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

Clotet B. Lancet 2014;383;  Design  Objective –Non inferiority of DTG at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (1-sided significance level of 2.5%, lower margin of the 95% CI for the difference = -12%, 90% power) DTG 50 mg QD + 2 NRTI** DRV/r 800/100 mg QD + 2 NRTI** Randomisation* 1 : 1 Open-label > 18 years ARV-naïve HIV RNA > 1,000 c/mL Any CD4 cell count No primary resistance in RT or protease *Randomisation (DTG vs DRV/r) was stratified by HIV RNA ( 100,000 c/mL) at screening and NRTI backbone N = 245 N = 243 W48W96 FLAMINGO **NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) was selected by investigator FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI

DTG + 2 NRTI N = 242 DRV/r + 2 NRTI N = 242 Median age, years34 Female13%17% HIV RNA (log 10 c/mL), median HIV RNA > 100,000 c/mL25% CD4 cell count (/mm 3 ), median CD4 < 200 per mm 3 10% Hepatitis B / hepatitis C coinfection4% / 7%2% / 7% Dual NRTI on day 1 : TDF/FTC / ABC/3TC67% / 33% Discontinuation by W4818 (7.4%)29 (12.0%) For lack of efficacyN = 2 For adverse event / For liver stopping criteriaN = 3 / N = 1N = 9 / N = 1 Lost to follow-upN = 6N = 10 Protocol deviation / Withdrew consentN = 3 / N = 1 Baseline characteristics and patient disposition Clotet B. Lancet 2014;383; FLAMINGO FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI

Response to treatment at week 48 Median CD4/mm 3 increase at W48 : in both groups Adjusted difference (95% CI) = 7.1% (0.9 ; 13.2) Adjusted difference (95% CI) = 7.4% (-1.4 ; 13.3) ITT, snapshotPer protocol DTG + 2 NRTI DRV/r + 2 NRTI HIV RNA < 50 c/mL Primary analysis % 0 Protocol-defined virologic failures (2 consecutive HIV RNA > 200 c/mL on or after W24) 2 on DTG + NRTI (TDF/FTC) 2 on DRV/r + NRTI (ABC/3TC) No resistance emergence in the 4 cases Clotet B. Lancet 2014;383; FLAMINGO FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI

HIV-1 RNA < 50 c/mL at week 48 by stratification factors (HIV-1 RNA and background NRTI) Clotet B. Lancet 2014;383; FLAMINGO FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI DTG + 2 NRTI N = 242 DRV/r + 2 NRTI N = 242 Difference in % (95% CI) DTG – DRV/r Number of Responders/N Assessed HIV RNA ≤ 100,000 c/mL160/181(88%) 157 / 181 (87%)1.7 (-5.1, 8.5) HIV RNA > 100,000 c/mL57/61 (93%) 43/61 (70%)23.0 (9.9, 36.0) ABC/3TC 71/79 (90%)68/80 (85%)4.9 (-5.4, 15.1) TDF/FTC 146/163 (90%)132/162 (81%)8.1 (0.5, 15.7) ABC/3TC ; ≤ 100,000 c/mL 59/66 (89%) 60/68 (88%) ABC/3TC ; > 100,000 c/mL 12/13 (92%) 8/12 (67%) TDF/FTC ; ≤ 100,000 c/mL 101/115 (88%) 97/113 (86%) TDF/FTCTC ; > 100,000 c/mL 45/48 (94%) 35/49 (71%)

Adverse events occurring in > 5% in either group at week 48 Clotet B. Lancet 2014;383; FLAMINGO FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI DTG + 2 NRTIDRV/r + 2 NRTI Any adverse event85% Diarrhea17%29% Nausea16%18% Headache15%10% Nasopharyngitis9%8% Upper respiratory tract infection5%10% Insomnia7%6% Cough5%7% Vomiting6% Fatigue6%5% Pyrexia5%6% Dizziness6%5% Rash4%6% Back pain4%5% Pharyngitis3%5% Bronchitis2%5% Sinusitis2%5% Depression5%2% Arthralgia2%5%

Safety at week 48 Clotet B. Lancet 2014;383; FLAMINGO FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI DTG + 2 NRTIDRV/r + 2 NRTI Any serious adverse event N = 26 (11%)N = 13 (5%) Infections and infestationsN = 5N = 8 Gastrointestinal disordersN = 6N = 2 Psychiatric disordersN = 4N = 1 Injury, poisoning and procedural complicationsN = 40 Nervous system disordersN = 40 Cardiac disordersN = 1 Articular disordersN = 20 Renal and urinary disordersN = 1 CholelithiasisN = 10 Drug hypersensitivity0N = 1 Hodgkin’s diseaseN = 10 AsthmaN = 10 Emergent ALT increase > 3 ULNN = 9 (4%)N = 6 (2%) Protocol liver stopping criteria (all related to other causes)N = 1N = 4 Mean difference in increase in fasting LDL-cholesterol, mmol/L-0.30 (95% CI: ; ; P<0.0001) Grade > 2 LDL-cholesterol2%7% (P=0.0001)

 Conclusion –DTG 50 mg QD achieved higher virologic success at week 48, than DRV/r QD, when combined with either TDF/FTC or ABC/3TC –In patients with high baseline viral load, the response rate was higher for DTG –No resistance mutations were detected through 48 weeks in the 2 groups –Adverse events leading to discontinuation occurred less frequently in the DTG group –No specific trends in adverse events With the exception of 2 patients reporting suicide attempt and overdose on DTG –No discontinuation due to renal events –Mean increases in creatinine with accompanying decreases in estimated glomerular filtration rate occurred by week 4, and stabilized up to week 48 –Once-daily DTG in combination with fixed-dose NRTIs represents an effective treatment option for HIV-1-infected, treatment-naive patients Clotet B. Lancet 2014;383; FLAMINGO FLAMINGO Study: DTG QD + 2 NRTI vs DRV/r QD + 2 NRTI