Comparison of INSTI vs EFV STARTMRK GSUS236 0102

Comparison of INSTI vs EFV § STARTMRK § GS-US-236 -0102 § SINGLE

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC § Design Randomisation* 1: 1 Double-blind > 18 years ARV-naïve HIV RNA > 5, 000 c/m. L Any CD 4 cell count No resistance to EFV, TDF or FTC W 48 W 240 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/m. L) and viral hepatitis co-infection status § Objective – Non inferiority of RAL vs EFV: % HIV RNA < 50 c/m. L by per protocol, noncompleter = failure analysis (lower margin of the 2 -sided 95% CI for the difference = - 12%, 90% power) STARTMRK Lennox JL. Lancet 2009; 374: 796 -806

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 281 282 Median age, years 37 36 19% 18% 41% / 12% / 47% 44% / 8% / 48% 5. 1 5. 0 HIV RNA > 100, 000 c/m. L 55% 51% HIV RNA > 50, 000 c/m. L 72% 70% CD 4 cell count (/mm 3), median 212 204 CD 4 < 50 per mm 3 10% 11% HBs. Ag+ or HCV Ab+ 6% 6% 24 (8. 5%) 35 (12. 4%) For lack of efficacy N=4 N=2 For adverse event N=8 N = 17 Female White/Black/Other HIV RNA (log 10 c/m. L), median Discontinuation by W 48 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

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Response to treatment at week 48 HIV RNA < 50 c/m. L RAL % 100 Primary analysis 86. 1 81. 9 EFV Per protocol, observed-failure * 91. 6 89. 1 75 50 HIV RNA < 50 c/m. L at W 48 (observed-failure analysis) by baseline factors Baseline RAL EFV RNA < 5 log 10 c/m. L RNA > 5 log 10 c/m. L 92. 5% 90. 9% 89. 1% 89. 2% CD 4 > 200/mm 3 CD 4 < 200/mm 3 94. 4% 88. 3% 92. 4% 85. 6% HIV-1 B subtype Non-B subtype 90. 3% 96. 3% 88. 5% 90. 9% 25 N = 281 282 263 258 PP, NC = F 95% CI for the difference = - 1. 9; 10. 3 STARTMRK 95% CI for the difference = - 2. 6; 7. 7 * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment Mean CD 4/mm 3 increase at W 48 (observed-failure analysis): 189 (RAL) vs 163 (EFV) (P = 0. 0184) Lennox JL. Lancet 2009; 374: 796 -806

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC § Safety at W 48 RAL Clinical adverse events Drug-related AE 44. 1% Serious drug-related AE 1. 4% Treatment discontinuation due to AE 3. 2% Laboratory adverse events Drug-related AE 5. 0% Treatment discontinuation due to AE 0 Clinical drug-related AE of moderate to severe intensity 16% Headache 4% Dizziness 1% Insomnia 4% Fatigue 1% Diarrhoea 1% 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) 1% Incidence of other abnormalities < 2% and not different between arms STARTMRK EFV P 77. 0% 1. 8% 6. 0% < 0. 0001 NS NS 8. 5% 0. 4% 32% 5% 6% 3% 3% 3% NS NS < 0. 0001 4% Lennox JL. Lancet 2009; 374: 796 -806

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

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 71. 0% 61. 3% 374 312 19. 6% 20. 9% Non response 3. 6% 8. 5% Rebound 16. 0% 12. 4% 5 (1. 8%) 71 (25. 2% 98 (34. 5%) Due to lack of efficacy 6 10 Due to clinical AE 14 25 Due to laboratory AE 0 3 Due to other reasons 51 60 52. 0% 80. 1% HIV RNA level < 50 c/m. L Mean CD 4/mm 3 change from baseline Virologic failure (confirmed HIV RNA > 50 c/m. L) Death Discontinuation Drug-related clinical adverse events STARTMRK Rockstroh JK, JAIDS 2013; 63: 77 -85

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

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Response to treatment at week 240 (5 years) HIV RNA < 50 c/m. L % 100 75 RAL Primary analysis PP, NC = F HIV RNA < 50 c/m. L (observed-failure analysis) by baseline factors EFV Per protocol, observed-failure * 89. 2 80. 7 71. 0 61. 3 50 Baseline RAL EFV RNA < 5 log 10 c/m. L RNA > 5 log 10 c/m. L 94% 85% 78% 83% CD 4 > 200/mm 3 CD 4 < 200/mm 3 82. 5% 88. 3% 78. 7% 85. 6% HIV-1 B subtype Non-B subtype 90% 87% 79% 84% 25 N = 279 Difference (95% CI) = 9. 5% (1. 7 ; 17. 3) Superiority 263 258 Difference (95% CI) = 8. 6% (1. 9 ; 15. 5) Superiority * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment STARTMRK Increases in fasting serum triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol from baseline were significantly lower at W 240 (P < 0. 005) in RAL than EFV Rockstroh JK, JAIDS 2013; 63: 77 -85

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Cumulative summary of genotypicresistance data for patients with RNA > 400 c/m. L at the time of virologic failure out to week 240 RAL N = 281 EFV N = 282 55 (19. 6%) 59 (20. 9%) 23* 20 RAL or EFV resistance alone 1 7 RAL or EFV resistance, and NRTI resistance 3 3 NRTI resistance alone 3 2 Protocol-defined virologic failure confirmed (HIV RNA > 50 c/m. L) Resistance data available (HIV RNA > 400 c/m. L) * 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 – – STARTMRK Q 148 H + G 140 S, Q 148 R + G 140 S, Y 143 Y/H + L 74 L/M + E 92 Q +T 97 A, Y 143 R Rockstroh JK, JAIDS 2013; 63: 77 -85

STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Drug-related adverse events in > 5% in either group over 5 years Gastrointestinal disorders Diarrhea Flatulence Nausea General disorders Fatigue Nervous system disorders Dizziness Headache Somnolence Psychiatric disorders Abnormal dreams Insomnia Nightmare Skin and subcutaneous tissue disorders Rash STARTMRK RAL EFV 5. 3% 3. 6% 8. 9% 9. 9% 5. 0% 11. 0% 4. 3% 8. 9% 7. 8% 9. 3% 1. 1% 35. 1% 14. 2% 7. 4% 6. 8% 7. 5% 2. 8% 13. 1% 8. 2% 5. 3% 1. 1% 8. 2% Rockstroh JK, JAIDS 2013; 63: 77 -85

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 W 24. 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/m. L for weeks 2 to 16) – Greater increase in CD 4 was observed in the RAL group. It was significant from W 156 – 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