1. Influence of Baseline Factors on Virologic Response to Darunavir/Ritonavir (DRV/r) vs Lopinavir/r (LPV/r): Week 48 Outcome in TITAN W. David Hardy, MD 1 ; Daniel Berger, MD 2 ; Els De Paepe, MSc 3 ; Sandra De Meyer, PhD 3 ; David Moriarty, PhD 4 ; Joseph Mrus, MD 5 ; Sabrina Spinosa-Guzman, MD 3 1 Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2 Northstar Medical Center, Chicago, IL, USA; 3 Tibotec BVBA, Mechelen, Belgium; 4 Tibotec Inc., Yardley, PA, USA; and 5 Tibotec Therapeutics, Bridgewater, NJ, USA TITAN = TMC114/r In Treatment-experienced pAtients Naïve to lopinavir

2. 2 TITAN (TMC114-C214): Study Design Phase III randomized, controlled trial with primary analysis at Week 48 *LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities VL = viral load; DRV/r = darunavir with low-dose ritonavir, LPV/r = lopinavir with low-dose ritonavir 785 patients screened, 595 randomized and treated Screening phase (4 weeks) Treatment phase (96 weeks) Treatment-experienced, LPV-naïve VL ≥1,000 copies/mL Stable HAART (≥12 wks) or STI (≥4 wks) DRV/r 600/100mg bid + OBR LPV/r * 400/100mg bid + OBR All patients received optimized background therapy (OBR) –Two to three ARVs from approved NRTI and/or NNRTI classes –Enfuvirtide disallowed Stratification factors: Baseline VL and use of NNRTI in OBR

3. 3 Summary of Previous Findings from TITAN DRV/r was virologically non-inferior and superior to LPV/r (VL <400 and VL<50 copies/mL) Twice as many patients receiving LPV/r experienced virologic failure (VF) compared with patients receiving DRV/r Following VF and compared with LPV/r, DRV/r-based therapy was associated with lower rates of development of –Primary PI mutations or NRTI RAMs –Phenotypic resistance to the PI or NRTI(s) in the study regimen DRV/r was safe and well tolerated, with a lower rate of diarrhea and lower increases in triglycerides than LPV/r, and a higher rate of rash Overall, in treatment-experienced, LPV-naïve patients: VL, viral load; RAM, resistance-associated mutation

4. 4 TITAN: Virologic Response through Week 48 (ITT-TLOVR) – All Patients *P value for superiority derived from logistic regression model including treatment and stratification factors: baseline log 10 VL and use of NNRTI in the optimized background regimen 100 Patients with VL <400 and <50 copies/mL (% [95% CI]) VL <400 copies/mL 50 40 30 20 10 90 80 70 60 77%* 67% P =.008* BAS481216243648 Time (weeks) LPV/r (n=297) DRV/r (n=298) VL <50 copies/mL P =.005* 71% 60% LPV/r (n=297) DRV/r (n=298) 0 BAS481216243648 Time (weeks) DRV/r was non-inferior and superior to LPV/r 50 40 30 20 10 90 80 70 60 100

5. 5 TITAN: Baseline Characteristics DRV/r (n=298)LPV/r (n=297) Demographics Male, n (%) Mean (±SD) age (years) 229 (77) 41  9.0 241 (81) 41  8.6 Disease characteristics Mean (± SD) baseline log 10 VL Median CD4 (cells/mm 3 [range]) 4.33  0.79 235 (3–831) 4.28  0.81 230 (2–1,096) History of ARV treatment Structured treatment interruption, n (%) Previous ARV experience, n (%) NRTIs: ≥4 NNRTIs: ≥1 PIs: 0 PIs: 1 PIs: ≥2 64 (21) 156 (52) 225 (76) 94 (32) 108 (36) 96 (32) 71 (24) 151 (51) 229 (77) 93 (31) 115 (39) 89 (30) Optimized background therapy Number of active NRTIs used, n (%)* 0 1 ≥2 Active NNRTI used, n (%) † 30 (10) 70 (24) 188 (65) 31 (10) 42 (15) 75 (26) 171 (59) 21 (7) Baseline fold change in EC 50 (FC) to PI DRV FC ≤10 LPV FC ≤10 287 (98) ‡ 263 (90) ‡ 286 (99) ‡ 261 (90) ‡ Activity of ARVs assessed by baseline phenotype (Antivirogram®); 576 of 582 patients with phenotype data used ≥1 NRTI in the OBR; † 54 patients used an NNRTI, irrespective of activity; ‡ 582 (DRV/r=292; LPV/r=290) patients had baseline phenotype available

6. 6 TITAN: Baseline Characteristics DRV/r (n=298)LPV/r (n=297) Demographics Male, n (%) Mean (±SD) age (years) 229 (77) 41  9.0 241 (81) 41  8.6 Disease characteristics Mean (± SD) baseline log 10 VL Median CD4 (cells/mm 3 [range]) 4.33  0.79 235 (3–831) 4.28  0.81 230 (2–1,096) History of ARV treatment Structured treatment interruption, n (%) Previous ARV experience, n (%) NRTIs: ≥4 NNRTIs: ≥1 PIs: 0 PIs: 1 PIs: ≥2 64 (21) 156 (52) 225 (76) 94 (32) 108 (36) 96 (32) 71 (24) 151 (51) 229 (77) 93 (31) 115 (39) 89 (30) Optimized background therapy Number of active NRTIs used, n (%)* 0 1 ≥2 Active NNRTI used, n (%) † 30 (10) 70 (24) 188 (65) 31 (10) 42 (15) 75 (26) 171 (59) 21 (7) Baseline fold change in EC 50 (FC) to PI DRV FC ≤10 LPV FC ≤10 287 (98) ‡ 263 (90) ‡ 286 (99) ‡ 261 (90) ‡ Activity of ARVs assessed by baseline phenotype (Antivirogram®); 576 of 582 patients with phenotype data used ≥1 NRTI in the OBR; † 54 patients used an NNRTI, irrespective of activity; ‡ 582 (DRV/r=292; LPV/r=290) patients had baseline phenotype available

7. 7 *Activity assessed by BL phenotype (Antivirogram®); † 522 patients did not use an NNRTI and 2 patients used an inactive NNRTI ITT, intent-to-treat; VL, viral load; OBR, optimized background regimen −50−40−30−20−1001020304050 n [DRV/r −LPV/r] (%) Overall (ITT) 595 11 Gender Male 470 11 Female 125 10 Baseline CD4 (cells/mm 3 ) <100 109 1 100– <200 126 6 200– <350 185 11  350 169 20 Baseline VL (copies/mL) <100,000 489 12  100,000 106 7 TITAN: Difference in Virologic Response (VL <50 copies/mL) at Week 48: Univariate Analysis Active ARVs* in OBR 0 56 11 113023 ≥23908 Active NRTIs* in OBR 07219 114516 ≥23598 Active NNRTI* in OBR Yes5225 No † 52410 DRV/r LPV/r FAVORS Difference in VL <50 copies/mL, % (95% CI)

8. 8 NRTIs TITAN: NRTIs and NNRTIs Used in the OBR TDF3TCZDVddIABCFTCd4T 2 47 9 58 41 26 22 18 13 3 54 44 38 28 26 15 12 5 EFVNVP Patients (%) 0 20 40 60 80 NNRTIs NRTI use was generally well-balanced between treatment groups and consistent with current practice NRTI/NNRTI activity assessed by baseline phenotype (Antivirogram®) DRV/r arm (N=298) NRTI/NNRTI sensitive NRTI/NNRTI resistant LPV/r arm (N=297) NRTI/NNRTI sensitive NRTI/NNRTI resistant

9. 9 TITAN: Baseline Characteristics DRV/r (n=298)LPV/r (n=297) Demographics Male, n (%) Mean (±SD) age (years) 229 (77) 41  9.0 241 (81) 41  8.6 Disease characteristics Mean (± SD) baseline log 10 VL Median CD4 (cells/mm 3 [range]) 4.33  0.79 235 (3–831) 4.28  0.81 230 (2–1,096) History of ARV treatment Structured treatment interruption, n (%) Previous ARV experience, n (%) NRTIs: ≥4 NNRTIs: ≥1 PIs: 0 PIs: 1 PIs: ≥2 64 (21) 156 (52) 225 (76) 94 (32) 108 (36) 96 (32) 71 (24) 151 (51) 229 (77) 93 (31) 115 (39) 89 (30) Optimized background therapy Number of active NRTIs used, n (%)* 0 1 ≥2 Active NNRTI used, n (%) † 30 (10) 70 (24) 188 (65) 31 (10) 42 (15) 75 (26) 171 (59) 21 (7) Baseline fold change in EC 50 (FC) to PI DRV FC ≤10 LPV FC ≤10 287 (98) ‡ 263 (90) ‡ 286 (99) ‡ 261 (90) ‡ Activity of ARVs assessed by baseline phenotype (Antivirogram®); 576 of 582 patients with phenotype data used ≥1 NRTI in the OBR; † 54 patients used an NNRTI, irrespective of activity; ‡ 582 (DRV/r=292; LPV/r=290) patients had baseline phenotype available

10. 10 −50−40−30−20−1001020304050 n [DRV/r −LPV/r] (%) Overall (ITT)59511 Baseline LPV FC ≤105247 >105845 Baseline DRV FC  ≤1057311 >10910 Baseline IAS-USA primary PI mutations 1 04033 ≥119027 Previous PI experience 0187-4 12237  2 18530 DRV/r LPV/r FAVORS Difference in VL <50 copies/mL, % (95% CI) 1 Johnson VA et al. Top in HIV Med 2006; 14:125-130 No. of LPV RAMs 1  <65266 ≥65944 No. of DRV RAMs 1  04907 15628 22441 ≥32314 TITAN: Difference in Virologic Response (VL <50 copies/mL) at Week 48: Univariate Analysis ITT, intent-to-treat; FC, fold change in EC 50 ; RAM, resistance-associated mutation

11. 11 TITAN: Impact of IAS-USA Primary PI Mutations* at Baseline on VL <50 Copies/mL at Week 48 Patients with non-missing genotype data; † Excludes patients with missing LPV FC at baseline 67 58 44 33 DRV/r (n=296) LPV/r (n=297) All Patients Number of IAS-USA primary PI mutations 70 79 68 69 0 10 20 30 40 50 60 70 80 90 012 ≥3≥3 % HIV RNA <50 copies/mL (ITT-TLOVR) *D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M 1 1 Johnson VA et al. Top in HIV Med 2007;15:119-125 Patients with Prior PI Experience † 69 78 68 62 53 42 31 0 10 20 30 40 50 60 70 80 90 012 ≥3≥3 % HIV RNA <50 copies/mL (ITT-TLOVR) DRV/r (n=203) LPV/r (n=204) n= 108 116 32 30 25 26 38 32 n= 199 204 33 33 25 27 39 33

12. 12 TITAN: Impact of IAS-USA Primary PI Mutations* at Baseline on VL <50 Copies/mL at Week 48— Patients with LPV FC ≤10 at BL Number of IAS-USA primary PI mutations *D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M 1 1 Johnson VA et al. Top in HIV Med 2007;15:119-125 Patients with non-missing genotype data; † Excludes patients with missing LPV FC at baseline DRV/r (n=263) LPV/r (n=261) All Patients with LPV FC ≤10 0 10 20 30 40 50 60 70 80 90 012 ≥3≥3 % HIV RNA <50 copies/mL (ITT-TLOVR) 66 59 50 43 69 78 68 65 DRV/r (n=172) LPV/r (n=174) Patients with Prior PI Experience and LPV FC ≤10 † 69 77 68 63 61 55 47 43 0 10 20 30 40 50 60 70 80 90 012 ≥3≥3 % HIV RNA <50 copies/mL (ITT-TLOVR) n = 106 114 31 29 19 17 16 14 n = 195 197 32 32 19 18 17 14

13. 13 Factors in Multivariate Logistic Regression Model Treatment, BL VL, number of prior PIs, and BL resistance to treatment PI were significantly associated with response, P <.05 Activity of ARVs assessed by baseline phenotype (Antivirogram®); *Includes interactions with treatment None (Unadjusted Result) - Baseline VL, - NNRTI in OBR TITAN: Difference in Virologic Response (VL <50 copies/mL, ITT-TLOVR): Multivariate Analyses −40−30−20−1001020304050 −50 Model A - Baseline VL, - Baseline CD4, - NNRTI in OBR, - Number of prior PIs* Model B - Baseline VL, - Baseline CD4, - Number of active ARVs in OBR - Baseline log 10 FC to DRV or LPV* Model C - Baseline VL, - Baseline CD4, - Number of active ARVs in OBR - Number of DRV resistance-associated mutations Model D - Baseline VL, -Baseline CD4, -Number of active ARVs in OBR - Number of LPV resistance-associated mutations* Model E DRV/r LPV/r FAVORS Difference in VL <50 copies/mL, % (95% CI) - Baseline VL, -Baseline CD4, -Number of active ARVs in OBR - Number of IAS-USA primary PI mutations* Model F

14. 14 TITAN Conclusions In treatment-experienced, LPV-naïve patients: The difference in virologic response (VL <50 copies/mL) favoring DRV/r was generally consistent across subgroups Multivariate analyses demonstrated that the difference in response favoring DRV/r was maintained after adjusting for baseline characteristics including VL and CD4, activity of OBR, PI resistance, and prior PI experience Overall, and in patients phenotypically sensitive to both PIs at baseline (FC ≤10), the presence of 1 or more IAS-USA primary PI mutations affected the response to LPV/r but not DRV/r –As the number of IAS-USA primary PI mutations increased, the difference in virologic response favoring DRV/r increased VL, viral load; OBR, optimized background regimen; PI, protease inhibitor

15. 15 TITAN: Acknowledgments The patients and their families for their participation and support during the study TMC114-C214 study team and the investigators and co-investigators –Argentina: Pedro Cahn, Arnaldo Casiró, Isabel Cassetti, Daniel David, Marcelo Losso and Sergio Lupo –Australia: David Cooper, Robert Finlayson, Jenny Hoy, Patricia Martinez, Marilyn McMurchie and Cassy Workman; –Austria: Armin Rieger and Norbert Vetter –Belgium: Nathan Clumeck, Jean-Christophe Goffard and Lutgarde Lynen –Brazil: Clovis Da Cunha, Beatriz Grinsztejn, Claudio Gonsalez, Jose Valdez-Madruga, Rogerio de Jesus Pedro, Jose Henrique Pilotto, –Mauro Schechter and Artur Timerman –Canada: John Gill, Norbert Gilmore, Don Kilby, Patrice Junod, Anita Rachlis, Benoit Trottier, Chris Tsoukas and Sharon Walmsley –Chile: Juan Ballesteros, Rebeca Northland and Carlos Pérez –Denmark: Henrik Nielsen –France: Jacques Durant, Pierre-Marie Girard, Christine Katlama, Christian Michelet, Jean-Michel Molina, Gilles Pialoux, Christophe Piketty, Dominique Salmon, Daniel Vittecoq and Patrick Yeni –Germany: Keikawus Arasteh, Gerd Fätkenheuer, Heribert Knechten, Antonius Mutz, Carl Knud Schewe, Dieter Schuster, Albrecht Stoehr and Andreas Trein –Greece: George Panos –Guatemala: Eduardo Arathoon and Carlos Mejia-Villatoro –Hungary: Denes Banhegyi –Italy: Andrea Antinori, Giampiero Carosi, Roberto Esposito, Adriano Lazzarin, Francesco Mazzotta, Anna Maria Orani, Stefano Rusconi, –Laura Sighinolfi and Fredy Suter –Malaysia: Adeeba Kamarulzaman and Christopher Lee –Mexico: Jaime Andrade –Netherlands: Kees Brinkman, Bart Rijnders and Herman Sprenger –Panama: Nestor Sosa –Portugal: Teresa Branco, António Diniz and Rui Sramento e Castro –Puerto Rico: Javier Morales Ramirez –Russia: Oleg Kozyrev, Grigory Moshkovich, Alexander Pronin, Oleg Romanenko, Elena Vinogradova and Alexey Yakovlev –South Africa: Ezio Baraldi, Francesca Conradie, Gulam Hoosan Latiff, Lerato Mohapi, Catherine Orrell, Osman Ebrahim and David Spencer –Spain: Jose Ramon Arribas, Angel Daniel Podzamczer and Maria Perez-Elias –Switzerland: Milos Opravil –Thailand: Ploenchan Chetchotisakd, Kiat Ruxrungtham, Wichai Techasathit and Chaiwat Ungsedhapand (key coordinator) –United Kingdom: Philippa Easterbrook and Anton Pozniak –United States: Ben Barnett, John Baxter, Paul Benson, Daniel S Berger, Jack Bissett, Cynthia Brinson, Alfred Burnside, Thomas Campbell, Amy Colson, Frederick Cruickshank, Edwin DeJesus, Robin Dretler, Robert Eng, Charles Farthing, Jeffrey Fessel, Michael Frank, David Hardy, Dushyantha Jayaweera, Thomas Jefferson, Harold Katner, Clifford Kinder, Harry Lampiris, Marc LaRiviere, Jason Leider, Steven Marlowe, Cynthia Mayer, David McDonough, Jose Montero, Karam Mounzer, Robert Myers, Dorece Norris, Frank Palella, Gerald Pierone, Bruce Rashbaum, Afsoon Roberts, Barry Rodwick, Peter Ruane, Kunthavi Sathasivam, Stefan Schneider, Shannon Schrader, Anita Scribner, Michael Sension, Peter Shalit, William Short, Stephen Smith, Alan Taege, Melanie Thompson, Timothy Wilkin and Bienvenido Yangco. Supported by Tibotec Tibotec biostatisticians