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

2.  Design  Objective –Non inferiority of RPV/FTC/TDF at W48: % HIV RNA < 50 c/mL 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) RPV/FTC/TDF QD STR EFV/FTC/TDF QD STR Randomisation* 1 : 1 Open-label > 18 years ARV-naïve HIV RNA > 2,500 c/mL Any CD4 cell count eGFR > 50 mL/min Sensitivity to EFV, FTC and TDF on genotype No RPV resistance mutations** * Randomisation was stratified by HIV RNA ( 100,000 c/mL) ** K101E/P, E138A/G/K/Q/R, Y181C/I/V, H221Y N = 392 N = 394 W48W96 Concomitant use of proton pump inhibitors was not allowed Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

3. RPV/FTC/TDF N = 394 EFV/FTC/TDF N = 392 Median age, years3735 Female7% HIV RNA (log 10 c/mL), median4.8 HIV RNA > 100,000 c/mL34%36% CD4 cell count (/mm 3 ), mean396385 Discontinuation by W48 (N)54 (13.7%)72 (18.4%) For lack of efficacy123 For adverse event1034 Lost to follow-up1510 Non compliance64 Withdrew consent513 Protocol violation11 Pregnancy20 Investigator’s decision33 Death01 Baseline characteristics and patient disposition Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

4. Response to treatment (HIV RNA < 50 c/mL) at week 48 Median CD4/mm 3 increase at W48: + 200 RPV/FTC/TDF vs + 191 EFV/FTC/TDF Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR 25 50 100 75 85.8 81.6 Adjusted difference (95% CI) = 4.1% (-1.1 ; 9.2) 79.9 81.7 Adjusted difference (95% CI) = 5.9% (0.6 ; 11.2) ITT, snapshotITT snapshot, by baseline HIV-1 RNA RPV/FTC/TDF EFV/FTC/TDF Primary analysis % 0 88.8 81.6 85.3 79.6 > 100,000 c/mL < 100,000 c/mL ITT, TLOVR Difference (95% CI) = 7.2% (1.1 ; 13.4) Difference (95% CI) = -1.8% (-11.1 ; 7.5)

5. RPV/FTC/TDFEFV/FTC/TDF Resistance analysis population*20 (5%)7 (2%) Resistance to antiretrovirals17 (4.3%)3 (0.8%) In patients with baseline HIV RNA < 100,000 c/mL1.9%0.8% In patients with baseline HIV RNA > 100,000 c/mL9.0%0.7% Any primary NNRTI resistance163 Y181C/I8- E138K/Q6- K101E5- K103N-1 Y188L-1 G190E/Q-1 Any primary NRTI resistance161 M184V/I151 K65R/N30 Resistance analysis through week 48 * HIV RNA > 400 c/mL and suboptimal virologic response (confirmed 50 c/mL after achieving 1 log 10 c/mL increase in HIV RNA from the nadir) or HIV RNA > 400 c/mL at W48 or last visit Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

6. RPV/FTC/TDFEFV/FTC/TDF Nervous system events29.7%50.5% Dizziness6.6%22.2% Insomnia9.6%14.0% Somnolence2.5%13.5% Headache12.4%13.5% Psychiatric events15.7%37.5% Abnormal dreams5.8%24.5% Depression6.6%8.9% Anxiety5.1%8.4% Rash events17.3%21.2% Folliculitis5.3%1.0% Rash6.1%12.0%  Treatment-emergent adverse events of specific interest in > 5% in either arm RPV/FTC/TDFEFV/FTC/TDF Grade 3-4 treatment-emergent adverse events7.4%13.8% Related to study drug1.8%4.8%  Safety through week 48 Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

7. Mean changes in fasting lipids (mg/dL) at week 48 Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR Change in total cholesterol/HDL-cholesterol at week 48 was -0.2 in both arms p < 0.001 for all between treatment groups using ANOVA Mean baseline values (mg/dL) 16416310410312112944 RPV/FTC/TDF EFV/FTC/TDF

8.  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/mL Virologic efficacy was similar for patients with baseline HIV-1 RNA > 100,000 c/mL –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 Cohen C. AIDS 2014;28:989-97 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

9. RPV/FTC/TDF N = 394 EFV/FTC/TDF N = 392 Virologic success (HIV-1 RNA < 50 c/mL)77.9%72.4% Difference (95% CI)5.5 (- 0.6 to 11.5) ; p = 0.076 Virologic failure9.4%5.9% HIV-1 RNA ≥ 50 c/mL1.5% Treatment discontinuation due to lack of efficacy4.1%1.0% Treatment discontinuations due to other reasons and last HIV-1 RNA ≥ 50 c/mL 3.8%3.3% No data in the study window12.7%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/mL 7.9%9.4% Missing data while receiving study drug1.8%1.5% Virologic outcomes at W96, snapshot analysis STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR Van Lunzen J. AIDS 2016;30:251-9

10. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR Response to treatment (HIV RNA < 50 c/mL) at week 96 W48 W96 W48 W96 1.17.213.4 15.1 7.6 0.2 7.5-1.8-11.1 -8.7 1.5 11.6 12%0-12% p = 0.046 p = 0.78 > 100,000 c/mL < 100,000 c/mL HIV RNA at baseline Favors EFV/FTC/TDF Favors RPV/FTC/TDF 0 20 40 60 80 100 231/ 260 204/ 250 205/ 260 178/ 250 107/ 134 116/ 142 102/ 134 106/ 142 RPV/FTC/TDF at W48 RPV/FTC/TDF at W96 EFV/FTC/TDF at W48 EFV/FTC/TDF at W96 89 82 79 71 80 82 76 75 < 100,000 c/mL> 100,000 c/mL Baseline HIV RNA % Van Lunzen J. AIDS 2016;30:251-9

11. STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR Response to treatment (HIV RNA < 50 c/mL) at week 96 14.0 7.7 1.3 - 26.7 -8.0 10.7 20%0-20% p = 0.018 p = 0.40 > 200/mm 3 < 200/mm 3 CD4 at baseline Favors EFV/FTC/TDF Favors RPV/FTC/TDF 0 20 40 60 80 100 5351341 RPV/FTC/TDFEFV/FTC/TDF 60.4 68.6 80.6 73 < 200/mm 3 > 200/mm 3 Baseline CD4+ cell count % Van Lunzen J. AIDS 2016;30:251-9

12. Resistance analysis at week 96 Porter DP. HIV Clin Trials 2015;16:30-8 ; Van Lunzen J. AIDS 2016;30:251-9 STAR RPV/FTC/TDF (N = 394)EFV/FTC/TDF (N = 392) Baseline-W48W48-W96Baseline-W48W48-W96 Subjects in the Resistance Analysis Population20 (5%)+4 (1%)7 (1.8%)+2 (0.5%) Subjects with Resistance Data20 (5%)+4 (1%)7 (1.8%)+2 (0.5%) Subjects with Resistance to ARVs17 (4%)+4 (1%)3 (0.8%)+1 (0.3%) Any primary NNRTI-R Key NNRTI-R 16 (4%) E138K/Q (N = 6) Y181C/I (N = 8) K101E (N = 5) V90I (N = 6) +4 (1%) +4 +0 +2 3 (1%) K103N (N = 1) Y188L (N = 1) G190E/Q (N = 1) M230L (N = 0) +1 (0.3%) +0 +1 Any primary NRTI-R Key NRTI-R 16 (4%) M184V/I (N = 15) K65R/N (N = 3) +4 (1%) +4 +0 1 (0.3%) M1841 (N = 1) +1 (0.3%) +1 With baseline HIV RNA < 100,000 c/mL > 100,000 c/mL 5/260 (2%) 12/134 (9%) +4 (1%) +0 2/250 (1%) 1/142 (0.7%) +1 (0.4%) +0 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF

13. Most frequently reported treatment-emergent adverse events leading to permanent study drug discontinuation Grade 3–4 treatment-emergent adverse event deemed related to study drug : 2.3% RPV vs 5.6% EFV Median changes from baseline to W96 in creatinine clearance : - 5.2 mL/min in the RPV group and + 4.3 mL/min in the EFV group 3 discontinuations for renal events : 1 in the RPV group and 2 in the EFV group Van Lunzen J. AIDS 2016;30:251-9 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR RPV/FTC/TDF (N = 394)EFV/FTC/TDF (N = 392) W1- W4 W5- W48 W48- W96 Total W1- W4 W5- W48 W48- W96 Total Psychiatric disorder0101 (0.3%)5118 24 (6.1%) Nervous system disorder0213 (0.8%)5218 (2.0%) Skin and subcutaneous tissue disorder (e.g. rash) 00007007 (1.8%) Clinical laboratory investigation0224 (1.0%)0202 (0.5%) General disorder (e.g. fatigue)00003115 (1.3%) Gastrointestinal disorder0101 (0.3%)1203 (0.8%)

14.  HIV Symptom Index Questionnaire at W96 –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 W96 –High in both groups  Quality of life (SF-12 V2 ) –The between-group difference in the median change from baseline at W96 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) Van Lunzen J. AIDS 2016;30:251-9 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

15.  Conclusion at W96 –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/mL and > 200 CD4/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/mL and CD4+ 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 W96 were low (5.3% RPV/FTC/TDF ; 1.0% EFV/FTC/TDF) with infrequent emergent resistance after W48 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/mL –Better safety and tolerability profile of RPV/FTC/TDF vs. EFV/FTC/TDF over 96 weeks of treatment (limitation: open-label trial) Van Lunzen J. AIDS 2016;30:251-9 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR