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

EASIER Study: Switch ENF to RAL Design Randomisation 1 : 1 Open-label W24 193 HIV+ adults History of triple class (NRTI, NNRTI, PI) failure or intolerance HIV-1 RNA < 400 c/mL > 3 months on an ENF-based regimen Integrase inhibitor-naïve N = 85 Continue ENF regimen + other ARVs N = 85 Switch to RAL 400 mg bid + continue other ARVs 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 EASIER De Castro N, CID 2009;49:1259-67

EASIER Study: Switch ENF to RAL ARV-trial.com EASIER Study: Switch ENF to RAL Baseline characteristics and patient disposition ENF, N = 85 RAL, N = 84 Median age, years 48.4 47.6 Female 14% 17% History of CDC class C diagnosis 55% 50% Hepatitis B or C co-infection 5% 8% CD4 cell count at baseline ; at nadir, /mm3 374 ; 56 410 ; 39 HIV-1 RNA < 50 c/mL at baseline 88% 85% Duration of prior ENF therapy, median years 2.2 2.5 Number of ARV drugs in baseline regimen (including ENF), median 4 ARV drugs in regimen: PI* ; NNRTI ; NRTI (TDF) 100% ; 6% ; 95% (54%) 99% ; 10% ; 94% (60%) Discontinuation before W24, N (%) 3 2 For adverse event For virologic failure 1 * TPV/r in 34% vs 44% and DRV/r in 40% vs 36%, in ENF vs RAL groups, respectively EASIER De Castro N, CID 2009;49:1259-67

EASIER Study: Switch ENF to RAL ARV-trial.com EASIER Study: Switch ENF to RAL Outcome at week 24 Virologic failure Other endpoints 1.2 88 89 ITT analysis ENF RAL % 20 40 60 80 100 95% CI for the difference = -6.7 ; 6.8 HIV-1 RNA < 50 c/mL On-treatment analysis 95% CI for the difference = -5.6 ; 8.1 Median CD4 increase ENF: +15/mm3 RAL: +11/mm3 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 EASIER De Castro N, CID 2009;49:1259-67

EASIER Study: Switch ENF to RAL Grade 3 or 4 emerging adverse events or laboratory abnormalities ENF RAL Adverse events occurred in 7 patients on ENF and 11 patients on RAL, with a total of 8 and 13 events, respectively Coronary events 2 Gastrointestinal 1 Infection 3 Nervous system Psychiatric Respiratory Other 4 Laboratory abnormalities occurred in 6 patients on ENF and 12 patients on RAL, with a total of 8 and 14 abnormalities, respectively Aminotransferase > 5 ULN Gamma GT > 5 ULN 6 Alkaline phosphatase > 5 ULN CPK > 5 ULN Triglyceride > 8.6 mmol/L Lipase > 3 ULN Potassium < 2.7 mmol/L EASIER De Castro N, CID 2009;49:1259-67

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 EASIER De Castro N, CID 2009;49:1259-67

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) EASIER Gallien S, JAC 2011;66:2099-2106

EASIER Study: Switch ENF to RAL Deferred switch Immediate switch 0% 10% 70% 80% 90% 100% Proportion of patients with HIV RNA < 50 copies/ml W0 85 84 W4 W8 W24 W28 79 W32 W16 W40 82 W48 83 Def Imm N patients 88% 89% 85% 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 Gallien S, JAC 2011;66:2099-2106

EASIER Study: Switch ENF to RAL Grade 3 or 4 emerging adverse events or laboratory abnormalities In both arms between weeks 24 and 48 (N = 168) n Grade 3-4 adverse events occurred in 12 patients (7%) Coronary events 1 Gastrointestinal 2 Infection 8 Nervous system Psychiatric Respiratory Other 10 Grade 3-4 laboratory abnormalities occurred in 20 patients (12%) Aminotransferase > 5 ULN 7 (all patients on TPV/r) Gamma GT > 5 ULN 7 Alkaline phosphatase > 5 ULN CPK > 5 ULN 7 (all asymptomatic) Hyperbilirubinemia > 5 ULN Lipase > 3 ULN Hypoglycemia < 2.2 mmol/L EASIER Gallien S, JAC 2011;66:2099-2106

EASIER substudy: Inflammatory and coagulation biomarkers 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 Log10 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 EASIER Silva EF, JID 2013;208:892-7

Values are median (IQR) EASIER substudy: Inflammatory and coagulation biomarkers IL-6 (log10 pg/ml) hsCRP (log10 mg/ml) 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 0.23 0.18 RAL ENF 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 ENF RAL D-dimer (mg/ml) Deferred Switch Immediate Switch 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 RAL ENF Values are median (IQR) 0.198 EASIER Silva EF, JID 2013;208:892-7