1. Comparison of NNRTI vs NNRTI  ENCORE  EFV vs RPV –ECHO-THRIVE –STAR  EFV vs ETR –SENSE

2. Gazzard B. AIDS 2011;25:2249-58 SENSE  Design  Primary endpoint –Difference in percentage of patients with at least one grade 1-4 treatment- emergent, drug related neuropsychiatric adverse event by week 12 (adjusted ITT analysis, two-sided test, 90% power) ETR 400 mg (4 tablets) QD + EFV placebo + 2 NRTI* EFV 600 mg QD + ETR placebo + 2 NRTI* Randomisation 1 : 1 Open-label ARV-naïve HIV RNA > 5,000 c/mL No R to study drugs SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI N = 78 N = 79 W12W48 Randomisation was stratified by HIV RNA ( 100,000 c/mL) at screening * Open-label NRTI combination selected by investigator : ZDV/3TC BID or ABC/3TC QD or TDF/FTC QD

3. ETR + 2 NRTI, N = 79EFV + 2 NRTI, N = 78 Mean age, years38 Female15%23% HIV RNA (log 10 c/mL), median4.8 CD4 cell count (/mm 3 ), median319273 > 1 IAS-USA NNRTI mutation12 (15%)*4 (5%)* > 1 IAS-USA NRTI mutation6%0 HCV antibody positive11%10% Selected NRTI TDF/FTC ; ABC/3TC ; ZD/3TC60% ; 26% ; 14% Discontinuation by W12N = 10N = 8 For adverse eventN = 4N = 8 Lost to follow-upN = 10 Withdrew consentN = 30 Other reasonsN = 20 Baseline characteristics and patient disposition Nelson M. AIDS 2011;25:335-40 * E138A, N = 5, V106I, N = 4, V108I, N = 1, V90I, N = 6 SENSE SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI

4. ETR + 2 NRTIEFV + 2 NRTIP All events grade 1-427.8%55.1%< 0.001 Drug-related (primary endpoint)16.5%46.2 %< 0.001 All events grade 2-410.1%19.2%0.103 Drug-related5.1%16.7%0.019 Nervous system adverse events, all grade20.2%33.4% Dizziness4%19% Psychiatric adverse events, all grade11 %39 % Sleep disorders9%32% DepressionN = 1N = 4  Neuropsychiatric adverse events during 12 weeks Serious adverse events : ETR, N = 5, EFV, N = 3 Grade 2-4 skin or subcutaneous AE : ETR, N = 8, EFV, N = 9 ; discontinuation for rash : 4/8 and 4/9 Grade 2-4 elevations in total cholesterol and LDL cholesterol : ETR = 3 and 6 ; EFV = 18 and 13 Nelson M. AIDS 2011;25:335-40 SENSE SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI

5. Response to treatment at week 48 Gazzard B. AIDS 2011;25:2249-58 SENSE SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI HIV RNA < 40 c/mL 25 50 100 75 75.9 74.4 % Difference (95% CI) = 1.6% (-12.0 ; 15.2) 74.1 66.7 ETR + 2 NRTI EFV + 2 NRTI ITT, TLOVR 76.8 78.4 Baseline HIV RNA < 100,000 c/ml Non-VF censored analysis Baseline HIV RNA > 100,000 c/ml All patients Baseline HIV RNA < 100,000 c/ml Baseline HIV RNA > 100,000 c/ml All patients 92.3 89.2 83.3 81.8 Difference (95% CI) = 2.9% (-5.8 ; 11.7) 97.6 93.0 0

6.  Protocol-defined criteria for genotype testing -Discontinuation with detectable HIV RNA -HIV RNA decrease 400 c/mL at week 12 -HIV RNA > 50 c/mL at week 48 -Virologic failure (2 consecutive HIV RNA > 50 c/mL) by TLOVR algorithm ETR + 2 NRTIEFV + 2 NRTI Virologic failure, n47 Baseline HIV RNA > 100,000 c/mL3/44/7 Presence of resistance mutations, n03 K103N V106I + M184I K103N + M184V + P225H 111111 Additional patients genotyped at time of discontinuation (HIV RNA > 50 c/mL), n 72 NNRTI mutation (V90I)10 Resistance data Gazzard B. AIDS 2011;25:2249-58 Among patients with baseline IAS-USA NNRTI mutations, 10/10 in the ETR arm and 4/4 in the EFV arm had HIV RNA < 50 c/mL at week 48 SENSE SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI

7.  Summary –First-line treatment with etravirine 400 mg once daily and two nucleoside reverse transcriptase inhibitors (NRTI) led to similar rates of HIV RNA suppression, compared with efavirenz and two NRTI –None of the patients with virological failure in the etravirine arm developed resistance to NNRTI –Etravirine was associated with significantly fewer neuropsychiatric adverse events than EFV. The difference was still statistically significant at the week 48 visit –There were greater rises in lipids in the EFV arm –The risk of grade 2-4 skin or subcutaneous adverse events was similar in the two arms Gazzard B. AIDS 2011;25:2249-58 SENSE SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI