Comparison of NNRTI vs NNRTI ENCORE EFV vs

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Comparison of NNRTI vs NNRTI § ENCORE § EFV vs RPV – ECHO-THRIVE –

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

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Design Randomisation* 1: 1 Open-label > 18 years

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Design Randomisation* 1: 1 Open-label > 18 years ARV-naïve HIV RNA > 2, 500 c/m. L Any CD 4 cell count e. GFR > 50 m. L/min Sensitivity to EFV, FTC and TDF on genotype No RPV resistance mutations** N = 394 N = 392 W 48 W 96 RPV/FTC/TDF QD STR EFV/FTC/TDF QD STR Concomitant use of proton pump inhibitors was not allowed * Randomisation was stratified by HIV RNA (< or > 100, 000 c/m. L) ** K 101 E/P, E 138 A/G/K/Q/R, Y 181 C/I/V, H 221 Y § Objective – Non inferiority of RPV/FTC/TDF at W 48: % HIV RNA < 50 c/m. L by intention to treat, snapshot analysis (1 -sided significance level of 2. 5%, lower margin of the 97. 5% CI for the difference = -12%, 95% power) STAR Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Baseline characteristics and patient disposition RPV/FTC/TDF N = 394

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Baseline characteristics and patient disposition RPV/FTC/TDF N = 394 EFV/FTC/TDF N = 392 Median age, years 37 35 Female 7% 7% HIV RNA (log 10 c/m. L), median 4. 8 HIV RNA > 100, 000 c/m. L 34% 36% CD 4 cell count (/mm 3), mean 396 385 54 (13. 7%) 72 (18. 4%) For lack of efficacy N = 12 N=3 For adverse event N = 10 N = 34 Lost to follow-up N = 15 N = 10 Non compliance N=6 N=4 Withdrew consent N=5 N = 13 Protocol violation N=1 Pregnancy N=2 - Investigator’s decision N=3 - N=1 Discontinuation by W 48 Death STAR Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Response to treatment (HIV RNA < 50 c/m. L)

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Response to treatment (HIV RNA < 50 c/m. L) at week 48 RPV/FTC/TDF % 100 EFV/FTC/TDF Primary analysis 85. 8 88. 8 81. 6 79. 9 81. 7 81. 6 85. 3 79. 6 75 50 25 0 ITT, snapshot Adjusted difference (95% CI) = 4. 1% (-1. 1 ; 9. 2) ITT snapshot, by baseline HIV-1 RNA > 100, 000 c/m. L < 100, 000 c/m. L Difference (95% CI) = -1. 8% (-11. 1 ; 7. 5) Difference (95% CI) = 7. 2% (1. 1 ; 13. 4) ITT, TLOVR Adjusted difference (95% CI) = 5. 9% (0. 6 ; 11. 2) Median CD 4/mm 3 increase at W 48 : + 200 RPV/FTC/TDF vs + 191 EFV/FTC/TDF STAR Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Resistance analysis through week 48 Resistance analysis population*

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Resistance analysis through week 48 Resistance analysis population* Resistance to antiretrovirals In patients with baseline HIV RNA < 100, 000 c/m. L In patients with baseline HIV RNA > 100, 000 c/m. L Any primary NNRTI resistance Y 181 C/I E 138 K/Q K 101 E K 103 N Y 188 L G 190 E/Q Any primary NRTI resistance M 184 V/I K 65 R/N RPV/FTC/TDF EFV/FTC/TDF 20 (5%) 17 (4. 3%) 1. 9% 9. 0% 16 8 6 5 16 15 3 7 (2%) 3 (0. 8%) 0. 8% 0. 7% 3 1 1 1 0 * HIV RNA > 400 c/m. L and suboptimal virologic response (confirmed < 1 log 10 c/m. L decrease in HIV RNA at W 8) virologic rebound (2 consecutive visits with HIV RNA > 50 c/m. L after achieving < 50 c/m. L, 2 consecutive visits with > 1 log 10 c/m. L increase in HIV RNA from the nadir) or HIV RNA > 400 c/m. L at W 48 or last visit STAR Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Safety through week 48 Grade 3 -4 treatment-emergent

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Safety through week 48 Grade 3 -4 treatment-emergent adverse events Related to study drug RPV/FTC/TDF EFV/FTC/TDF 7. 4% 1. 8% 13. 8% 4. 8% § Treatment-emergent adverse events of specific interest in > 5% in either arm Nervous system events Dizziness Insomnia Somnolence Headache Psychiatric events Abnormal dreams Depression Anxiety Rash events Folliculitis Rash STAR RPV/FTC/TDF EFV/FTC/TDF 29. 7% 6. 6% 9. 6% 2. 5% 12. 4% 15. 7% 5. 8% 6. 6% 5. 1% 17. 3% 5. 3% 6. 1% 50. 5% 22. 2% 14. 0% 13. 5% 37. 5% 24. 5% 8. 9% 8. 4% 21. 2% 1. 0% 12. 0% Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Mean changes in fasting lipids (mg/d. L) at week

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Mean changes in fasting lipids (mg/d. L) at week 48 RPV/FTC/TDF EFV/FTC/TDF P<0. 001 for all between treatment groups using ANOVA Mean baseline values (mg/d. L) 164 163 104 103 121 129 44 44 Change in total cholesterol/HDL-cholesterol at week 48 was -0. 2 in both arms STAR Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Conclusion at week 48 – In treatment-naive HIV-infected

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Conclusion at week 48 – In treatment-naive HIV-infected patients, RPV/FTC/TDF demonstrated non inferior efficacy and improved tolerability compared with EFV/FTC/TDF, at week 48 • RPV/FTC/TDF was statistically significant superiority in efficacy for patients with baseline HIV-1 RNA ≤ 100, 000 c/m. L • Virologic efficacy was similar for patients with baseline HIV-1 RNA > 100, 000 c/m. L – More discontinuations due to adverse events in the EFV/FTC/TDF arm – Significantly lower rates of nervous system and psychiatric adverse events in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm • Differences primarily due to dizziness and abnormal dreams – Virologic failures rates were similar between the 2 treatment arms • A greater proportion of patients in the RPV/FTC/TDF arm developed primary emergent NRTI or NNRTI resistance mutations at virologic failure STAR Cohen C. AIDS 2014; 28: 989 -97

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Response to treatment (HIV RNA < 50 c/m. L)

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Response to treatment (HIV RNA < 50 c/m. L) at week 96 % 100 RPV/FTC/TDF at W 48 EFV/FTC/TDF at W 48 RPV/FTC/TDF at W 96 EFV/FTC/TDF at W 96 Favors EFV/FTC/TDF 89 82 80 80 79 82 76 71 Favors RPV/FTC/TDF 75 HIV RNA at baseline 60 < 100, 000 c/m. L W 48 40 W 96 1. 1 7. 2 0. 2 7. 6 W 48 0 W 96 231/ 204/ 205/ 178/ 260 250 107/ 116/ 102/ 106/ 134 142 < 100, 000 c/m. L > 100, 000 c/m. L -11. 1 -1. 8 7. 5 1. 5 -8. 7 -12% 15. 1 P=0. 046 > 100, 000 c/m. L 20 13. 4 0 11. 6 P=0. 78 12% Baseline HIV RNA STAR Cohen C. IAC 2014 Melbourne, Abs. WEPE 064

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Resistance analysis at week 96 RPV/FTC/TDF (N = 394)

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Resistance analysis at week 96 RPV/FTC/TDF (N = 394) EFV/FTC/TDF (N = 392) Baseline-W 48 -W 96 Subjects in the Resistance Analysis Population 20 (5%) +4 (1%) 7 (1. 8%) +2 (0. 5%) Subjects with Resistance Data 20 (5%) +4 (1%) 7 (1. 8%) +2 (0. 5%) Subjects with Resistance to ARVs 17 (4%) +4 (1%) 3 (0. 8%) +1 (0. 3%) Any primary NNRTI-R Key NNRTI-R 16 (4%) E 138 K/Q (N=6) Y 181 C/I (N=8) K 101 E (N=5) +4 (1%) +4 +0 +0 3 (1%) K 103 N (N=1) Y 188 L (N=1) G 190 E/Q (N=1) M 230 L (N=0) +1 (0. 3%) +0 +0 +0 +1 Any primary NRTI-R Key NRTI-R 16 (4%) M 184 V/I (N=15) K 65 R/N (N=3) +4 (1%) +4 +0 1 (0. 3%) M 1841 (N=1) +1 (0. 3%) +1 5/260 (2%) 12/134 (9%) +4 (1%) +0 2/250 (1%) 1/142 (0. 7%) +1 (0. 4%) +0 With baseline HIV RNA < 100, 000 c/m. L > 100, 000 c/m. L STAR Cohen C. IAC 2014 Melbourne, Abs. WEPE 064