1. Comparison of INSTI vs EFV  STARTMRK  GS-US-236-0102  SINGLE

2. Lennox JL. Lancet 2009;374:796-806 STARTMRK  Design  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) RAL 400 mg BID + EFV placebo TDF/FTC fdc QD EFV 600 mg QD + RAL placebo TDF/FTC fdc QD > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count No resistance to EFV, TDF or FTC *Randomisation was stratified by baseline HIV RNA ( 50,000 c/mL) and viral hepatitis co-infection status STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Randomisation* 1 : 1 Double-blind N = 284 N = 282 W240W48

3. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC RALEFV Randomized, N282284 Treated eligible patients, N281282 Median age, years3736 Female19%18% White/Black/Other41% / 12% / 47%44% / 8% / 48% HIV RNA (log 10 c/mL), median5.15.0 HIV RNA > 100,000 c/mL55%51% HIV RNA > 50,000 c/mL72%70% CD4 cell count (/mm 3 ), median212204 CD4 < 50 per mm 3 10%11% HBsAg+ or HCV Ab+6% Discontinuation by W4824 (8.5%)35 (12.4%) For lack of efficacyN = 4N = 2 For adverse eventN = 8N = 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 Baseline characteristics and patient disposition

4. BaselineRALEFV RNA < 5 log 10 c/mL RNA > 5 log 10 c/mL 92.5% 90.9% 89.1% 89.2% CD4 > 200/mm 3 CD4 < 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% Response to treatment at week 48 * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment STARTMRK STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Lennox JL. Lancet 2009;374:796-806 HIV RNA < 50 c/mL at W48 (observed-failure analysis) by baseline factors Mean CD4/mm 3 increase at W48 (observed-failure analysis): 189 (RAL) vs 163 (EFV) (P = 0.0184) 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 * 95% CI for the difference = - 2.6; 7.7 281282263258 25 50 100 75 % Primary analysis RALEFV PP, NC = F N =

5. RALEFVP Clinical adverse events Drug-related AE44.1%77.0%< 0.0001 Serious drug-related AE1.4%1.8%NS Treatment discontinuation due to AE3.2%6.0%NS Laboratory adverse events Drug-related AE5.0%8.5%NS Treatment discontinuation due to AE00.4%NS Clinical drug-related AE of moderate to severe intensity16%32%< 0.0001 Headache4%5% Dizziness1%6% Insomnia4%3% Fatigue1%3% Diarrhoea1%3% 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%4% Incidence of other abnormalities < 2% and not different between arms STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC  Safety at W48 STARTMRK Lennox JL. Lancet 2009;374:796-806

6. 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

7. RAL N = 281 EFV N = 282 HIV RNA level < 50 c/mL71.0%61.3% Mean CD4/mm 3 change from baseline374312 Virologic failure (confirmed HIV RNA > 50 c/mL)19.6%20.9% Non response3.6%8.5% Rebound16.0%12.4% Death5 (1.8%) Discontinuation71 (25.2%98 (34.5%) Due to lack of efficacy610 Due to clinical AE1425 Due to laboratory AE03 Due to other reasons5160 Drug-related clinical adverse events52.0%80.1% Cumulative treatment outcome for the entire 5 years study STARTMRK STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Rockstroh JK, JAIDS 2013;63:77-85

8. STARTMRK STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Rockstroh JK, JAIDS 2013;63:77-85 Cumulative Discontinuation Rate due to AE (%) 0 2 4 Log rank P-value = 0,023 6 8 10 12 14 16 18 20 016324860728496120140168192216240 Weeks 281272265262255246236231227223217190 282272257254245235221213203200196183 Number at risk RALEFV

9. BaselineRALEFV RNA < 5 log 10 c/mL RNA > 5 log 10 c/mL 94% 85% 78% 83% CD4 > 200/mm 3 CD4 < 200/mm 3 82.5% 88.3% 78.7% 85.6% HIV-1 B subtype Non-B subtype 90% 87% 79% 84% Response to treatment at week 240 (5 years) * Exclusion of discontinuations due to intolerability or reasons unrelated to treatment STARTMRK STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC HIV RNA < 50 c/mL (observed-failure analysis) by baseline factors 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 263258 25 50 100 75 % Primary analysis RALEFV PP, NC = F N = Difference (95% CI) = 8.6% (1.9 ; 15.5)  Superiority 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 Rockstroh JK, JAIDS 2013;63:77-85

10. 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 alone17 RAL or EFV resistance, and NRTI resistance33 NRTI resistance alone32 Cumulative summary of genotypicresistance data for patients with RNA > 400 c/mL at the time of virologic failure out to week 240 * Integrase gene could not be amplified in 5 cases STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK  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

11. RALEFV Gastrointestinal disorders Diarrhea5.3%9.9% Flatulence3.6%5.0% Nausea8.9%11.0% General disorders Fatigue4.3%8.9% Nervous system disorders Dizziness7.8%35.1% Headache9.3%14.2% Somnolence1.1%7.4% Psychiatric disorders Abnormal dreams6.8%13.1% Insomnia7.5%8.2% Nightmare2.8%5.3% Skin and subcutaneous tissue disorders Rash1.1%8.2% Drug-related adverse events in > 5% in either group over 5 years STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC Rockstroh JK, JAIDS 2013;63:77-85 STARTMRK

12. 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