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Comparison of NNRTI vs NNRTI

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

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Comparison of NNRTI vs NNRTI

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

  2. 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 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% CIfor the difference = 12%, 95% power) Molina JM. Lancet 2011;378:238:46 ECHO

  3. ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Baseline characteristics and patient disposition Molina JM. Lancet 2011;378:238:46 ECHO

  4. ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Response to treatment at week 48 HIV RNA < 50 c/mL RPV + TDF/FTC % EFV + TDF/FTC Primaryanalysis 100 84 83 83 83 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 : -12.5 ; -3.3]) 75 50 25 Mean CD4/mm3 increase at W48 : • + 196 (RPV + TDF/FTC) vs • + 182 (EFV + TDF/FTC), p = 0.13 0 ITT, TLOVR Per protocol, TLOVR Adjusted difference from logistic-regression model (95% CI)= - 0.4% (- 5.9 ; 5.2) Adjusted difference (95% CI)= 0.8 % (- 4.8 ; 6.5) Molina JM. Lancet 2011;378:238:46 ECHO

  5. 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 HIV RNA < 50 c/mL (ITT, TLOVR) according to adherence rate RPV + TDF/FTC EFV + TDF/FTC % % 90 100 100 87 86 83 83 81 79 73 68 75 75 62 50 50 25 25 0 0 181 163 131 134 34 47 275 262 44 56 < 100,000 c/mL 100,000-500,000 c/mL > 500,000 c/mL Adherence > 95% Adherence < 95% Molina JM. Lancet 2011;378:238:46 ECHO

  6. 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 increaseof HIV RNA > 0.5 log10c/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 Molina JM. Lancet 2011;378:238:46 ECHO

  7. Treatment-emergent adverse events ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46 ECHO

  8. Adverse events of interest of any grade ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD Molina JM. Lancet 2011;378:238:46 ECHO

  9. ECHO Study: RPV + TDF/FTC QD vs EFV + TDF/FTC QD • Grade 3-4 laboratory abnormalities • Mean (95% CI) change in fasting lipids from baseline to week 48 Molina JM. Lancet 2011;378:238:46 ECHO

  10. 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 Molina JM. Lancet 2011;378:238:46 ECHO

  11. 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 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) Cohen CJ. Lancet 2011;378:229-37 THRIVE

  12. THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Baseline characteristics and patient disposition Cohen CJ. Lancet 2011;378:229-37 THRIVE

  13. THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Response to treatment at week 48 HIV RNA < 50 c/mL RPV + 2 NRTI % EFV + 2 NRTI Primaryanalysis 100 86 86 82 82 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 : - 6.3 ; 2.2]) 75 50 25 Mean CD4/mm3 increase at W48 : • + 189 (RPV + 2 NRTI) vs • + 171 (EFV + 2 NRTI), P = 0.09 0 ITT, TLOVR Per protocol, TLOVR Adjusted difference from logistic-regression model (95% CI)= 3.5% (- 1.7 ; 8.8) Adjusted difference (95% CI)= 3.7 % (- 1.9 ; 9.3) Cohen CJ. Lancet 2011;378:229-37 THRIVE

  14. THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Virologic response to treatment at week 48 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 % % 91 100 100 90 89 84 82 80 77 69 75 75 64 62 50 50 25 25 0 0 187 167 118 136 35 35 272 230 36 39 < 100,000 c/mL 100,000-500,000 c/mL > 500,000 c/mL Adherence > 95% Adherence < 95% Cohen CJ. Lancet 2011;378:229-37 THRIVE

  15. 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 resistancetesting • All virologicalfailures Resistance data at week 48 Cohen CJ. Lancet 2011;378:229-37 THRIVE

  16. Treatment-emergent adverse events THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Cohen CJ. Lancet 2011;378:229-37 THRIVE

  17. Adverse events of interest of any grade, n (% of patients) THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI Cohen CJ. Lancet 2011;378:229-37 THRIVE

  18. THRIVE Study: RPV + 2 NRTI vs EFV + 2 NRTI • Grade 3-4 laboratoryabnormalities • Mean (95% CI) change in fasting lipids from baseline to week 48 Cohen CJ. Lancet 2011;378:229-37 THRIVE

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

  20. ECHO & THRIVE Study: W96 results Response to treatment at week 96 HIV RNA < 50 c/mL RPV + 2 NRTI* % EFV + 2 NRTI* Primaryanalysis * TDF/FTC = 80%, ZDV/3TC = 15%, ABC/3TC = 5% 100 79 78 78 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 : - 9.9 ; - 2.5]) 75 50 Discontinuation by 96 weeks (RPV vs EFV) • For virologic endpoint : 8% vs 3% • For adverse events : 4% vs 9% 25 0 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) Cohen CJ. AIDS 2013;27:939-50 ECHO-THRIVE

  21. 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 81 80 76 73 71 75 75 65 65 56 50 50 25 25 0 0 368 329 249 270 69 83 552 499 87 100 < 100,000 c/mL 100,000-500,000 c/mL > 500,000 c/mL Adherence > 95% Adherence < 95% Cohen CJ. AIDS 2013;27:939-50 ECHO-THRIVE

  22. ECHO & THRIVE Study: W96 results 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) • 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 Cohen CJ. AIDS 2013;27:939-50 ; Rimsky L. JAIDS 2012;59:39-46 ; Rimsky L. AntivirTher 2013;18:967-77 ECHO-THRIVE

  23. Adverse events and treatment-emergent grade 2-4 laboratory abnormalities ECHO & THRIVE Study: W96 results Cohen CJ. AIDS 2013;27:939-50 ECHO-THRIVE

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