Comparison of INSTI vs PI FLAMINGO GS236 0103

Comparison of INSTI vs PI § § § FLAMINGO GS-236 -0103 ACTG A 5257 WAVES ARIA

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women § Design Randomisation* 1: 1 Double-blind Women ARV-naïve HIV RNA > 500 c/m. L Any CD 4 cell count Sensitivity to FTC, TDF and ATV e. GFR > 70 m. L/min W 48 N = 289 EVG/C/FTC/TDF 150/200/300 mg QD ATV + r + TDF/FTC placebo Open-label extension N = 286 ATV + r 300/100 mg + FTC/TDF QD EVG/C/FTC/TDF placebo *Randomisation was stratified by HIV RNA (< 100, 000 or 100, 000 -400, 000 or > 400, 000 c/m. L) at screening and race (black or non-black) § Objective – Non inferiority of EVG/C/FTC/TDF at W 48: % HIV RNA < 50 c/m. L by intention to treat, snapshot analysis (lower margin of the 2 -sided 95% CI for the difference = -12%) WAVES Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women Baseline characteristics and patient disposition EVG/C/FTC/TDF N = 289 ATV + r + FTC/TDF N = 286 100% 34 35 44% / 50% / 3% 42% / 47% / 6% 4% 5% 4. 46 (4. 09 -4. 97) 4. 56 (4. 02 -5. 00) HIV RNA 100, 000 -400, 000 c/m. L HIV RNA ≥ 400, 000 c/m. L 15% 9% 18% 8% CD 4 cell count (/mm 3), median 344 370 CD 4 < 200 per mm 3 17% 18% Hepatitis B / hepatitis C coinfection 4% / 8% 3% / 9% Discontinuation by W 48, N (%) 29 (10%) 45 (16%) For lack of efficacy N=0 N=1 For adverse event N=5 N = 19 Lost to follow-up / Withdrew consent N = 12 / N = 6 N = 12 / N = 5 Non-compliance / Other N=4/N=2 N=5/N=3 Female Median age, years White / Black / Asian AIDS HIV RNA (log 10 c/m. L), median (Q 1 -Q 3) WAVES Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women Response to treatment at week 48 % 100 HIV RNA < 50 c/m. L (ITT, snapshot) 87 81 EVG/C/FTC/TDF (N = 289) ATV + r + FTC/TDF (N = 286) 75 50 25 9 0 Virologic success Adjusted difference (95% CI) = 6. 5 % (0. 4 ; 12. 6) p = 0. 034 WAVES 12 Virologic failure 4 7 No virologic data Mean CD 4/mm 3 increase at W 48 : + 221 (EVG/C/FTC/TDF) vs + 212 (ATV + r + FTC/TDF) Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women HIV RNA < 50 c/m. L at W 48 by baseline HIV RNA and CD 4 count EVG/C/FTC/TDF ATV + r + FTC/TDF % 100 87 81 90 86 82 220 214 88 78 82 86 131 143 79 75 50 25 0 286 Overall < 100, 000 69 72 > 100, 000 HIV RNA (copies/m. L) WAVES 146 < 350 154 > 350 CD 4 cell count (/mm 3) Squires K. IAS 2015 Vancouver, Abs. MOLBPE 08 ; Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women Emergence of resistance EVG/C/FTC/TDF ATV + r + FTC/TDF Resistance analysis population 19 21 Final RAP* 7 12 Resistance mutations emergence 0 3 NRTI-resistance 1 3 D 67 D/N 1 0 M 184 V/I 0 3 K 65 R 0 0 INSTI-resistance 0 0 Primary PI-resistance 0 0 * Criteria : - Suboptimal response (HIV RNA ≥ 50 c/m. L and < 1 log 10 reduction from baseline by W 8, confirmed) - Virologic rebound (> 400 c/m. L after achieving HIV RNA < 50 c/m. L, or 2 consecutive visits with > 1 log 10 increase from nadir) - HIV RNA > 400 c/m. L at W 48 Exclusion of patients with HIV RNA < 50 c/m. L at subsequent visits WAVES Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women Renal and bone mineral density (DXA) assessments EVG/C/FTC/TDF ATV + r + FTC/TDF 138 ; 120 136 ; 118 150 ; 128 Lumbar spine - 3. 23 % - 3. 28 % 0. 69 Hip - 2. 99 % - 2. 68 % 0. 37 - 6. 1 - 2. 4 0. 15 DXA assessment at baseline, spine ; hip, N at W 48, spine ; hip, N p Median change from baseline in BMD Median change from baseline in e. GFR (m. L/min), Cockroft-Gault formula Median change from baseline in fasting lipids (mg/d. L) Total cholesterol EVG/C/FTC/TDF ATV + r + FTC/TDF p +7 +2 0. 02 Other lipid parameters (LDL-c, HDL-c, Triglycerides, Total cholesterol: HDL-cholesterol ratio WAVES ns Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women Adverse events and Grade 3 -4 laboratory abnormalities Adverse events leading to discontinuation, N Hepatobiliary disorder Gastro-intestinal disorder Pulmonary tuberculosis Renal Skin disorder Drug hypersensitivity Adverse event in ≥ 10% of patients, % Headache Upper respiratory tract infection Nausea Vomiting Jaundice / Icterus Grade 3 -4 laboratory abnormalities in ≥ 2%, % Serum amylase elevation Neutropenia < 1000/mm 3 ALT elevation Hyperbilirubinemia Glycosuria WAVES EVG/C/FTC/TDF ATV + r + FTC/TDF 5 discontinuations 1 3 1 0 2 0 16 16 15 10 <1/<1 19 discontinuations 4 4 0 2 9 1 0 15 15 14 14 11 / 12 2 <1 0 2 3 2 46 2 Squires K. Lancet HIV 2016; 3(9): e 410 -e 420

Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women § Summary – EVG/C/FTC/TDF QD was virologically non inferior and superior to ATV + r + FTC/TDF – Similar virologic response of the 2 regimens in different subgroups of patients, including those with high HIV RNA or CD 4 < 350/mm 3 at enrolment – Development of major resistance mutations occurred in • No patients on EVG/C/FTC/TDF • 3 patients on ATV + r + /FTC/TDF: NRTI mutations, no PI mutations – Discontinuation because of adverse events was lower with EVG/C/FTC/TDF – Less incidence of icterus and hyperbilirubinemia with EVG/C/FTC/TDF Comparable changes in fasting lipids in both groups, except for total cholesterol which elevation was higher with EVG/C/FTC/TDF – Median decreases in estimated glomerular filtration rate and in spine and hip BMD were modest and not different between the 2 groups WAVES Squires K. Lancet HIV 2016; 3(9): e 410 -e 420