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

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 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 Discontinuation by W 48 (N) 54 (13. 7%) 72 (18. 4%) For lack of efficacy 12 3 For adverse event 10 34 Lost to follow-up 15 10 Non compliance 6 4 Withdrew consent 5 13 Protocol violation 1 1 Pregnancy 2 0 Investigator’s decision 3 3 Death 0 1 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) 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 Difference (95% CI) = -1. 8% (-11. 1 ; 7. 5) < 100, 000 c/m. L 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* 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 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 48 RPV/FTC/TDF TC 25 LDL EFV/FTC/TDF TG 22 p < 0. 001 for all between treatment groups using ANOVA 20 14 15 8 10 5 HDL 1 8 2 1 0 -5 -10 Mean baseline values (mg/d. L) -8 164 163 104 103 121 129 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 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 Virologic outcomes at W 96, snapshot analysis Virologic success (HIV-1 RNA < 50 c/m. L) Difference (95% CI) Virologic failure EFV/FTC/TDF N = 392 77. 9% 72. 4% 5. 5 (- 0. 6 to 11. 5) ; p = 0. 076 9. 4% 5. 9% HIV-1 RNA ≥ 50 c/m. L 1. 5% Treatment discontinuation due to lack of efficacy 4. 1% 1. 0% Treatment discontinuations due to other reasons and last HIV-1 RNA ≥ 50 c/m. L 3. 8% 3. 3% 12. 7% 21. 7% Treatment discontinuation due to adverse event or death 3. 0% 10. 7% Treatment discontinuations due to other reasons and last HIV-1 RNA < 50 c/m. L 7. 9% 9. 4% Missing data while receiving study drug 1. 8% 1. 5% No data in the study window STAR RPV/FTC/TDF N = 394 Van Lunzen J. AIDS 2016; 30: 251 -9

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 71 76 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 Van Lunzen J. AIDS 2016; 30: 251 -9

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 80. 6 80 60 EFV/FTC/TDF 68. 6 Favors EFV/FTC/TDF 73 Favors RPV/FTC/TDF CD 4 at baseline 60. 4 < 200/mm 3 - 26. 7 40 -8. 0 10. 7 1. 3 7. 7 > 200/mm 3 p = 0. 40 14. 0 p = 0. 018 20 0 -20% 53 51 < 200/mm 3 341 0 20% 341 > 200/mm 3 Baseline CD 4+ cell count STAR Van Lunzen J. AIDS 2016; 30: 251 -9

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) V 90 I (N = 6) +4 (1%) +4 +0 +0 +2 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 Porter DP. HIV Clin Trials 2015; 16: 30 -8 ; Van Lunzen J. AIDS 2016; 30: 251 -9

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Most frequently reported treatment-emergent adverse events leading to permanent study drug discontinuation RPV/FTC/TDF (N = 394) EFV/FTC/TDF (N = 392) W 1 W 4 W 5 W 48 W 96 Total Psychiatric disorder 0 1 (0. 3%) 5 11 8 24 (6. 1%) Nervous system disorder 0 2 1 3 (0. 8%) 5 2 1 8 (2. 0%) Skin and subcutaneous tissue disorder (e. g. rash) 0 0 7 (1. 8%) Clinical laboratory investigation 0 2 2 4 (1. 0%) 0 2 (0. 5%) General disorder (e. g. fatigue) 0 0 3 1 1 5 (1. 3%) Gastrointestinal disorder 0 1 (0. 3%) 1 2 0 3 (0. 8%) Grade 3– 4 treatment-emergent adverse event deemed related to study drug : 2. 3% RPV vs 5. 6% EFV Median changes from baseline to W 96 in creatinine clearance : - 5. 2 m. L/min in the RPV group and + 4. 3 m. L/min in the EFV group 3 discontinuations for renal events : 1 in the RPV group and 2 in the EFV group STAR Van Lunzen J. AIDS 2016; 30: 251 -9

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § HIV Symptom Index Questionnaire at W 96 – RPV/FTC/TDF: significant reduction in occurrence of 18/20 symptoms vs baseline (p < 0. 039) – EFV/FTC/TDF: significant reduction in occurrence of 7/20 symptoms vs baseline (p < 0. 033) – Significant between-group differences in symptom occurrence vs baseline for 8 symptoms, all favoring RPV/FTC/TDF § Overall satisfaction (HIV Treatment Satisfaction Questionnaire) at W 96 – High in both groups § Quality of life (SF-12 V 2) – The between-group difference in the median change from baseline at W 96 for the physical health composite score was not significant – The difference for the mental health composite score was significant, favoring RPV/FTC/TDF (p = 0. 014) STAR Van Lunzen J. AIDS 2016; 30: 251 -9

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF § Conclusion at W 96 – In treatment-naive, HIV-1 -infected adults, 96 -week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF • Significant differences in virologic success between subgroups with HIV-1 RNA ≤ 100, 000 c/m. L and > 200 CD 4/mmm 3 could be related to the higher rate of discontinuations due to adverse events in the EFV/FTC/TDF group • The higher virologic failure rates observed for RPV/FTC/TDF with baseline HIV -1 RNA > 500 000 c/m. L and CD 4+ cell count ≤ 200/mm 3 were mainly due to a higher rate of discontinuation due to lack of efficacy in this group (limitation: low number of patients in those categories) – Rates of resistance development through W 96 were low (5. 3% RPV/FTC/TDF ; 1. 0% EFV/FTC/TDF) with infrequent emergent resistance after W 48 • Development of resistance at failure: 88% RPV/FTC/TDF vs 44% EFV/FTC/TDF ; resistance in RPV/FTC/TDF group was more frequent if baseline HIV-1 RNA > 100, 000 c/m. L – Better safety and tolerability profile of RPV/FTC/TDF vs. EFV/FTC/TDF over 96 weeks of treatment (limitation: open-label trial) STAR Van Lunzen J. AIDS 2016; 30: 251 -9