Comparison of PI vs PI  ATV/r vs DRV/rATADAR

ATV/r 300/100 mg + TDF/FTC qd N = 91 N = 89 DRV/r 800/100 mg + TDF/FTC qd  Design Randomisation 1: 1 Open-label  Objective –Primary Endpoint : mean change in total cholesterol at W24 (ITT analysis) –90 patients per arm needed to detect a difference ≥ 21 mg/dL between arms in total cholesterol change, power 80%, 5% bilateral significance –Secondary endpoints : mean change in other lipid parameters, insulin resistance, total bilirubin, eGFR (MDRD equation), CD4 and CD8 cell counts, HIV RNA, discontinuation for AEs ATADAR Martinez E. HIV Medicine 2014;15:330-8 ≥ 18 years Antiretroviral naïve HIV RNA > 1,000 c/mL No diabetes, BMI < 30 kg/m 2 No current use of drugs affecting lipid or glucose metabolism W24W96 ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC

Baseline characteristics and disposition ATV/r + TDF/FTC, N = 90DRV/r + TDF/FTC, N = 88 Age, years3537 Female13%11% HIV RNA log 10 c/mL4.8 CD4/mm Total cholesterol, mg/dL158 LDL-cholesterol, mg/dL9798 HDL-cholesterol, mg/dL39 Total cholesterol:HDL-cholesterol ratio Triglycerides, mg/dL HOMA-IR Total bilirubin, mg/dL eGFR (MDRD), mL/min/1.73 m Discontinued at W24N = 8 (9%) Adverse event53 Withdrew consent / lost to follow-up1 / 20 / 5 Data expressed as mean ATADAR ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC Martinez E. HIV Medicine 2014;15:330-8

Virological efficacy and overall tolerability at W24 ATV/r + TDF/FTC, N = 90 DRV/r + TDF/FTC, N = 88 Confirmed HIV RNA > 50 c/mL, n78 Any AE, all grade, % Grade 3-4 AEs, % (p< 0.01) Bilirubin elevations, n170 Jaundice3/170 AEs leading to study drug discontinuation, n (%)5 (5.6%)3 (3.4%) Jaundice, n30 Rash, n12 Suicide attempt, n10 Gastrointestinal symptoms, n01 ATADAR ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC Martinez E. HIV Medicine 2014;15:330-8

Lipid changes from baseline to W24 ATV/r + TDF/FTC N = 90 DRV/r + TDF/FTC N = 88 p Total cholesterol, mg/dL ± ± LDL-cholesterol, mg/dL ± ± HDL-cholesterol, mg/dL ± ± Total:HDL-cholesterol ratio ± ± Triglycerides ± ± No participant was prescribed lipid-lowering agents or other drugs potentially affecting plasma lipids ATV/r + TDF/FTC N = 90 DRV/r + TDF/FTC N = 88 p HOMA-IR ± ± Total bilirubin, mg/dL ± ± 0.30 < 0.01 eGFR, mL/min/1.73m / ± Other laboratory changes from baseline to W24 ATADAR ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC Martinez E. HIV Medicine 2014;15:330-8

 Metabolic sub-study in 86 participants (ATV/r = 45, DRV/r = 41) – LDL subfraction phenotype and Lp-PLA2 at W48, Framingham risk score change. Patients assessed at W48 : 40/45 and 37/41 – LDL subfraction phenotype : predominance of the more favorable phenotype at baseline (around 75% of participants) – ATV/r : increase in cholesterol content in small and dense LDL particles, associated with coronary artery disease risk (p = 0.015) at W48 – DRV/r : increase in LDL size (p = 0.017) and large LDL particles (p = 0.008) (improved atherogenic properties) at W48 – No change in total Lp-PLA2 activity and no shift in its relative distribution in LDL or HDL particles at W48, with no differences between arms – Framingham score very low at baseline (1%) with no changes at W48 – Insulin increased only in the ATV/r group (p = 0.017), but HOMA-IR showed no changes in either arm at W48 – BMI increased in the ATV/r arm (+1.01 kg/m 2 at W48, p = 0.004) [p= 0.06 vs DRV/r] – Waist increased in the DRV/r arm (+ 3 cm at W48, p < 0.001) [p = vs ATV/r] ATADAR Saumoy M. J AntimicrobChemother 2015;70: ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC

 W96 results (efficacy and resistance) ATV/r + TDF/FTC N = 90 DRV/r + TDF/FTC N = 88 Discontinuation by W9621 (23%)17 (19%) For AE / virologic failure7 / 25 / 2 % free of treatment failure62%70%95% CI : to 21.6 % free of virologic failure (VF) 79%85%95% CI : to 17.6 Resistance testing ♯ 6/17 VF5/13 VF PI mutations detected (none major)4*/64**/5 * V45M ; E35D + K43K/N + D60E + I93L ; A71V + E35D + M36I + I62V + I93L ; L24I/V ** I15V ; E35D + L63P ; E35D + L63P ; I13V + M36I/M + I62I/V + L63H/Q ♯ no baseline resistance test ATADAR ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC Martinez E. CID 2015;60:811-20

 W96 results (safety) ATV/r + TDF/FTC, N = 72DRV/r + TDF/FTC, N = 74p Serious AEs26%8%0.002 Grade 3-4 AEs44%14%< AE leading to discontinuation7.8%5.7%0.25 ATV/rDRV/r p Total cholesterol, mg/dL All non significant LDL-cholesterol, mg/dL HDL-cholesterol, mg/dL Total:HDL-cholesterol ratio Triglycerides eGFR (MDRD), mL/min/1.73 m Overall safety Lipid and other laboratory changes, mean ATADAR ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC Martinez E. CID 2015;60:811-20

ATV/r + TDF/FTC, N = 78DRV/r + TDF/FTC, N = 80p BMI, kg/m Body fat, g Body fat-free mass, g Limb fat, g Trunk fat, g Subcutaneous abdominal adipose tissue, cm Visceral adipose tissue, cm Total abdominal adipose tissue, cm Bone mineral content, g Changes in body composition (DXA and abdominal CT-scan) at W96 Data expressed as mean In the ATV/r arm : significant correlations between changes in HOMA-IR and changes in BMI, body fat, and SAT In the DRV/arm : no correlations between HOMA-IR changes and changes in BMI and body fat parameters ATADAR ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC Martinez E. CID 2015;60:811-20

 Conclusion – No major differences between ATV/r + TDF/FTC and DRV/r + TDF/FTC in efficacy, clinically relevant side effects, or plasma cholesterol fractions, over 96 weeks – However, ATV/r led to higher triglycerides and more total and subcutaneous fat than DRV/r – Fat gains with ATV/r were associated with insulin resistance – In contrast with what occurred in the ATV/r arm, the LDL subfraction phenotype improved with DRV/r at W48. This difference was associated with a lower impact on plasma triglycerides with DRV/r – Most Grade 3-4 AE were due to hyperbilirubinemia, in the ATV/r arm ATADAR Martinez E. CID 2015;60: ; Saumoy M. J AntimicrobChemother 2015;70: ATADAR Study: ATV/r + TDF/FTC vs DRV/r + TDF/FTC