary Endpoint Secondary Endpoint N = 317 N = 159 PI/r + 2 NRTIs TDF/FTC/RPV STR  Design Randomisation 2 : 1 Open-label 24 weeks Primary Endpoint 48 weeks Secondary Endpoint  Objective –Primary Endpoint : Non-inferiority in the proportion of patients with HIV-1 RNA < 50 c/mL at W24 (FDA snapshot analysis) ; upper limit of the 95% CI for the difference = 12% –Secondary Endpoints: Proportion of HIV1 RNA < 50 copies/mL at W48 ; Change in fasting lipid and CD4 cell count at W24 and W48 ; Safety and tolerability SPIRIT Palella F, AIDS 2014;28: HIV+ adults Stable PI + RTV + 2 NRTI ≥ 6 months with HIV RNA < 50 c/mL On 1 st or 2 nd regimen No prior NNRTI use No known resistance to study agents W24W48

Baseline characteristics and disposition TDF/FTC/RPV N = NRTI + PI/r N = 317 Female14%9% Baseline CD4/mm 3 (mean) Time since first ART, years (median) Discontinued before W24N = 20N = 7 Adverse event / Lack of efficacy7 / 10 / 0 Discontinued between W24 and W48N = 7N = 9 Adverse event / Lack of efficacy0 / 15 / 1 NRTIPI/r TDF/FTC 81% ATV/r 37% ABC/3TC 13% DRV/r 20% ZDV/3TC 3.4% FPV/r 33% LPV/r 33% ART at screening SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV SPIRIT Palella F, AIDS 2014;28:335-44

HIV RNA < 50 c/mL at W24 and W48 (ITT, snapshot) 2 NRTI + PI/r (D1 to W24)TDF/FTC/RPV (D1 to W24) ≠ (95%CI) 3.8 (- 1.6 ; 9.1) : non inferiority ≠ (95%CI) : 3.2 (- 4.8 ; 11.3) ≠ (95%CI) : 5.8 (- 1.4 ; 12.9) HIV RNA < 50 c/mL, ITT, M = excluded RPV = 99.7% vs PI/r = 94.7% Non inferiority HIV RNA, pre-ART (23 patients TDF/FTC/RPV and 14 PI/r excluded from analysis [data not avalaible]) > c/ml < c/ml 152/ / 93 48/ / 134 % % SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV SPIRIT TDF/FTC/RPV (delayed switch, W24 to W48) 3/3178/1592/152 Virologic failure % TDF/FTC/RPV (immediate switch, D1 to W48) 89.3 HIV RNA < 50 c/mL at W24 according to pre-ART HIV RNA 2.5 8/317 Palella F, AIDS 2014;28:335-44

 Among the 24 patients with the K103N mutation on historical genotype –18 in the immediate switch arm All maintain HIV RNA < 50 c/mL at W24 1 virologic failure at W48 (pre-existing mutations : K103N + V179I, emergence : M184V, E138K and V108V/I) –6 in the delayed switch arm 5 maintain HIV RNA < 50 c/mL at W48 (24 weeks after switch) 1 without data at W48 (HIV RNA < 50 c/mL 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 K103N + L100I + M184I M184I E138E/K + M184M/V E138K + V108V/I + M184V SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV SPIRIT Palella F, AIDS 2014;28:335-44

Mean change from baseline at W P < for all comparisons 2 NRTI + PI/r Total-chol (mg/dl) LDL-c (mg/dl) TG (mg/dl) HDL-c (mg/dl) Ratio total-c HDL-c dL TDF/FTC/RPV Discontinuation for adverse event (W24) –TDF/FTC/RPV, N = 6 tubulopathy, N = 1 neuro-psychiatric events, N = 4 (depression, headache, insomnia, psychiatric event) –2 NRTI + PI/r, N = 0 GFR decrease significantly more important with RPV SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV SPIRIT Grade 3-4 Adverse events and laboratoratory abnormalities to W48 Palella F, AIDS 2014;28: RPV Immediate switch (at W48) PI/r (at W24) Adverse events 5.7 %6.9 %7.9% Laboratory abnormalities 8.8 %11.3 %15.2% RPV Delayed switch (at W24)

 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 K103 resistance mutation (probably transmitted) did not affect efficacy of switch to TDF/FTC/RPV in participants of the study SPIRIT study: Switch PI/r + 2 NRTI to TDF/FTC/RPV SPIRIT Palella F, AIDS 2014;28:335-44