1. Y. Yazdanpanah 1, C. Fagard 2, D. Descamps 3, A.M. Taburet 4, B. Roquebert 3, I. Tschope 2, C. Katlama 5, G. Pialoux 6, C. Jacomet 7, C. Piketty 8, D. Bollens 9, J.-M. Molina 10, G. Chene 2 and the ANRS 139 TRIO Trial Group 1 Tourcoing Hospital, Tourcoing, France; 2 INSERM U897, Bordeaux, France; 3 Bichat-Claude Bernard Hosp, Paris, France; 4 Kremlin Bicetre Hosp, Paris, France; 5 Pitie-Salpetriere Hosp, Paris, France; 6 Tenon Hosp, Paris, France; 7 Clermont-Ferrand Hosp, Clermont-Ferrand, France; 8 Georges Pompidou Hosp, Paris, France; 9 Saint-Antoine Hosp, Paris, France; 10 Saint-Louis Hosp, Paris, France High rate of virologic success with raltegravir plus etravirine and darunavir/ritonavir in treatment-experienced patients with multidrug-resistant virus : Results of the ANRS 139 TRIO trial

2. ANRS 139 TRIO Trial – Mexico 2008 2 Objectives of the TRIO trial Primary To assess the 24-week virologic efficacy of an ART regimen containing raltegravir, etravirine and darunavir/r in HIV-1 infected patients failing cART with multidrug- resistant virus Secondary – Safety and tolerability – Immunologic response – 48 and 96 week virologic efficacy – Drug-drug interactions

3. ANRS 139 TRIO Trial – Mexico 2008 3 Study design +/- NRTIs and/or enfuvirtide ( based on the physician’s discretion) Primary endpoint: 24 week viral suppression (HIV RNA < 50 cp/ml ) Follow-up to 96 weeks: ongoing Phase II non-comparative multicenter trial raltegravir + etravirine + darunavir/r

4. ANRS 139 TRIO Trial – Mexico 2008 4 Eligibility criteria Patients failing cART with HIV RNA > 1000 /mL No CD4 restriction Naïve to raltegravir, etravirine and darunavir With multidrug-resistant virus –≥ 3 major PI mutations (IAS list 2006) But susceptible to darunavir (1 st Power algorithm) : ≤ 3 mutations among V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89V –≥ 3 NRTI mutations (IAS list 2006) –Previous virologic failure on NNRTIs But susceptible to etravirine (1st Tibotec analyses for ETR) < 3 NNRTI mutations among A98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F

5. ANRS 139 TRIO Trial – Mexico 2008 5 Trial Profile 170 patients screened 67 ineligible ( 67% genotypic criteria, 19% HIV RNA < 1000/ml) 103 patients included all received the study treatment 2 discontinued - One lost to follow-up - One grade 4 clinical AE 101 patients completed through week 24

6. ANRS 139 TRIO Trial – Mexico 2008 6 Baseline characteristics (n = 103) Age in yrs, median (IQR)45(41 – 52) Male, %88 HIV RNA log 10, copies/ml, median (IQR)4.0(3.6 – 4.6) CD4 cells/mm 3, median (IQR)255(132 – 350) CD4 Nadir in cells/mm 3, median (IQR) 79(25– 169) ART duration prior to enrollment yrs, median (IQR) 13(11 – 15) No. mutations at screening, median (IQR) Major PI4(3 – 5) NRTIs5(4 – 6) NNRTIs1(0 – 2) % patients with 0 / 1 / 2 / 3 mutations DRV4% / 31% / 30% / 35% ETR34% / 31% / 31% / 3%

7. ANRS 139 TRIO Trial – Mexico 2008 Optimized background therapy received with raltegravir, etravirine and darunavir % of patients None14% NRTIs83% Enfuvirtide12% (10 /12 were enfuvirtide naive) Genotypic Sensitivity score of OBT (ANRS algorithm) 0 20% 0.5 39% 1 24% > 1 17% 7

8. ANRS 139 TRIO Trial – Mexico 2008 8 Results : Proportion of patients with HIV RNA < 50 copies/ml at 24 weeks (missing = failure) 90% (95%CI 85% to 96%)

9. 9 Change in HIV RNA from baseline: median and IQR (log 10 copies/ml) -2.4 log 10 copies/ml (-1.9 to -2.9)

10. ANRS 139 TRIO Trial – Mexico 2008 10 Patients with HIV RNA ≥ 50 copies/ml at week 24 (n=10/103) Patient HIV RNA baseline HIV RNA wk 20 HIV RNA wk 24 HIV RNA wk 32 143530not done26553Lost to follow-up 229228102320not doneARV discontinued (SAE) 348083439330523 VL > 400 copies/ml 461000018001200 5696002997432 6200000< 50240 50 < VL < 400 copies/ml 7681845360 83548< 5060< 50 Not confirmed at week 32 911859< 5052< 50 105141< 5050< 50

11. 11 CD4 change from baseline: median and IQR (cells/mm 3 ) + 99 cells/mm 3 (32-147)

12. ANRS 139 TRIO Trial – Mexico 2008 12 Grade 4 adverse events, possibly related to investigational drugs 2 clinical adverse events 1 rash and fever that led to treatment discontinuation 1 nephrolithiasis that did not lead to treatment discontinuation 5 laboratory-related adverse events 4 Creatine kinase elevation (> 10 X ULN) –all asymptomatic –all returned to normal values without treatment discontinuation 1 GGT elevation (> 10 X ULN) –In a HCV co-infected patient with intermittent GGT fluctuation –No treatment discontinuation required

13. ANRS 139 TRIO Trial – Mexico 2008 13 Results of clinical trials in treatment experienced patients with MDR virus DRV/r 304 103 454131 Lancet 2007, Lancet 2007, N Eng J Med 2008 Control 124 295235 % pts with HIV RNA < 50 cp/ml 308296 ETRControl ETRControl RALControl

14. ANRS 139 TRIO Trial – Mexico 2008 14 Conclusion Summary of TRIO results at 24 weeks In patients with resistant viruses and historically few remaining treatment options, raltegravir + etravirine + darunavir/r: –resulted in a high rate of virologic suppression (= 90%) –was generally well tolerated Ongoing analyses in the TRIO study include –Durability of virological efficacy and tolerability up to 96 wks –Genotypic analysis of resistance among failing patients –Drug-drug interactions

15. ANRS 139 TRIO Trial – Mexico 2008 15 Acknowledgments The patients for their participation and their commitment during the study and the TRIO Study Group: ANRS JF Delfraissy MJ. Commoy S. Couffin-Cadiergues A. Bouxin-Metro A. Diallo CTU INSERM U897/ISPED G. Chêne C. Fagard C. Jean-Marie A. Beuscart I. Tschöpe C. Colin M. Bertoncello S. Martiren DSMB D. Costagliola J. Caron F. Berdougo D. Rey O. Patey Merck Sharpe & Dohme-Chibret (provided raltegravir) A. Aslan E. Dohin Tibotec, a division of Janssen Cilag (provided etravirine) A. Cheret MB. Hadacek SCIENTIFIC COMMITTEE Y. Yazdanpanah (Chair) G. Chêne D. Descamps V. Dubar C. Jacomet C. Katlama JM. Molina C. Piketty B. Roquebert AM. Taburet CLINICAL CENTERS Saint-Louis, Paris (JM. Molina) Pitié-Salpêtrière, Paris (C. Katlama) Tenon, Paris (G. Pialoux) Saint-Antoine, Paris (PM. Girard) Saint-Louis, Paris (D. Sereni) Tourcoing (Y. Yazdanpanah) Bichat, Paris (P. Yeni) HEGP, Paris (L. Weiss) Nantes (F. Raffi) Paul Brousse, Villejuif (D. Vittecoq) Edouard Herriot, Lyon (F. Jeanblanc) Necker, Paris (JP. Viard) Marseille (I. Poizot-Martin) Lariboisière, Paris (A. Rami) Angers (JM. Chennebault) Garches (P. De Truchis) Saint-Louis, Paris (L. Gerard) Bicêtre (C. Goujard) Nice (J. Durant) Corbeil-Essones (P. Chevojon) Besançon (C. Drobacheff) Antoine Béclère,Clamart (F. Boué) Cochin, Paris (D. Salmon-Ceron) Bordeaux (P. Morlat) Grenoble (P. Leclercq) Saint-Louis, Paris (FJ. Timsit) Saint-Denis(MA. Khuong-Josse) Hôtel-Dieu, Lyon (C. Trepo) Bordeaux (JM. Ragnaud) Belfort (JP. Faller) Nice (E. Rosenthal) Toulouse (L. Cuzin) Créteil (Y. Lévy) Avicenne, Bobigny (M. Bentata) Annecy (J. Gaillat) La Roche/Yon (P. Perré) Rennes (F. Souala) Avignon (G. Pichancourt) Mulhouse (G. Beck-Wirth) Avicenne, Bobigny(S. Abgrall) Pitié-Salpêtrière, Paris (A. Simon) Bordeaux (M. Dupon) Clermont-Ferrand (C. Jacomet) Caen (R. Verdon) Dijon (L. Piroth) Hôtel-Dieu, Paris (A. Compagnucci) Perpignan (H. Aumaitre) Tours (F. Bastides) Pontoise (L. Blum)