Comparison of INSTI vs EFV ARV-trial.com Comparison of INSTI vs EFV STARTMRK GS-US-236-0102 SINGLE 1

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Design Randomisation* 1 : 1 Double-blind W48 W240 > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count No resistance to EFV, TDF or FTC N = 282 RAL 400 mg BID + EFV placebo TDF/FTC fdc QD N = 284 EFV 600 mg QD + RAL placebo TDF/FTC fdc QD *Randomisation was stratified by baseline HIV RNA (< or > 50,000 c/mL) and viral hepatitis co-infection status Objective Non inferiority of RAL vs EFV: % HIV RNA < 50 c/mL by per protocol, non-completer = failure analysis (lower margin of the 2-sided 95% CI for the difference = - 12%, 90% power) STARTMRK Lennox JL. Lancet 2009;374:796-806 2

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Baseline characteristics and patient disposition RAL EFV Randomized, N 282 284 Treated eligible patients, N 281 Median age, years 37 36 Female 19% 18% White/Black/Other 41% / 12% / 47% 44% / 8% / 48% HIV RNA (log10 c/mL), median 5.1 5.0 HIV RNA > 100,000 c/mL 55% 51% HIV RNA > 50,000 c/mL 72% 70% CD4 cell count (/mm3), median 212 204 CD4 < 50 per mm3 10% 11% HBsAg+ or HCV Ab+ 6% Discontinuation by W48 24 (8.5%) 35 (12.4%) For lack of efficacy N = 4 N = 2 For adverse event N = 8 N = 17 RAL was administered with or without food, EFV on an empty stomach at bedtime, TDF/FTC in the morning with food STARTMRK Lennox JL. Lancet 2009;374:796-806 3

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Response to treatment at week 48 HIV RNA < 50 c/mL 86.1 81.9 95% CI for the difference = - 1.9; 10.3 91.6 89.1 Per protocol, observed-failure * = - 2.6; 7.7 281 282 263 258 25 50 100 75 % Primary analysis RAL EFV PP, NC = F N = HIV RNA < 50 c/mL at W48 (observed-failure analysis) by baseline factors Baseline RAL EFV RNA < 5 log10 c/mL RNA > 5 log10 c/mL 92.5% 90.9% 89.1% 89.2% CD4 > 200/mm3 CD4 < 200/mm3 94.4% 88.3% 92.4% 85.6% HIV-1 B subtype Non-B subtype 90.3% 96.3% 88.5% Mean CD4/mm3 increase at W48 (observed-failure analysis): 189 (RAL) vs 163 (EFV) (P = 0.0184) * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment STARTMRK Lennox JL. Lancet 2009;374:796-806 4

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Safety at W48 RAL EFV P Clinical adverse events Drug-related AE 44.1% 77.0% < 0.0001 Serious drug-related AE 1.4% 1.8% NS Treatment discontinuation due to AE 3.2% 6.0% Laboratory adverse events 5.0% 8.5% 0.4% Clinical drug-related AE of moderate to severe intensity 16% 32% Headache 4% 5% Dizziness 1% 6% Insomnia 3% Fatigue Diarrhoea No difference in incidence in other AE occurring in > 2% of patients Grade 3 or 4 laboratory abnormality Fasting LDL-cholesterol > 4.92 mmol/L (190 mg/dl) Incidence of other abnormalities < 2% and not different between arms STARTMRK Lennox JL. Lancet 2009;374:796-806 5

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Safety: neuropsychiatric symptoms At Week 8 CNS-related adverse events had occurred in 10% of RAL patients vs 18% of EFV patients (P = 0.0149) Retrospective sensitivity analysis (additional symptoms): > 1 CNS-related adverse event: 20% vs 52% (P < 0.0001) Most symptoms were self-limited At Week 48 Cumulative incidence of CNS-related adverse event was significantly lower in patients on RAL: 14% vs 23% in the main analysis (P = 0.0044); 26% vs 59% in the sensitivity analysis (P < 0.0001) These events were generally mild: 62% of RAL vs 79% of EFV Only 1 patient, on EFV, discontinued the trial because of CNS-related adverse event STARTMRK Lennox JL. Lancet 2009;374:796-806 6

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Cumulative treatment outcome for the entire 5 years study RAL N = 281 EFV N = 282 HIV RNA level < 50 c/mL 71.0% 61.3% Mean CD4/mm3 change from baseline 374 312 Virologic failure (confirmed HIV RNA > 50 c/mL) 19.6% 20.9% Non response 3.6% 8.5% Rebound 16.0% 12.4% Death 5 (1.8%) Discontinuation 71 (25.2% 98 (34.5%) Due to lack of efficacy 6 10 Due to clinical AE 14 25 Due to laboratory AE 3 Due to other reasons 51 60 Drug-related clinical adverse events 52.0% 80.1% STARTMRK Rockstroh JK, JAIDS 2013;63:77-85 7

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Cumulative Discontinuation Rate due to AE (%) 2 4 Log rank P-value = 0,023 6 8 10 12 14 16 18 20 32 48 60 72 84 96 120 140 168 192 216 240 Weeks 281 272 265 262 255 246 236 231 227 223 217 190 282 257 254 245 235 221 213 203 200 196 183 Number at risk RAL EFV STARTMRK Rockstroh JK, JAIDS 2013;63:77-85 8

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Response to treatment at week 240 (5 years) HIV RNA < 50 c/mL 71.0 61.3 Difference (95% CI) = 9.5% (1.7 ; 17.3) Superiority 89.2 80.7 Per protocol, observed-failure * 279 263 258 25 50 100 75 % Primary analysis RAL EFV PP, NC = F N = = 8.6% (1.9 ; 15.5)  Superiority HIV RNA < 50 c/mL (observed-failure analysis) by baseline factors Baseline RAL EFV RNA < 5 log10 c/mL RNA > 5 log10 c/mL 94% 85% 78% 83% CD4 > 200/mm3 CD4 < 200/mm3 82.5% 88.3% 78.7% 85.6% HIV-1 B subtype Non-B subtype 90% 87% 79% 84% Increases in fasting serum triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol from baseline were significantly lower at W240 (P < 0.005) in RAL than EFV * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment STARTMRK Rockstroh JK, JAIDS 2013;63:77-85 9

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Cumulative summary of genotypicresistance data for patients with RNA > 400 c/mL at the time of virologic failure out to week 240 RAL N = 281 EFV N = 282 Protocol-defined virologic failure confirmed (HIV RNA > 50 c/mL) 55 (19.6%) 59 (20.9%) Resistance data available (HIV RNA > 400 c/mL) 23* 20 RAL or EFV resistance alone 1 7 RAL or EFV resistance, and NRTI resistance 3 NRTI resistance alone 2 * Integrase gene could not be amplified in 5 cases Emergence of RAL resistance in 4 patients (1.4%) Sequencing data of the 4 patients with emergence of RAL-associated mutations Q148H + G140S, Q148R + G140S, Y143Y/H + L74L/M + E92Q +T97A, Y143R STARTMRK Rockstroh JK, JAIDS 2013;63:77-85 10

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Drug-related adverse events in > 5% in either group over 5 years RAL EFV Gastrointestinal disorders Diarrhea 5.3% 9.9% Flatulence 3.6% 5.0% Nausea 8.9% 11.0% General disorders Fatigue 4.3% Nervous system disorders Dizziness 7.8% 35.1% Headache 9.3% 14.2% Somnolence 1.1% 7.4% Psychiatric disorders Abnormal dreams 6.8% 13.1% Insomnia 7.5% 8.2% Nightmare 2.8% Skin and subcutaneous tissue disorders Rash STARTMRK Rockstroh JK, JAIDS 2013;63:77-85 11

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC ARV-trial.com STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Summary – Conclusion At 48 weeks of treatment, RAL was non-inferior to EFV, in combination with TDF/FTC. Virologic non-inferiority of RAL was confirmed through W24. RAL was superior to EFV for virologic outcome at week 240 RAL + TDF/FTC led to more rapid viral load decline (significantly more patients with HIV RNA < 50 c/mL for weeks 2 to 16) Greater increase in CD4 was observed in the RAL group. It was significant from W156 Upon virologic failure, resistance mutations to RAL was found in few cases RAL was associated with significantly fewer overall and drug-related clinical adverse events, and CNS-related adverse events than was EFV Mean changes in lipid parameters were smaller for RAL than for EFV RAL + TDF/FTC is an alternative to EFV + TDF/FTC as a first-line combination regimen in treatment-naïve HIV-infected patients STARTMRK Lennox JL. Lancet 2009;374:796-806; Rockstroh JK, JAIDS 2013;63:77-85 12