Comparison of NNRTI vs NNRTI ENCORE EFV vs

Comparison of NNRTI vs NNRTI § ENCORE § EFV vs RPV – ECHO-THRIVE – STAR § EFV vs ETR – SENSE § DOR vs EFV – DRIVE-AHEAD

SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI § Design Randomisation 1: 1 Open-label W 12 W 48 N = 79 ETR 400 mg (4 tablets) QD + EFV ARV-naïve HIV RNA > 5, 000 c/m. L No R to study drugs placebo + 2 NRTI* N = 78 EFV 600 mg QD + ETR placebo + 2 NRTI* Randomisation was stratified by HIV RNA (< or > 100, 000 c/m. L) at screening * Open-label NRTI combination selected by investigator : ZDV/3 TC BID or ABC/3 TC QD or TDF/FTC QD § Primary endpoint – Difference in percentage of patients with at least one grade 1 -4 treatmentemergent, drug related neuropsychiatric adverse event by week 12 (adjusted ITT analysis, two-sided test, 90% power) SENSE Gazzard B. AIDS 2011; 25: 2249 -58

SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Baseline characteristics and patient disposition ETR + 2 NRTI, N = 79 EFV + 2 NRTI, N = 78 38 38 15% 23% HIV RNA (log 10 c/m. L), median 4. 8 CD 4 cell count (/mm 3), median 319 273 12 (15%)* 4 (5%)* > 1 IAS-USA NRTI mutation 6% 0 HCV antibody positive 11% 10% Mean age, years Female > 1 IAS-USA NNRTI mutation Selected NRTI TDF/FTC ; ABC/3 TC ; ZD/3 TC Discontinuation by W 12 60% ; 26% ; 14% N = 10 N=8 For adverse event N=4 N=8 Lost to follow-up N=1 0 Withdrew consent N=3 0 Other reasons N=2 0 * E 138 A, N = 5, V 106 I, N = 4, V 108 I, N = 1, V 90 I, N = 6 SENSE Nelson M. AIDS 2011; 25: 335 -40

SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI § Neuropsychiatric adverse events during 12 weeks ETR + 2 NRTI EFV + 2 NRTI P 27. 8% 55. 1% < 0. 001 16. 5% 46. 2 % < 0. 001 All events grade 2 -4 10. 1% 19. 2% 0. 103 Drug-related 5. 1% 16. 7% 0. 019 20. 2% 33. 4% 4% 19% 11 % 39 % 9% 32% N=1 N=4 All events grade 1 -4 Drug-related (primary endpoint) Nervous system adverse events, all grade Dizziness Psychiatric adverse events, all grade Sleep disorders Depression 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 SENSE Nelson M. AIDS 2011; 25: 335 -40

SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI Response to treatment at week 48 ETR + 2 NRTI EFV + 2 NRTI 100 ITT, TLOVR % Non-VF censored analysis 92. 3 89. 2 75. 9 75 HIV RNA < 40 c/m. L 74. 4 76. 8 78. 4 97. 6 93. 0 83. 3 81. 8 74. 1 66. 7 50 25 0 All patients Difference (95% CI) = 1. 6% (-12. 0 ; 15. 2) SENSE Baseline HIV RNA < 100, 000 c/ml Baseline HIV RNA > 100, 000 c/ml All patients Difference (95% CI) = 2. 9% (-5. 8 ; 11. 7) Baseline HIV RNA < 100, 000 c/ml Baseline HIV RNA > 100, 000 c/ml Gazzard B. AIDS 2011; 25: 2249 -58

SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI § Protocol-defined criteria for genotype testing - Discontinuation with detectable HIV RNA decrease < 1 log 10 c/m. L or > 400 c/m. L at week 12 HIV RNA > 50 c/m. L at week 48 Virologic failure (2 consecutive HIV RNA > 50 c/m. L) by TLOVR algorithm Resistance data Virologic failure, n Baseline HIV RNA > 100, 000 c/m. L Presence of resistance mutations, n ETR + 2 NRTI EFV + 2 NRTI 4 7 3/4 4/7 0 3 K 103 N 1 V 106 I + M 184 I 1 K 103 N + M 184 V + P 225 H 1 Additional patients genotyped at time of discontinuation (HIV RNA > 50 c/m. L), n NNRTI mutation (V 90 I) 7 2 1 0 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/m. L at week 48 SENSE Gazzard B. AIDS 2011; 25: 2249 -58

SENSE Study: ETR QD + 2 NRTI vs EFV QD + 2 NRTI § 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 SENSE Gazzard B. AIDS 2011; 25: 2249 -58