Comparison of NNRTI vs NNRTI

Comparison of NNRTI vs NNRTI
ARV-trial.com Comparison of NNRTI vs NNRTI ENCORE EFV vs RPV ECHO-THRIVE STAR EFV vs ETR SENSE DOR vs EFV DRIVE-AHEAD 1

ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD
ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Design Randomisation* 1 : 1 Double-blind W48 W96 > 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 N = 346 RPV 25 mg QD + TDF/FTC QD EFV placebo EFV 600 mg QD + TDF/FTC QD RPV placebo N =348 * Randomisation was stratified by HIV RNA (< or > 100,000 c/mL, < 500,000 or > 500,000 c/mL ) at screening RPV taken with meal, EFV taken on an empty stomach in the evening 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) ECHO Molina JM. Lancet 2011;378:238:46 2

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Baseline characteristics and patient disposition RPV + TDF/FTC N = 346 EFV + TDF/FTC N = 344 Mean age, years 36 Female 23% 20% HIV RNA (log10c/mL), median 5 HIV RNA> 100,000 to < 500,000 c/mL 38% 39% HIV RNA > 500,000 c/mL 10% 14% CD4 cell count (/mm3), median 240 257 Clade B 71% Hepatitis B / hepatitis C coinfection 3% / 2% 6% / 3% Discontinuation by W48 50 (14.4%) 56 (16.3%) For lack of efficacy N = 23 N = 6 For adverse event N = 8 N = 28 Protocol violations N = 11 N = 14 Non-compliance N = 1 N = 2 ECHO Molina JM. Lancet 2011;378:238:46 3

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Response to treatment at week 48 HIV RNA < 50 c/mL 25 50 100 75 83 % Adjusted difference from logistic-regression model (95% CI)= - 0.4% (- 5.9 ; 5.2) 84 Primary analysis (95% CI)= 0.8 % (- 4.8 ; 6.5) ITT, TLOVR Per protocol, TLOVR RPV + TDF/FTC EFV + TDF/FTC 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]) Mean CD4/mm3 increase at W48 : + 196 (RPV + TDF/FTC) vs + 182 (EFV + TDF/FTC), p = 0.13 ECHO Molina JM. Lancet 2011;378:238:46 4

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Virologic response to treatment at week 48 by subgroups HIV RNA < 50 c/mL (ITT, TLOVR) according to baseline HIV RNA 25 50 100 75 90 83 % 79 RPV + TDF/FTC EFV + TDF/FTC 86 87 68 73 < 100,000 c/mL 100, ,000 c/mL > 500,000 c/mL 62 81 181 163 131 134 34 47 according to adherence rate Adherence > 95% 275 262 Adherence < 95% 44 56 ECHO Molina JM. Lancet 2011;378:238:46 5

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Virologic failure definition Never suppressed : never achieved 2 consecutive HIV RNA < 50 c/mL and increase of HIV RNA > 0.5 log10 c/mL above the nadir Rebounder : achieved 2 consecutive HIV RNA < 50 c/mL with 2 subsequent consecutive (or 1 if last available) HIV RNA > 50 c/mL Criteria for resistance testing All virological failures Resistance data at week 48 RPV + TDF/FTC, N = 346 EFV + TDF/FTC, N = 344 Virologic failure 45 (13%) 19 (6%) Resistance data at time of failure 40 13 Emergent NNRTI mutations 26 8 Most frequent mutations E138K K101E Y181C K103N 18 5 7 Emergent NRTI mutations 28 4 M184V/I K65R 3 ECHO Molina JM. Lancet 2011;378:238:46 6

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Treatment-emergent adverse events RPV + TDF/FTC EFV + TDF/FTC P Treatment-related adverse event of grade > 2 55 (16%) 108 (31%) < AE leading to permanent discontinuation 8 (2%) 27 (8%) - Serious AE 23 (7%) 31 (9%) Treatment-related AE of grade > 2 in > 2% in either group Dizziness 4 23 Abnormal dreams or nightmares 5 18 Insomnia 10 Nausea 3 8 Rash 6 26 0.0002 ECHO Molina JM. Lancet 2011;378:238:46 7

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Adverse events of interest of any grade RPV + TDF/FTC EFV + TDF/FTC P Neurological events 55 (16%) 126 (37%) < Dizziness 22 85 Headache 15 - Somnolence 12 21 Disturbance in attention 2 10 Psychiatric events 50 (15%) 86 (25%) 0.0006 Abnormal dreams and nightmares 32 49 0.045 Insomnia 14 23 Depression 6 9 Anxiety 8 Sleep Disorder 11 Rash 12 (4%) Grade 3 1 Discontinuation because of rash 3 Mean change in QTcF, ms (95% CI) 10.9 (9.0 to 12.8) 12.0 (10.1 to 13.7) ECHO Molina JM. Lancet 2011;378:238:46 8

ARV-trial.com ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Grade 3-4 laboratory abnormalities RPV + TDF/FTC EFV + TDF/FTC Any abnormality in > 2% in either group 34 (10%) 55 (16%) Pancreatic amylase 11 16 AST 8 12 Hypophosphatemia 6 4 ALT LDL cholesterol 3 Triglycerides 1 5 Total cholesterol Mean (95% CI) change in fasting lipids from baseline to week 48 RPV + TDF/FTC EFV + TDF/FTC P 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 ECHO Molina JM. Lancet 2011;378:238:46 9

ARV-trial.com 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 ECHO Molina JM. Lancet 2011;378:238:46 10

THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI
ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Design Randomisation 1 : 1 Double-blind W48 W96 > 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 N = 340 RPV 25 mg QD + 2 NRTI* EFV placebo* EFV 600 mg QD + 2 NRTI* RPV placebo* N = 340 Randomisation was stratified by HIV RNA (< or > 100,000 c/mL, < 500,000 or > 500,000 c/mL ) at screening * Open-label NRTI combination selected by investigator : ZDV+3TC BID or ABC+3TC QD or TDF+FTC QD 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) THRIVE Cohen CJ. Lancet 2011;378:229-37 11

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Baseline characteristics and patient disposition RPV + 2 NRTI N = 340 EFV + 2 NRTI N = 338 Mean age, years 36 Female 26% 28% HIV RNA (log10c/mL), median 5 HIV RNA> 100,000 to < 500,000 c/mL 35% 40% HIV RNA > 500,000 c/mL 10% CD4 cell count (/mm3), median 263 Clade B 70% 65% Hepatitis B / hepatitis C coinfection 4% / 5% 4% / 6% Selected NRTI combination N = 23 N = 6 TDF + FTC 60% ZDV + 3TC 30% ABC + 3TC (HLAB57*01 negative) Discontinuation by W48 44 (12.9%) 56 (16.6%) For lack of efficacy N = 13 N = 8 For adverse event N = 158 N = 25 THRIVE Cohen CJ. Lancet 2011;378:229-37 12

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Response to treatment at week 48 RPV + 2 NRTI EFV + 2 NRTI HIV RNA < 50 c/mL 25 50 100 75 86 82 % Adjusted difference from logistic-regression model (95% CI)= 3.5% (- 1.7 ; 8.8) (95% CI)= 3.7 % (- 1.9 ; 9.3) ITT, TLOVR Per protocol, TLOVR Primary analysis 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/mm3 increase at W48 : + 189 (RPV + 2 NRTI) vs + 171 (EFV + 2 NRTI), P = 0.09 THRIVE Cohen CJ. Lancet 2011;378:229-37 13

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Virologic response to treatment at week 48 by subgroups 25 50 100 75 91 84 % 80 82 89 90 64 62 77 69 187 167 118 136 35 272 230 36 39 HIV RNA < 50 c/mL (ITT, TLOVR) according to baseline HIV RNA RPV + 2 NRTI EFV + 2 NRTI according to adherence rate < 100,000 c/mL 100, ,000 c/mL > 500,000 c/mL Adherence > 95% Adherence < 95% THRIVE Cohen CJ. Lancet 2011;378:229-37 14

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Virologic failure definition Never suppressed : never achieved 2 consecutive HIV RNA < 50 c/mL and increase of HIV RNA > 0.5 log10 c/mL above the nadir Rebounder : achieved 2 consecutive HIV RNA < 50 c/mL with 2 subsequent consecutive (or 1 if last available) HIV RNA > 50 c/mL Criteria for resistance testing All virological failures Resistance data at week 48 RPV + 2 NRTI, N = 340 EFV + 2 NRTI, N = 338 Virologic failure 27 (8%) 20 (6%) Resistance data at time of failure 22 15 Emergent NNRTI mutations 13 7 Most frequent mutations E138K K101E K103N 10 3 1 4 Emergent NRTI mutations 14 5 M184V/I K65R 12 2 THRIVE Cohen CJ. Lancet 2011;378:229-37 15

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Treatment-emergent adverse events RPV + 2 NRTI EFV + 2 NRTI P Treatment-related adverse event of grade > 2 54 (16%) 104 (31%) < AE leading to permanent discontinuation 15 (4%) 25 (7%) - Serious AE 22 (7%) 24 (7%) Treatment-related AE of grade > 2 in > 2% in either group Insomnia 7 6 Headache 5 9 Nausea 2 Dizziness 20 Rash 1 30 THRIVE Cohen CJ. Lancet 2011;378:229-37 16

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Adverse events of interest of any grade, n (% of patients) RPV + 2 NRTI EFV + 2 NRTI P Neurological events 62 (18%) 132 (39%) < Dizziness 10% 28% Headache 6% 8% Somnolence 4% - Disturbance in attention 1% 2% Psychiatric events 52 (15%) 69 (20%) 0.09 Abnormal dreams and nightmares 7% 11% 0.06 Insomnia 5% Sleep Disorder 3% Rash 9 (3%) 43 (13%) Grade 3 1 Discontinuation because of rash 5 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 17

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Grade 3-4 laboratory abnormalities RPV + 2 NRTI EFV + 2 NRTI Any abnormality in > 2% in either group 41 (12%) 63 (19%) Pancreatic amylase 3% ALT 2% AST LDL cholesterol 1% 6% Triglycerides < 1% Total cholesterol Mean (95% CI) change in fasting lipids from baseline to week 48 RPV + 2NRTI EFV + 2 NRTI P 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) THRIVE Cohen CJ. Lancet 2011;378:229-37 18

ARV-trial.com THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI 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 Cohen CJ. Lancet 2011;378:229-37 19

ECHO & THRIVE Study: W96 results
ARV-trial.com ECHO & THRIVE Study: W96 results Response to treatment at week 96 HIV RNA < 50 c/mL RPV + 2 NRTI* % Primary analysis EFV + 2 NRTI* 100 * TDF/FTC = 80%, ZDV/3TC = 15%, ABC/3TC = 5% 78 78 79 78 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]) 75 50 Discontinuation by 96 weeks (RPV vs EFV) For virologic endpoint : 8% vs 3% For adverse events : 4% vs 9% 25 ITT, TLOVR Per protocol, TLOVR Adjusted difference from logistic-regression model (95% CI)= - 0.4% (- 4.6 ; 3.8) Adjusted difference (95% CI)= 0.4 % (- 4.0 ; 4.9) ECHO-THRIVE Cohen CJ. AIDS 2013;27:939-50 20

ARV-trial.com ECHO & THRIVE Study: W96 results Virologic response to treatment at week 96 by subgroups HIV RNA < 50 c/mL (ITT, TLOVR) according to baseline HIV RNA HIV RNA < 50 c/mL (ITT, TLOVR) according to adherence rate RPV + 2 NRTI EFV + 2 NRTI % % 100 100 84 84 80 81 76 73 71 75 65 75 65 56 50 50 25 25 368 329 249 270 69 83 552 499 87 100 < 100,000 c/mL 100, ,000 c/mL > 500,000 c/mL Adherence > 95% Adherence < 95% ECHO-THRIVE Cohen CJ. AIDS 2013;27:939-50 21

ARV-trial.com ECHO & THRIVE Study: W96 results Resistance data at week 96 RPV + 2 NRTI, N = 340 EFV + 2 NRTI, N = 682 Virologic failure 96 (14%) 52 (8%) Rebounder 52 34 Never suppressed 44 18 Resistance data at time of failure 86 42 Emergent NNRTI mutations 46 (53%) 20 (48%) Most frequent mutations E138K K103N 31 - 14 Emergent NRTI mutations 48 (56%) 11 (26%) M184I M184V 32 6 The majority of virologic failures occurred in the first 48 weeks (76% in the RPV group and 69% in the EFV group) 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 ECHO-THRIVE Cohen CJ. AIDS 2013;27: ; Rimsky L. JAIDS 2012;59:39-46 ; Rimsky L. AntivirTher 2013;18:967-77 22

ARV-trial.com ECHO & THRIVE Study: W96 results Adverse events and treatment-emergent grade 2-4 laboratory abnormalities RPV + 2 NRTI EFV + 2 NRTI P Treatment-related adverse event of grade > 2 116 (17%) 226 (33%) < AE leading to permanent discontinuation 28 (4%) 58 (9%) - Serious AE 65 (9%) 71 (10%) Treatment-related AE of grade > 2 in > 10% in either group Any neurologic AE 119 (17%) 259 (38%) Dizziness 55 (8%) 182 (27%) Any psychiatric AE 107 (16%) 166 (24%) Abnormal dreams or nightmares 57 (8%) 90 (13%) 0.003 Rash 29 (4%) 103 (15%) Any grade 2-4 laboratory abnormality 317 (46%) 395 (58%) LDL-cholesterol 7% 18% Total cholesterol 22% AST / ALT 6% / 6% 10% / 11% ECHO-THRIVE Cohen CJ. AIDS 2013;27:939-50 23

Comparison of NNRTI vs NNRTI

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