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

2.  Design  Objective –Non inferiority of EFV 400 mg at W48: % HIV RNA < 200 c/mL by modified intention to treat analysis (all randomised participants who received at least 1 dose of study drug and at least one follow-up visit), 2-sided significance level of 5%, lower margin of the 95% CI for the difference = -10%, 90% power TDF/FTC + EFV 400 mg (2 x 200 mg pills + 1 placebo pill) QD TDF/FTC + EFV 600 mg (3 x 200 mg pills) QD Randomisation* 1 : 1 Double-blind > 16 years ARV-naïve HIV RNA > 1,000 c/mL CD4 cell count: 50-500/mm 3 Creatinine clearance > 50 mL/min *Randomisation was stratified by clinical site and by HIV RNA ( 100,000 c/mL) at screening N = 312 N = 324 W48W96 ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1 Study Group, Puls R. Lancet 2014;383:1474-82; ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802

3. EFV 400 + TDF/FTC N = 321 EFV 600 + TDF/FTC N = 309 Mean age, years3635.8 Female31%33% HIV RNA (log 10 c/mL), median4.764.73 HIV RNA > 100,000 c/mL33.3%34.6% CD4 cell count (/mm 3 ), mean273272 CD4 < 200 per mm 3 24%26% Hepatitis B / hepatitis C coinfection5% / 2%4% / 19% Discontinuation by W4810 (3.1%)14 (3.6%) DiedN = 2N = 3 Withdrew consentN = 3 Lost to follow-upN = 4N = 3 Missed week 48 visitN = 1N = 5 Discontinuation by W9622 (7%)23 (7%) Died / withdrew / lost to follow-up, N5 / 9 / 85 / 5 / 13 Baseline characteristics and patient disposition ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1 Study Group, Puls R. Lancet 2014;383:1474-82; ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802

4. Response to treatment at week 48, globally and by baseline HIV RNA ( 100,000 c/mL) ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1 Study Group, Puls R. Lancet 2014;383:1474-82 HIV RNA < 200 c/mL 25 50 100 75 94.1 92.2 % Difference (95% CI) =1.8% (-3.7 ; 7.4) 82.3 80.4 mITT 88.3 86.3 HIV RNA < 5 log 90.4 88.9 ITT, NC= F HIV RNA > 5 log All patients 80.6 77.7 87.7 86.1 HIV RNA < 50 c/mL mITTPer protocol All patients HIV RNA < 5 log HIV RNA > 5 log All patients HIV RNA < 5 log HIV RNA > 5 log Difference (95% CI) =1.8% (-2.1 ; 5.8) 86.0 84.1 84.3 78.7 92.2 90.6 Difference (95% CI) =1.5% (-3.5 ; 6.5) 0 EFV 400 + TDF/FTC EFV 600 + TDF/FTC

5. Response to treatment at week 96, globally and by baseline HIV RNA ( 100,000 c/mL) ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC Difference (95% CI) : - 1.1% (- 4.9 ; 2.8) HIV RNA < 200 c/mL 25 50 100 75 90.0 90.6 % Difference (95% CI) : -0.4% (-5.8 ; 4.9) 86.3 87.5 EFV 400 + TDF/FTC EFV 600 + TDF/FTC mITT 86.3 HIV RNA < 5 log 94.3 95.3 ITT, NC= F HIV RNA > 5 log All patients 83.1 82.1 94.5 94.8 HIV RNA < 50 c/mL mITTPer protocol All patients HIV RNA < 5 log HIV RNA > 5 log All patients HIV RNA < 5 log HIV RNA > 5 log Difference (95% CI) : - 0.6% (- 5.2 ; 4.0) 86.3 86.7 81.7 78.2 94.1 95.6 0 ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802

6.  Mean CD4 cell counts increase at W96 –+ 235/mm 3 in the EFV 400 group –+ 209/mm 3 in the EFV 600 group (p = 0.018)  No difference between groups in the mean change –In CD4 cell percentage –In CD8 cell counts –Of total lymphocyte counts  At 96 weeks, –Change in DASS-21 depression, anxiety, and stress Z scores did not differ between the groups ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802 ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC

7. EFV 400 + TDF/FTCEFV 600 + TDF/FTC p Patients with adverse events89.1%88.4% Grade 172.9%73.1% Grade 222.5%21.5% Grade 34.1%5.0% Grade 40.4% Serious adverse events, N patients23 (7.1%)22 (7.1%) Related to study drugsN = 3N = 4 Adverse events definitively or probably related to study drug, N patients 118 (36.8%)146 (47.2%)0.008 Discontinuation due to drug-related adverse event N = 6 (1.9%)N = 18 (5.8%)0.01 Adverse events of specific interest Neuro-psychiatric45%51%NS CNSN = 231N = 272 PsychiatricN = 13N = 12 RashN = 68N = 105 GastrointestinalN = 62N = 78 HepatotoxicityN = 1N = 0 Adverse events at week 48 ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1 Study Group, Puls R. Lancet 2014;383:1474-82

8.  Other safety aspects at week 48 –By week 48, discontinuation of EFV : 26 (8%) in EFV 400 vs 34 (11%) in EFV 600 –Frequency of serious adverse events was similar in both groups –No difference between randomised groups in quality of life, depression, anxiety and stress, and EFV-related symptoms over 48 weeks –No significant differences between EFV 400 and EFV 600 in change from baseline to week 48 for most laboratory parameters, except Neutrophils Mean change in creatinine clearance : 1.29 mL/min vs – 2.17 mL/min Mean alkaline phosphatase increase : + 26 vs + 33 IU/L  At Week 96 –Only significant between-group difference : mean change in alkaline phosphatase : + 21 vs + 27 U/L (p = 0.046) ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1 Study Group, Puls R. Lancet 2014;383:1474-82; ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802

9. EFV 400 + TDF/FTC N = 321 EFV 600 + TDF/FTC N = 309 p Patients with adverse events91%92%ns % of AE of Grade 34%5% % of AE of Grade 41% Serious adverse events, N events (N patients)32 (24)48 (32)ns Related to EFVN = 2 *N = 4 ** Adverse events related to EFV (N patients)126 (39%)148 (48%)0.03 Discontinuation of EFV due to drug-related adverse event N = 16 (5%)N = 34 (11%)0.03 Adverse events at week 96 ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC * Grade 3 dizziness ; possible Stevens Johnson syndrome ** Rash with fever and septic shock ; rash with labial oedema ; suicide ; attempted suicide  Mean changes in fasting lipids at W96 –Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride concentrations increased modestly, but mean changes did not differ between the groups ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802

10.  Virologic response in patients with baseline NNRTI resistance –570 patients with baseline genotypic test : NNRTI resistance, N = 18 10 assigned EFV 400 –6 suppressed at W96 (all on EFV) –4 not suppressed at W96 (3/4 on EFV, 1/4 with also baseline FTC resistance) 8 assigned EFV 600 –7 suppressed at W96 (6/7 on EFV) –1 not suppressed at W96 (not on EFV) Virologic failure* EFV 400 + TDF/FTC N = 321 EFV 600 + TDF/FTC N = 309 Resistance testing available, N1013 NNRTI resistance, N23 * 2 consecutive HIV RNA > 500 c/mL Among the 36 virologic failures, 5 had baseline NNRTI resistance and 8 were not amplifiable, 23 genotypes could be interpreted ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1

11.  Conclusion –A reduced dose of 400 mg EFV QD is non-inferior to the standard dose of 600 mg QD, when combined with TDF/FTC over 96 weeks in ART-naive adults with HIV-1 infection –Overall, the frequency of adverse events did not differ and there was no evidence of difference in treatment cessation between groups –However, adverse events related to the study drug were more frequent with 600 mg EFV than with 400 mg, and discontinuation due to adverse events more frequent with EFV 600 mg –Quality of life, negative emotional state, and efavirenz side-effect based on specific questionnaires did not differ between EFV 600 and 400 mg QD –These findings provide an opportunity to reduce the unit costs of treatment and care models that are based on EFV use (caution when used with rifampicin) ENCORE1 ENCORE1 Study: (EFV 400 mg vs 600 mg QD) + TDF/FTC ENCORE1 Study Group, Puls R. Lancet 2014;383:1474-82; ENCORE1 Study Group. Lancet Infect Dis 2015;15:793-802