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

 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: STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

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 ), mean Discontinuation by W4854 (13.7%)72 (18.4%) For lack of efficacyN = 12N = 3 For adverse eventN = 10N = 34 Lost to follow-upN = 15N = 10 Non complianceN = 6N = 4 Withdrew consentN = 5N = 13 Protocol violationN = 1 PregnancyN = 2- Investigator’s decisionN = 3 Death-N = 1 Baseline characteristics and patient disposition Cohen C. AIDS 2014;28: STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

Response to treatment (HIV RNA < 50 c/mL) at week 48 Median CD4/mm 3 increase at W48 : RPV/FTC/TDF vs EFV/FTC/TDF Cohen C. AIDS 2014;28: STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR Adjusted difference (95% CI) = 4.1% (-1.1 ; 9.2) 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 % > 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)

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: STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

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: STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

Mean changes in fasting lipids (mg/dL) at week 48 Cohen C. AIDS 2014;28: 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) RPV/FTC/TDF 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/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: STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF STAR

STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Cohen C. IAC 2014 Melbourne, Abs. WEPE064 STAR Response to treatment (HIV RNA < 50 c/mL) at week 96 W48 W96 W48 W %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 / / / / / / / / 142 RPV/FTC/TDF at W48 RPV/FTC/TDF at W96 EFV/FTC/TDF at W48 EFV/FTC/TDF at W < 100,000 c/mL> 100,000 c/mL Baseline HIV RNA %

Resistance analysis at week 96 STAR Study: RPV/FTC/TDF vs EFV/FTC/TDF Cohen C. IAC 2014 Melbourne, Abs. WEPE064 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) +4 (1%) (1%) K103N (N=1) Y188L (N=1) G190E/Q (N=1) M230L (N=0) +1 (0.3%) Any primary NRTI-R Key NRTI-R 16 (4%) M184V/I (N=15) K65R/N (N=3) +4 (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