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

Molina JM. Lancet 2011;378:238:46 ECHO  Design  Objective –Non inferiority of RPV vs EFV at W48: % HIV RNA < 50 c/mL by intention to treat, TLOVR analysis (lower margin of the 2-sided 95% CI for the difference = 12%, 95% power) RPV 25 mg QD + TDF/FTC QD EFV placebo EFV 600 mg QD + TDF/FTC QD RPV placebo Randomisation* 1 : 1 Double-blind > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count eGFR> 50 mL/min No R to TDF or FTC No NNRTI resistance mutations No HIV-2 infection * Randomisation was stratified by HIV RNA ( 100,000 c/mL, 500,000 c/mL ) at screening ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD N =348 N = 346 W48W96 RPV taken with meal, EFV taken on an empty stomach in the evening

RPV + TDF/FTC N = 346 EFV + TDF/FTC N = 344 Mean age, years36 Female23%20% HIV RNA (log 10 c/mL), median55 HIV RNA> 100,000 to < 500,000 c/mL38%39% HIV RNA > 500,000 c/mL10%14% CD4 cell count (/mm 3 ), median Clade B71% Hepatitis B / hepatitis C coinfection3% / 2%6% / 3% Discontinuation by W4850 (14.4%)56 (16.3%) For lack of efficacyN = 23N = 6 For adverse eventN = 8N = 28 Protocol violationsN = 11N = 14 Non-complianceN = 1N = 2 Baseline characteristics and patient disposition ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46

Mean CD4/mm 3 increase at W48 : – (RPV + TDF/FTC) vs – (EFV + TDF/FTC), p = 0.13 Response to treatment at week 48 ITT-TLOVR censoring for non-virologic failure, HIV RNA < 50 c/mL : – RPV + TDF/FTC = 86% – EFV + TDF/FTC = 94% (difference : -7.9% [95% CI : ; -3.3]) ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46 HIV RNA < 50 c/mL % Adjusted difference from logistic-regression model (95% CI)= - 0.4% (- 5.9 ; 5.2) Primary analysis Adjusted difference (95% CI)= 0.8 % (- 4.8 ; 6.5) ITT, TLOVRPer protocol, TLOVR RPV + TDF/FTC EFV + TDF/FTC 0

Virologic response to treatment at week 48 by subgroups ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46 HIV RNA < 50 c/mL (ITT, TLOVR) according to baseline HIV RNA % RPV + TDF/FTC EFV + TDF/FTC % < 100,000 c/mL100, ,000 c/mL> 500,000 c/mL HIV RNA < 50 c/mL (ITT, TLOVR) according to adherence rate Adherence > 95% Adherence < 95%

 Virologic failure definition –Never suppressed : never achieved 2 consecutive HIV RNA 0.5 log 10 c/mL above the nadir –Rebounder : achieved 2 consecutive HIV RNA 50 c/mL  Criteria for resistance testing –All virological failures RPV + TDF/FTC, N = 346EFV + TDF/FTC, N = 344 Virologic failure45 (13%)19 (6%) Resistance data at time of failure4013 Emergent NNRTI mutations268 Most frequent mutations E138K K101E Y181C K103N Emergent NRTI mutations284 Most frequent mutations M184V/I K65R Resistance data at week 48 ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46

RPV + TDF/FTCEFV + TDF/FTCP Treatment-related adverse event of grade > 255 (16%)108 (31%)< AE leading to permanent discontinuation8 (2%)27 (8%)- Serious AE23 (7%)31 (9%) Treatment-related AE of grade > 2 in > 2% in either group Dizziness423- Abnormal dreams or nightmares518- Insomnia510- Nausea38- Rash  Treatment-emergent adverse events ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46

 Adverse events of interest of any grade RPV + TDF/FTCEFV + TDF/FTCP Neurological events55 (16%)126 (37%)< Dizziness2285< Headache2215- Somnolence1221- Disturbance in attention210- Psychiatric events50 (15%)86 (25%) Abnormal dreams and nightmares Insomnia1423 Depression69 Anxiety28 Sleep Disorder211 Rash12 (4%)50 (15%)< Grade 312 Discontinuation because of rash13 Mean change in QTcF, ms (95% CI)10.9 (9.0 to 12.8)12.0 (10.1 to 13.7) ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46

RPV + TDF/FTCEFV + TDF/FTCP Total cholesterol (mmol/L)0.03 ( to 0.11)0.63 (0.53 to 0.73)< HDL cholesterol (mmol/L)0.07 (0.04 to 0.10)0.24 (0.21 to 0.27)< Total cholesterol/HDL cholesterol ratio ( to 0.05) ( to )0.25 LDL cholesterol (mmol/L) ( to 0.03)0.31 (0.23 to 0.39)< Triglycerides (mmol/L) ( to )0.16 ( to 0.38)0.01  Mean (95% CI) change in fasting lipids from baseline to week 48 RPV + TDF/FTCEFV + TDF/FTC Any abnormality in > 2% in either group34 (10%)55 (16%) Pancreatic amylase1116 AST812 Hypophosphatemia64 ALT412 LDL cholesterol38 Triglycerides15 Total cholesterol16  Grade 3-4 laboratory abnormalities ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46

ECHO ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD  Summary of week 48 results –RPV QD is virologically non inferior to EFV, when given in combination with TDF/FTC –Response rate was lower in the RPV group for patients with highest baseline viral loads –Discontinuation because of virologic failure was higher for RPV, and discontinuation because of adverse events was higher for EFV –Proportion of virological failures with > 1 emergent NNRTI resistance-associated mutation : similar in both groups Most frequent mutations on RPV lead to NNRTI cross resistance At EFV failure, K103 N was the most frequent mutation, with conserved sensitivity to etravirine > 1 emergent NRTI resistance mutation : higher in the RPV group –More favorable overall safety profile of RPV than EFV : lower rate of grade 2-4 AE possibly related to treatment rash neurological and psychiatric adverse events increases in proatherogenic lipid parameters

Cohen CJ. Lancet 2011;378: THRIVE  Design  Objective –Non inferiority of RPV vs EFV at W48: % HIV RNA < 50 c/mL by intention to treat, TLOVR analysis (lower margin of the 2-sided 95% CI for the difference = 12%, 95% power) RPV 25 mg QD + 2 NRTI* EFV placebo* EFV 600 mg QD + 2 NRTI* RPV placebo* Randomisation 1 : 1 Double-blind > 18 years ARV-naïve HIV RNA > 5,000 c/mL Any CD4 cell count eGFR> 50 mL/min No R to background NtRTI No NNRTI resistance mutations No HIV-2 infection Randomisation was stratified by HIV RNA ( 100,000 c/mL, 500,000 c/mL ) at screening THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI N = 340 W48W96 * Open-label NRTI combination selected by investigator : ZDV+3TC BID or ABC+3TC QD or TDF+FTC QD

RPV + 2 NRTI N = 340 EFV + 2 NRTI N = 338 Mean age, years36 Female26%28% HIV RNA (log 10 c/mL), median55 HIV RNA> 100,000 to < 500,000 c/mL35%40% HIV RNA > 500,000 c/mL10% CD4 cell count (/mm 3 ), median263 Clade B70%65% Hepatitis B / hepatitis C coinfection4% / 5%4% / 6% Selected NRTI combinationN = 23N = 6 TDF + FTC60% ZDV + 3TC30% ABC + 3TC (HLAB57*01 negative)10% Discontinuation by W4844 (12.9%)56 (16.6%) For lack of efficacyN = 13N = 8 For adverse eventN = 158N = 25 Baseline characteristics and patient disposition THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Cohen CJ. Lancet 2011;378:229-37

Response to treatment at week 48 THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI ITT-TLOVR censoring for non-virologic failure, % HIV RNA < 50 c/mL : – RPV + 2 NRTI = 91% – EFV + 2 NRTI = 94% (difference : -2.0% [95% CI : ; 2.2]) Mean CD4/mm 3 increase at W48 : – (RPV + 2 NRTI) vs – (EFV + 2 NRTI), P = 0.09 Cohen CJ. Lancet 2011;378: RPV + 2 NRTI EFV + 2 NRTI HIV RNA < 50 c/mL % Adjusted difference from logistic-regression model (95% CI)= 3.5% (- 1.7 ; 8.8) Adjusted difference (95% CI)= 3.7 % (- 1.9 ; 9.3) ITT, TLOVRPer protocol, TLOVR Primary analysis 0

Virologic response to treatment at week 48 by subgroups THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Cohen CJ. Lancet 2011;378: % % HIV RNA < 50 c/mL (ITT, TLOVR) according to baseline HIV RNA RPV + 2 NRTIEFV + 2 NRTI HIV RNA < 50 c/mL (ITT, TLOVR) according to adherence rate < 100,000 c/mL100, ,000 c/mL> 500,000 c/mLAdherence > 95%Adherence < 95% 0 0

 Virologic failure definition –Never suppressed : never achieved 2 consecutive HIV RNA 0.5 log 10 c/mL above the nadir –Rebounder : achieved 2 consecutive HIV RNA 50 c/mL  Criteria for resistance testing –All virological failures RPV + 2 NRTI, N = 340EFV + 2 NRTI, N = 338 Virologic failure27 (8%)20 (6%) Resistance data at time of failure2215 Emergent NNRTI mutations137 Most frequent mutations E138K K101E K103N Emergent NRTI mutations145 Most frequent mutations M184V/I K65R THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Resistance data at week 48 Cohen CJ. Lancet 2011;378:229-37

RPV + 2 NRTIEFV + 2 NRTIP Treatment-related adverse event of grade > 254 (16%)104 (31%)< AE leading to permanent discontinuation15 (4%)25 (7%)- Serious AE22 (7%)24 (7%) Treatment-related AE of grade > 2 in > 2% in either group Insomnia76- Headache59- Nausea29- Dizziness020- Rash130<  Treatment-emergent adverse events THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Cohen CJ. Lancet 2011;378:229-37

 Adverse events of interest of any grade, n (% of patients) THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI RPV + 2 NRTIEFV + 2 NRTIP Neurological events62 (18%)132 (39%)< Dizziness10%28%< Headache6%8%< Somnolence4%8%- Disturbance in attention1%2%- Psychiatric events52 (15%)69 (20%)0.09 Abnormal dreams and nightmares7%11%0.06 Insomnia6%5% Sleep Disorder2%3% Rash9 (3%)43 (13%)< Grade 301 Discontinuation because of rash05 Mean change in QTcF, ms (95% CI)12 (10.1 to 13.8)14.1 (12.3 to 16.0) THRIVE Cohen CJ. Lancet 2011;378:229-37

RPV + 2NRTIEFV + 2 NRTIP Total cholesterol (mmol/L)0.08 ( to 0.16)0.79 (0.69 to 0.90)< HDL cholesterol (mmol/L)0.11 (0.08 to 0.13)0.27 (0.24 to 0.30)< Total cholesterol/HDL cholesterol ratio ( to 0.25) ( to )0.25 LDL cholesterol (mmol/L) ( to 0.05)0.44 (0.34 to 0.53)< Triglycerides (mmol/L) ( to 0.04)0.14 (0.01 to 0.26)<  Mean (95% CI) change in fasting lipids from baseline to week 48 RPV + 2 NRTIEFV + 2 NRTI Any abnormality in > 2% in either group41 (12%)63 (19%) Pancreatic amylase3% ALT2%3% AST2% LDL cholesterol1%6% Triglycerides< 1%3% Total cholesterol03% THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI  Grade 3-4 laboratory abnormalities Cohen CJ. Lancet 2011;378:229-37

 Summary of week 48 results –RPV QD is virologically non inferior to EFV, when given in combination with 2 NRTI –Response rates seemed highest in the RPV group for patients with lowest baseline viral loads –Background NRTI regimen had no significant effect on responses (limitation : no randomisation, no stratification by NRTI) –Discontinuation because of adverse events or other reasons was lower for RPV –Proportion of virological failures with > 1 emergent NNRTI resistance-associated mutation : similar in both groups, > 1 emergent NRTI resistance mutation : higher in the RPV group –More favorable overall safety profile of RPV than EFV : lower rate of grade 2-4 AE possibly related to treatment rash dizziness increases in proatherogenic lipid parameters THRIVE THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Cohen CJ. Lancet 2011;378:229-37

Response to treatment at week 96 Cohen CJ. AIDS 2013;27: ECHO-THRIVE ECHO & THRIVE Study: W96 results RPV + 2 NRTI* EFV + 2 NRTI* HIV RNA < 50 c/mL % Adjusted difference from logistic-regression model (95% CI)= - 0.4% (- 4.6 ; 3.8) Adjusted difference (95% CI)= 0.4 % (- 4.0 ; 4.9) ITT, TLOVRPer protocol, TLOVR Primary analysis * TDF/FTC = 80%, ZDV/3TC = 15%, ABC/3TC = 5% ITT-TLOVR censoring for non-virologic failure, % HIV RNA < 50 c/mL : – RPV + 2 NRTI = 85% – EFV + 2 NRTI = 91% (difference : - 6.2% [95% CI : ; - 2.5]) Discontinuation by 96 weeks (RPV vs EFV) – For virologic endpoint : 8% vs 3% – For adverse events : 4% vs 9% 0

Virologic response to treatment at week 96 by subgroups % % ECHO-THRIVE ECHO & THRIVE Study: W96 results < 100,000 c/mL100, ,000 c/mL> 500,000 c/mLAdherence > 95%Adherence < 95% HIV RNA < 50 c/mL (ITT, TLOVR) according to baseline HIV RNA RPV + 2 NRTI EFV + 2 NRTI HIV RNA < 50 c/mL (ITT, TLOVR) according to adherence rate Cohen CJ. AIDS 2013;27:

RPV + 2 NRTI, N = 340EFV + 2 NRTI, N = 682 Virologic failure96 (14%)52 (8%) Rebounder5234 Never suppressed4418 Resistance data at time of failure8642 Emergent NNRTI mutations46 (53%)20 (48%) Most frequent mutations E138K K103N Emergent NRTI mutations48 (56%)11 (26%) Most frequent mutations M184I M184V Resistance data at week 96  The majority of virologic failures occurred in the first 48 weeks (76% in the RPV group and 69% in the EFV group) Cohen CJ. AIDS 2013;27: ; Rimsky L. JAIDS 2012;59:39-46 ; Rimsky L. AntivirTher 2013;18: ECHO-THRIVE ECHO & THRIVE Study: W96 results  Virologic failure and treatment-emergent RT mutations were similar at low baseline viral load but more frequent at high baseline viral load in RPV-treated than in EFV-treated patients

RPV + 2 NRTIEFV + 2 NRTIP Treatment-related adverse event of grade > 2116 (17%)226 (33%)< AE leading to permanent discontinuation28 (4%)58 (9%)- Serious AE65 (9%)71 (10%)- Treatment-related AE of grade > 2 in > 10% in either group Any neurologic AE119 (17%)259 (38%)< Dizziness55 (8%)182 (27%)< Any psychiatric AE107 (16%)166 (24%)< Abnormal dreams or nightmares57 (8%)90 (13%)0.003 Rash29 (4%)103 (15%)< Any grade 2-4 laboratory abnormality317 (46%)395 (58%) LDL-cholesterol7%18% Total cholesterol7%22% AST / ALT6% / 6%10% / 11%  Adverse events and treatment-emergent grade 2-4 laboratory abnormalities Cohen CJ. AIDS 2013;27: ECHO & THRIVE Study: W96 results ECHO-THRIVE