Comparison of INSTI vs PI  FLAMINGO  GS  ACTG A5257  WAVES

Squires K. IAS 2015 Vancouver, Abs. MOLBPE08  Design  Objective –Non inferiority of EVG/C/FTC/TDF at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (lower margin of the 2-sided 95% CI for the difference = -12%) EVG/C/FTC/TDF 150/150/200/300 mg QD ATV + r + TDF/FTC placebo ATV + r 300/100 mg + FTC/TDF QD EVG/C/FTC/TDF placebo Randomisation* 1 : 1 Double-blind Women ARV-naïve HIV RNA > 500 c/mL Any CD4 cell count Sensitivity to FTC, TDF and ATV eGFR > 70 mL/min *Randomisation was stratified by HIV RNA ( 400,000 c/mL) at screening and race (black or non-black) Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women N = 286 N = 289 W48 WAVES Open-label extension

EVG/C/FTC/TDF N = 289 ATV + r + FTC/TDF N = 286 Female100% Median age, years3435 White / Black / Asian44% / 49% / 3%42% / 47% / 6% AIDS4%5% HIV RNA (log 10 c/mL), median (Q1-Q3)4.46 ( )4.56 ( ) HIV RNA 100, ,000 c/mL HIV RNA ≥ 400,000 c/mL 15% 9% 17% 8% CD4 cell count (/mm 3 ), median CD4 < 200 per mm 3 17%18% Hepatitis B / hepatitis C coinfection3% / 8%2% / 9% Discontinuation by W48, N (%)29 (10%)45 (16%) For lack of efficacyN = 0N = 1 For adverse eventN = 5N = 19 Lost to follow-up / Withdrew consentN = 12 / N = 6N = 12 / N = 5 Non-compliance / OtherN = 4 / N = 2N = 5 / N = 3 Baseline characteristics and patient disposition Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES

Response to treatment at week 48 Mean CD4/mm 3 increase at W48 : (EVG/C/FTC/TDF) vs (ATV + r + FTC/TDF) EVG/C/FTC/TDF (N = 289) ATV + r + FTC/TDF (N = 286) HIV RNA < 50 c/mL (ITT, snapshot) Adjusted difference (95% CI) = 6.5 % (0.4 ; 12.6) p = Virologic successVirologic failure % No virologic data Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES

HIV RNA < 50 c/mL at W48 by baseline HIV RNA and CD4 count EVG/C/FTC/TDF ATV + r + FTC/TDF % Overall< 100, < 350> > 100,000 HIV RNA (copies/mL)CD4 cell count (/mm 3 ) Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES

Emergence of resistance EVG/C/FTC/TDFATV + r + FTC/TDF Resistance analysis population1921 Final RAP*712 Resistance mutations emergence03 NRTI-resistance13 D67D/N10 M184V/I03 K65R00 INSTI-resistance00 Primary PI-resistance00 * Criteria : -Suboptimal response (HIV RNA ≥ 50 c/mL and < 1 log 10 reduction from baseline by W8, confirmed) -Virologic rebound (> 400 c/mL after achieving HIV RNA 1 log 10 increase from nadir) -HIV RNA > 400 c/mL at W48 Exclusion of patients with HIV RNA < 50 c/mL at subsequent visits Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES

EVG/C/FTC/TDFATV + r + FTC/TDFp DXA assessment at baseline, spine ; hip, N at W48, spine ; hip, N 138 ; ; ;128 Median change from baseline in BMD Lumbar spine % %0.69 Hip % %0.37 Median change from baseline in eGFR (mL/min), Cockroft-Gault formula Renal and bone mineral density (DXA) assessments EVG/C/FTC/TDFATV + r + FTC/TDFp Total cholesterol Other lipid parameters (LDL-c, HDL-c, Triglycerides, Total cholesterol:HDL-cholesterol rations Median change from baseline in fasting lipids (mg/dL) Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES

EVG/C/FTC/TDFATV + r + FTC/TDF Adverse events leading to discontinuation, N Hepatobiliary disorder14 Gastro-intestinal disorder34 Pulmonary tuberculosis10 Renal02 Skin disorder29 Drug hypersensitivity01 Adverse event in ≥ 10% of patients, %0 Headache1615 Upper respiratory tract infection1615 Nausea1514 Vomiting1014 Jaundice / Icterus< 1 / < 111 / 12 Grade 3-4 laboratory abnormalities in ≥ 2%, % Serum amylase elevation22 Neutropenia < 1000/mm 3 23 ALT elevation22 Hyperbilirubinemia< 146 Glycosuria02 Adverse events and Grade 3-4 laboratory abnormalities Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES

 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 CD4 < 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 Squires K. IAS 2015 Vancouver, Abs. MOLBPE08 Study WAVES: EVG/C/FTC/TDF QD vs ATV + r + FTC/TDF QD in Women WAVES