1. Switch to RAL-containing regimen  Canadian Study  CHEER  Montreal Study  EASIER  SWITCHMRK  SPIRAL  Switch ER

2. EASIER Study: Switch ENF to RAL  Design  Objective  Non inferiority in the proportion of patients with virologic failure at W24 (Intent-to-treat analysis) ; upper limit of the 95% CI for the difference = 10%, 80% power  Virologic failure : confirmed HIV-1 RNA ≥ 400 c/mL, or a single HIV-1 RNA ≥ 400 c/mL followed by treatment modification or last HIV-1 RNA ≥ 400 c/mL without confirmation Switch to RAL 400 mg bid + continue other ARVs Continue ENF regimen + other ARVs Randomisation 1 : 1 Open-label 193 HIV+ adults History of triple class (NRTI, NNRTI, PI) failure or intolerance HIV-1 RNA 3 months on an ENF-based regimen Integrase inhibitor-naïve N = 85 W24 De Castro N, CID 2009;49:1259-67 EASIER

3. EASIER Study: Switch ENF to RAL ENF, N = 85RAL, N = 84 Median age, years48.447.6 Female14%17% History of CDC class C diagnosis55%50% Hepatitis B or C co-infection5%8% CD4 cell count at baseline ; at nadir, /mm 3 374 ; 56410 ; 39 HIV-1 RNA < 50 c/mL at baseline88%85% Duration of prior ENF therapy, median years2.22.5 Number of ARV drugs in baseline regimen (including ENF), median 44 ARV drugs in regimen: PI* ; NNRTI ; NRTI (TDF) 100% ; 6% ; 95% (54%) 99% ; 10% ; 94% (60%) Discontinuation before W24, N (%)32 For adverse event00 For virologic failure11 Baseline characteristics and patient disposition * TPV/r in 34% vs 44% and DRV/r in 40% vs 36%, in ENF vs RAL groups, respectively De Castro N, CID 2009;49:1259-67 EASIER

4. EASIER Study: Switch ENF to RAL Outcome at week 24 Other endpoints  Median CD4 increase –ENF: +15/mm 3 –RAL: +11/mm 3  No AIDS events  No difference in the overall incidence of adverse reactions between both groups  Higher incidence of grade 1 to 4 laboratory abnormalities in the RAL arm (p = 0.001)  Median increases in triglycerides and total cholesterol were significantly higher in the RAL group Virologic failure De Castro N, CID 2009;49:1259-67 EASIER 1.2 88 1.2 89 ITT analysis ENF RAL % 0 20 40 60 80 100 95% CI for the difference = -6.7 ; 6.8 HIV-1 RNA < 50 c/mL 0 1.2 On-treatment analysis 95% CI for the difference = -5.6 ; 8.1 ITT analysis

5. EASIER Study: Switch ENF to RAL ENFRAL Adverse events occurred in 7 patients on ENF and 11 patients on RAL, with a total of 8 and 13 events, respectively Coronary events22 Gastrointestinal11 Infection03 Nervous system01 Psychiatric11 Respiratory21 Other24 Laboratory abnormalities occurred in 6 patients on ENF and 12 patients on RAL, with a total of 8 and 14 abnormalities, respectively Aminotransferase > 5 ULN12 Gamma GT > 5 ULN26 Alkaline phosphatase > 5 ULN02 CPK > 5 ULN32 Triglyceride > 8.6 mmol/L02 Lipase > 3 ULN10 Potassium < 2.7 mmol/L10 De Castro N, CID 2009;49:1259-67 EASIER Grade 3 or 4 emerging adverse events or laboratory abnormalities

6. EASIER Study: Switch ENF to RAL  Conclusions from W24 data –In patients infected with multidrug-resistant HIV-1 receiving suppressive enfuvirtide-containing antiretroviral therapy, a switch from enfuvirtide to RAL is: Safe Well-tolerated And virologically non-inferior to the maintenance of ENF De Castro N, CID 2009;49:1259-67 EASIER

7. EASIER Study: Switch ENF to RAL  At week 24 –ENF arm switched to RAL (deferred RAL), n = 84 –RAL arm continued on RAL (immediate RAL), n = 84  Week 48 analyses –Primary : cumulative proportion of patients with confirmed HIV RNA ≥ 400 c/mL, or last HIV RNA ≥ 400 c/mL or treatment change after a single HIV RNA ≥ 400 c/mL (on-treatment and intent-to-treat analyses) –Secondary Proportion of patients with HIV RNA < 50 c/mL Emergence of resistance in patients with virologic failure Changes from baseline in CD4 cell counts Proportion of patients with permanent discontinuation of RAL Safety  Baseline GSS assessed on cumulative historical genotypes –GSS ≥ 1 : 86% ; 0.5 : 11% ; 0 : 3% (n = 5) Gallien S, JAC 2011;66:2099-2106 EASIER

8. Gallien S, JAC 2011;66:2099-2106 EASIER Study: Switch ENF to RAL  On-treatment analysis : 1 virologic failure (W8) in immediate arm ; baseline GSS = 0, no emergence of RAL-associated resistance mutations  No significant changes in the median CD4 cell counts following RAL switch in either arm  No significant changes between baseline and W48 in glucose levels or fasting lipids in either arm EASIER Deferred switch Immediate switch 0% 10% 70% 80% 90% 100% Proportion of patients with HIV RNA < 50 copies/ml W0 85 84 W4 85 84 W8 85 84 W24 84 W28 84 79 W32 84 W16 85 84 W40 82 84 W48 83 Def Imm N patients 88% 89% 90% 88% 85%

9. n Grade 3-4 adverse events occurred in 12 patients (7%) Coronary events1 Gastrointestinal2 Infection8 Nervous system1 Psychiatric0 Respiratory0 Other10 Grade 3-4 laboratory abnormalities occurred in 20 patients (12%) Aminotransferase > 5 ULN7 (all patients on TPV/r) Gamma GT > 5 ULN7 Alkaline phosphatase > 5 ULN1 CPK > 5 ULN7 (all asymptomatic) Hyperbilirubinemia > 5 ULN1 Lipase > 3 ULN1 Hypoglycemia < 2.2 mmol/L1 Grade 3 or 4 emerging adverse events or laboratory abnormalities In both arms between weeks 24 and 48 (N = 168) Gallien S, JAC 2011;66:2099-2106 EASIER Study: Switch ENF to RAL EASIER

10.  164 patients, Immediate switch (n = 83) ; deferred switch (n = 81)  Biomarkers –IL-6 –hsCRP –D-dimer  Primary objective : changes in IL-6, hsCRP and D-dimer plasma levels from baseline to W24 between the immediate and deferred arms –Log 10 transformation of levels –Median changes from baseline assessed by 1-sample t tests –Comparison between arms used 2-sample t tests with no adjustment for baseline factors  Similar analyses to compare changes from baseline to W48 Silva EF, JID 2013;208:892-7 EASIER EASIER substudy: Inflammatory and coagulation biomarkers

11. Silva EF, JID 2013;208:892-7 D-dimer (  g/ml) Deferred Switch Immediate Switch EASIER IL-6 (log 10 pg/ml) hsCRP (log 10  g/ml) 0.198 Values are median (IQR) 0.0 -0.4 -0.8 0.4 0.8 1.2 1.6 2.0 W0 81 83 W24 78 79 W48 75 71 0.63 0.74 0.20 p=0.0003 0.66 0.32 0.20 ENF RAL 0.0 0.4 0.8 1.2 1.6 2.0 W0 81 83 W24 78 79 W48 75 72 0.56 0.61 0.28 p<0.001 0.54 0.230.18 RAL ENF 0.5 0.4 0.3 0.2 0.1 0.0 W0 81 83 W24 78 79 W48 75 72 0.369 0.387 0.189 p<0.0001 0.369 0.189 RAL ENF EASIER substudy: Inflammatory and coagulation biomarkers