TITAN = TMC114/r In Treatment-experienced pAtients Naïve to lopinavir TTCA0063-07282-1 Influence of Baseline Factors on Virologic Response to PREZISTA/Ritonavir (PREZISTA/r) vs Lopinavir/r (LPV/r): Week 48 Outcome in TITAN  W. David Hardy, MD1; Daniel Berger, MD2; Els De Paepe, MSc3; Sandra De Meyer, PhD3; David Moriarty, PhD4; Joseph Mrus, MD5; Sabrina Spinosa-Guzman, MD3 1Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Northstar Medical Center, Chicago, IL, USA; 3Tibotec BVBA, Mechelen, Belgium; 4Tibotec Inc., Yardley, PA, USA; and 5Tibotec Therapeutics, Bridgewater, NJ, USA TITAN = TMC114/r In Treatment-experienced pAtients Naïve to lopinavir Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN (TMC114-C214): Study Design TTCA0063-07282-2 Phase III randomized, controlled trial with primary analysis at Week 48 Screening phase (4 weeks) Treatment phase (96 weeks) PREZISTA/r 600/100mg bid + OBR Treatment-experienced, LPV-naïve VL ≥1,000 copies/mL Stable HAART (≥12 wks) or STI (≥4 wks) LPV/r * 400/100mg bid + OBR 785 patients screened, 595 randomized and treated TITAN is an ongoing, randomised, controlled trial. It is an international 96-week study, with primary analysis at Week 48. Patients were screened for eligibility and had to be: treatment experienced but naïve to lopinavir have documented HIV infection have a viral load of greater than one thousand copies per mL to have been on stable HAART therapy or off treatment for 12 weeks or more. A total of 595 patients were randomised to treatment of either, PREZISTA 600mg with 100mg ritonavir or lopinavir 400mg, again with the same low dose of ritonavir. Both treatments were administered twice daily, and all patients also received an optimised background regimen. This consisted of at least 2 to 3 antiretrovirals from the NRTI and NNRTI classes. LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities. At the time of this analysis 18% had switched top the new formulation. Background Patients co-infected with chronic hepatitis B or C were allowed to enter the trial if their condition was clinically stable and they were not expected to require hepatitis treatment during the study period. Randomisation was performed using a centralised system to ensure balance across treatments groups and across two stratification factors (the use of an NNRTI in the OBR and screening plasma viral load of <50,000 or 50,000 copies/mL). PREZISTA was administered as 300-mg tablets, ritonavir as 100-mg capsules and lopinavir-ritonavir as 133.3/33.3-mg capsules. During the study, a new formulation of lopinavir-ritonavir (200/50-mg tablet) became available. The study protocol was amended to allow patients randomised to lopinavir-ritonavir to switch to the new formulation as soon as it was approved by local regulatory authorities; subsequently, all patients on this arm would be switched to the new formulation. Patients who experienced virological failure (defined as plasma viral load >400 copies by week 16 or beyond) or a treatment-related grade 4 AE or a confirmed grade 4 laboratory abnormality were eligible to participate in the planned rollover phase. Results of the 48-week primary analysis are reported here. 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 *LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities VL = viral load; PREZISTA/r = PREZISTA with low-dose ritonavir, LPV/r = lopinavir with low-dose ritonavir Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

Summary of Previous Findings from TITAN TTCA0063-07282-3 Overall, in treatment-experienced, LPV-naïve patients: PREZISTA/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 PREZISTA/r Following VF and compared with LPV/r, PREZISTA/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 PREZISTA/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 VL, viral load; RAM, resistance-associated mutation Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN: Virologic Response through Week 48 (ITT-TLOVR) – All Patients TTCA0063-07282-4 VL <400 copies/mL VL <50 copies/mL 100 100 90 P =.008* 90 P =.005* 80 77%* 80 70 70 71% 67% 60 60 60% Patients with VL <400 and <50 copies/mL (% [95% CI]) 50 50 PREZISTA/r (n=298) 40 40 PREZISTA/r (n=298) LPV/r (n=297) 30 30 LPV/r (n=297) 20 20 10 10 BAS 4 8 12 16 24 36 48 BAS 4 8 12 16 24 36 48 Time (weeks) Time (weeks) PREZISTA/r was non-inferior and superior to LPV/r *P value for superiority derived from logistic regression model including treatment and stratification factors: baseline log10 VL and use of NNRTI in the optimized background regimen Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN: Baseline Characteristics TTCA0063-07282-5 PREZISTA/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 log10 VL Median CD4 (cells/mm3 [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) 93 (31) 115 (39) 89 (30) Optimized background therapy Number of active NRTIs used, n (%)* 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 EC50 (FC) to PI PREZISTA FC ≤10 LPV FC ≤10 287 (98)‡ 263 (90)‡ 286 (99)‡ 261 (90)‡ The demographic, disease characteristics and treatment history were well balanced across both treatment arms Patients had an average age of 41 years. Mean plasma viral load was 4.3 log10 copies/mL and median CD4 cell count was 232 cells/mm3 The population of patients in this trial were representative of those we see failing in clinical practice Baseline resistance characteristics were also well balanced between treatment arms. Background The mean duration of study treatment was similar in both groups (53·5 weeks for PREZISTA-ritonavir and 51·5 weeks for lopinavir-ritonavir). 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 (PREZISTA/r=292; LPV/r=290) patients had baseline phenotype available Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN: Baseline Characteristics TTCA0063-07282-9 PREZISTA/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 log10 VL Median CD4 (cells/mm3 [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) 93 (31) 115 (39) 89 (30) Optimized background therapy Number of active NRTIs used, n (%)* 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 EC50 (FC) to PI PREZISTA FC ≤10 LPV FC ≤10 287 (98)‡ 263 (90)‡ 286 (99)‡ 261 (90)‡ The demographic, disease characteristics and treatment history were well balanced across both treatment arms Patients had an average age of 41 years. Mean plasma viral load was 4.3 log10 copies/mL and median CD4 cell count was 232 cells/mm3 The population of patients in this trial were representative of those we see failing in clinical practice Baseline resistance characteristics were also well balanced between treatment arms. Background The mean duration of study treatment was similar in both groups (53·5 weeks for PREZISTA-ritonavir and 51·5 weeks for lopinavir-ritonavir). 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 (PREZISTA/r=292; LPV/r=290) patients had baseline phenotype available Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

Difference in VL <50 copies/mL, % (95% CI) TTCA0063-07282-7 TITAN: Difference in Virologic Response (VL <50 copies/mL) at Week 48: Univariate Analysis Difference in VL <50 copies/mL, % (95% CI) n [PREZISTA/r −LPV/r] (%) Overall (ITT) 595 11 Gender Male 470 11 Female 125 10 Baseline CD4 (cells/mm3) <100 109 1 100– <200 126 6 200– <350 185 11 ³350 169 20 Baseline VL (copies/mL) <100,000 489 12 ³100,000 106 7 LPV/r FAVORS PREZISTA/r Active ARVs* in OBR 0 56 11 1 130 23 ≥2 390 8 Active NRTIs* in OBR 0 72 19 1 145 16 ≥2 359 8 Active NNRTI* in OBR Yes 52 25 No† 524 10 −50 −40 −30 −20 −10 10 20 30 40 50 *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 Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN: NRTIs and NNRTIs Used in the OBR TTCA0063-07282-8 TITAN: NRTIs and NNRTIs Used in the OBR PREZISTA/r arm (N=298) NRTI/NNRTI sensitive NRTI/NNRTI resistant LPV/r arm (N=297) NRTI/NNRTI sensitive NRTI/NNRTI resistant 80 60 58 54 Patients (%) 47 44 41 38 40 28 26 26 22 18 20 15 13 12 9 5 2 3 TDF 3TC ZDV ddI ABC FTC d4T EFV NVP NRTIs NNRTIs NRTI use was generally well-balanced between treatment groups and consistent with current practice NRTI/NNRTI activity assessed by baseline phenotype (Antivirogram®) Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN: Baseline Characteristics TTCA0063-07282-6 PREZISTA/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 log10 VL Median CD4 (cells/mm3 [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) 93 (31) 115 (39) 89 (30) Optimized background therapy Number of active NRTIs used, n (%)* 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 EC50 (FC) to PI PREZISTA FC ≤10 LPV FC ≤10 287 (98)‡ 263 (90)‡ 286 (99)‡ 261 (90)‡ The demographic, disease characteristics and treatment history were well balanced across both treatment arms Patients had an average age of 41 years. Mean plasma viral load was 4.3 log10 copies/mL and median CD4 cell count was 232 cells/mm3 The population of patients in this trial were representative of those we see failing in clinical practice Baseline resistance characteristics were also well balanced between treatment arms. Background The mean duration of study treatment was similar in both groups (53·5 weeks for PREZISTA-ritonavir and 51·5 weeks for lopinavir-ritonavir). 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 (PREZISTA/r=292; LPV/r=290) patients had baseline phenotype available Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

Difference in VL <50 copies/mL, % (95% CI) TTCA0063-07282-10 TITAN: Difference in Virologic Response (VL <50 copies/mL) at Week 48: Univariate Analysis n [PREZISTA/r −LPV/r] (%) Overall (ITT) 595 11 Difference in VL <50 copies/mL, % (95% CI) LPV/r FAVORS PREZISTA/r Previous PI experience 0 187 -4 1 223 7 2 185 30 Baseline LPV FC ≤10 524 7 >10 58 45 Baseline PREZISTA FC ≤10 573 11 >10 9 10 No. of LPV RAMs1 <6 526 6 ≥6 59 44 No. of PREZISTA RAMs1 0 490 7 1 56 28 2 24 41 ≥3 23 14 Baseline IAS-USA primary PI mutations1 0 403 3 ≥1 190 27 ITT, intent-to-treat; FC, fold change in EC50; RAM, resistance-associated mutation −50 −40 −30 −20 −10 10 20 30 40 50 1Johnson VA et al. Top in HIV Med 2006; 14:125-130 Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN: Impact of IAS-USA Primary PI Mutations TITAN: Impact of IAS-USA Primary PI Mutations* at Baseline on VL <50 Copies/mL at Week 48 TTCA0063-07282-11 All Patients Patients with Prior PI Experience † 69 78 68 62 53 42 31 10 20 30 40 50 60 70 80 90 1 2 ≥3 % HIV RNA <50 copies/mL (ITT-TLOVR) PREZISTA/r (n=203) LPV/r (n=204) PREZISTA/r (n=296) LPV/r (n=297) 90 79 80 70 68 69 70 67 58 44 33 60 50 % HIV RNA <50 copies/mL (ITT-TLOVR) 40 30 20 10 1 2 ≥3 Number of IAS-USA primary PI mutations n= 199 204 33 33 25 27 39 33 n= 108 116 32 30 25 26 38 32 Patients with non-missing genotype data; †Excludes patients with missing LPV FC at baseline *D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M1 1Johnson VA et al. Top in HIV Med 2007;15:119-125 Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

All Patients with LPV FC ≤10 TITAN: Impact of IAS-USA Primary PI Mutations* at BL on VL <50 Copies/mL at Week 48—Patients with LPV FC ≤10 at BL TTCA0063-07282-12 All Patients with LPV FC ≤10 PREZISTA/r (n=172) LPV/r (n=174) Patients with Prior PI Experience and LPV FC ≤10† 69 77 68 63 61 55 47 43 10 20 30 40 50 60 70 80 90 1 2 ≥3 % HIV RNA <50 copies/mL (ITT-TLOVR) n = 106 114 31 29 19 17 16 14 PREZISTA/r (n=263) LPV/r (n=261) 90 78 80 69 68 70 66 65 59 60 50 50 % HIV RNA <50 copies/mL (ITT-TLOVR) 43 40 30 20 10 1 2 ≥3 Number of IAS-USA primary PI mutations n = 195 197 32 32 19 18 17 14 Patients with non-missing genotype data; †Excludes patients with missing LPV FC at baseline *D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M1 1Johnson VA et al. Top in HIV Med 2007;15:119-125 Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

Difference in VL <50 copies/mL, % (95% CI) TITAN: Difference in Virologic Response (VL <50 copies/mL, ITT-TLOVR): Multivariate Analyses TTCA0063-07282-13 Difference in VL <50 copies/mL, % (95% CI) Factors in Multivariate Logistic Regression Model LPV/r FAVORS PREZISTA/r None (Unadjusted Result) Model A - Baseline VL, NNRTI in OBR - Baseline VL, - Baseline CD4, - NNRTI in OBR, - Number of prior PIs* Model B - Baseline VL, Baseline CD4, Number of active ARVs in OBR - Baseline log10 FC to PREZISTA or LPV* Model C - Baseline VL, - Baseline CD4, - Number of active ARVs in OBR - Number of PREZISTA resistance-associated mutations Model D How the different covariates were modeled in the multivariate analyses: log10 baseline HIV RNA - continuous baseline CD4 count (cells/mm3) - continuous log 10 FC PREZISTA - continuous log10 FC LPV - continuous NNRTI in OB (yes=1/no=0) number of active ARVs: 0, 1, >=2 number of PREZISTA/LPV mutations: 0, 1, 2, >=3 Number of primary PI mutations (IAS): 0, >=1 - Baseline VL, Baseline CD4, Number of active ARVs in OBR - Number of LPV resistance-associated mutations* Model E - Baseline VL, Baseline CD4, Number of active ARVs in OBR - Number of IAS-USA primary PI mutations* Model F −50 −40 −30 −20 −10 10 20 30 40 50 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 Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.

TITAN Conclusions In treatment-experienced, LPV-naïve patients: TTCA0063-07282-14 In treatment-experienced, LPV-naïve patients: The difference in virologic response (VL <50 copies/mL) favoring PREZISTA/r was generally consistent across subgroups Multivariate analyses demonstrated that the difference in response favoring PREZISTA/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 PREZISTA/r As the number of IAS-USA primary PI mutations increased, the difference in virologic response favoring PREZISTA/r increased VL, viral load; OBR, optimized background regimen; PI, protease inhibitor Hardy WD, et al. Oral presentation presented at IDSA 2007. Abst 1209.