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BMS-045 Mean Percent Change (SE) in Fasting LDL Cholesterol From Baseline Treated Subjects

ATV 300/RTV (N = 119). ATV 400/SQV (N = 110). LPV/RTV (N = 118). BMS-045 Mean Percent Change (SE) in Fasting LDL Cholesterol From Baseline Treated Subjects. 1. Percent Change. -8. -10. Weeks. 6G-8. ATV 300/RTV (N = 119). ATV 400/SQV (N = 110). LPV/RTV (N = 118).

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BMS-045 Mean Percent Change (SE) in Fasting LDL Cholesterol From Baseline Treated Subjects

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  1. ATV 300/RTV (N = 119) ATV 400/SQV (N = 110) LPV/RTV (N = 118) BMS-045Mean Percent Change (SE) in Fasting LDL Cholesterol From BaselineTreated Subjects 1 Percent Change -8 -10 Weeks 6G-8

  2. ATV 300/RTV (N = 119) ATV 400/SQV (N = 110) LPV/RTV (N = 118) BMS-045Mean Percent Change (SE) in Fasting Triglycerides From BaselineTreated Subjects 34 Percent Change 2 -15 Weeks 6J-8

  3. Studies Conducted: Atazanavir Comparative Metabolic Profile • Preclinical models used to study ATV and 6 other PIs • Glucose transport (GLUT-4, -1) in adipocytes, myocytes • Hepatocyte lipogenesis • Preadipocyte differentiation • Mature adipocyte lipogenesis • Gene expression profiles in PI-treated adipocyte and hepatocyte models (Affymetrics chips, q-PCR) • Proteasome activity inhibition in vitro • ATV exhibited weaker effects with higher concentration- dependency (> Cmax) in above assays vs. other PIs, which exhibited more potent, higher magnitude effects consistent with published reports from several labs 6E-2

  4. Relationship of Bilirubin vs ATV Cmin by Genotype 7/7 6/7 6/6 Cmin (ng/mL) 4N-1

  5. ATV LPV/RTV BMS-043-Efficacy CohortWeek 24 TLOVR Proportions in Responseby Resistance Sub-Groups(PI Sensitivity, Prior PI, NRTI Mutations) (LOQ = 400 c/mL) N = 114 115 84 101 26 12 85 83 28 31 32 26 82 89 Overall PIPhenotype£ 2.5 x IC50of Control PIPhenotype> 2.5 x IC50of Control OnePrior PI > 1 Prior PI No NRTIMutations ³ 1 NRTIMutations 2J-2

  6. BMS-045Week 24 TLOVR Proportions in Response (LOQ = 400 c/mL) Effect of PI and NRTI Mutations and PI Sensitivity ATV/RTV ATV/SQV LPV/RTV N = 120 115 123 88 83 88 32 30 33 81 77 78 39 38 45 18 22 17 102 93 106 Overall PIPhenotype£ 2.5 x IC50of Control PIPhenotype> 2.5 x IC50of Control < 4 PIMutations ³ 4 PIMutations No NRTIMutations ³ 1 NRTIMutations 2K-2

  7. Coverage of Resistant Clinical Isolates 10A-2

  8. *p = <0.0005 ATV 14 Key Substitutions Analysis of 399 susceptible & 544 ATV resistant clinical isolates 10A-16

  9. 1000 100 ATV Susceptibility (FC) 10 1 Median EC50s 0.6 0.7 1.0 1.6 2.4 3.2 5.8 15 22 49 0.1 -1 0 1 2 3 4 5 6 7 8 9 10 Number of Key Substitutions Key Substitutions vs Fold Change 10A-18

  10. Plasma Metabolites of ATV 14-20% of plasma radioactivity Cmax = 0.27 M Steady state AUCm / AUCp = 0.14 12-18% of plasma radioactivity Cmax = 0.54 M Steady state AUCm / AUCp = 0.29 ATV 47-54% of plasma radioactivity Cmax = 4.6 M 16 metabolites; 8 in plasma (3 metabolites > 3% of plasma radioactivity) 11-14% of plasma radioactivity Structure postulated 13D-1

  11. AI424034 TLOVR Response Rate Comparisonfor LOQ = 400, LOQ = 200 and LOQ = 50 2A-2

  12. BMS-034Frequency of HIV RNABetween 50 and 400 c/mL at Week 48 HIV RNA 50 - < 400 Number of Subjects Number of Subjects HIV RNA (c/mL) ATV EFV 2A-3

  13. Impact on NRTI Resistance * Defined as  2 fold increase in phenotype to FC  2.5, or evidence of I50L substitution 10B-7

  14. BMS-034I50L Identified in All ATV-Resistant Isolates Treatment Regimen ATV EFV N = 404 N = 401 Virologic failure through 48 weeks* 69 69 Phenotypeable, N 26 20 Phenotype  2.5 x IC50 of control, N (%) ATV 6 (23) 1 (5) EFV 1 (4) 13 (65) Genotypeable, N 26 20 I50L or I50I/L, N (%) 6 (23) 0 (0) K103N or K103K/N, N (%) 1 (4) 13 (65) 41, 70, 210, or 215 (ZDV), N (%) 3 (12) 2 (10) M184 (3TC), N (%) 14 (54) 11 (55) Reasons for no result include: HIV RNA level  1000 c/mL (n = 44), isolate non-typeable (n = 23)or sample unavailable (n = 25) *TLOVR (LOQ = 400 c/mL) Core Backup-41

  15. Overall Frequency of ALT Grades 3 – 4*, N (%) Comparator ATV Hep B/C + 13/131 (10) 10/88 (11) Hep B/C - 20/777 (3) 8/542 (1) Grade 3 – 4 ALT Elevations Hepatitis B and/or C Co-Infection Frequency of ALT Grades 3 – 4*, N (%) Experienced Naïve BMS -008 BMS -034 BMS -043 ATV 400 / ATV 600 ATV 400 EFV ATV 400 LPV / RTV NFV Hep B/C + 5/53 (9) 2/12 (17) 6/50 (12) 8/59 (14) 2/28 (7) 0/17 (0) Hep B/C - 6/316 (2) 5/79 (6) 8/347 (2) 2/335 (<1) 6/114 (5) 1/128 (<1) *> 5 x ULN 7B-11

  16. Comparator Studies of PRData in HIV-infected Subjects PR Interval (msec) Number with AV Block (%) AI424041a AI424034 AI424043 AI424045 ATV Combined (N = 152) NFV (N = 48) ATV 400 (N = 353) EFV (N = 329) ATV 400 (N = 137) LPV / RTV (N = 141) ATV 300 / RTV (N = 117) ATV 400 / SQV (N = 105) LPV / RTV (N = 111) 1° AV Block,N (%) 8 (5) 5 (10) 17 (5) 10 (3) 8 (6) 8 (6) 5 (4) 6 (6) 5 (4)  2° or 3 ° AV Block, N (%) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Source: Updated Summary of Clinical Safety a Two cohorts, one each from Studies AI424007 and AI424009, rolled onto Study AI424041. ECG analyses wereperformed on the AI424007 cohort only due to the very limited sample size of the AI424009 cohort. 5-BU-18

  17. Comparator Studies of QTcFData in HIV-infected Subjects QTcF(msec) QTcF Intervals AI424041a AI424034 AI424043 AI424045 ATV Combined NFV ATV 400 EFV ATV 400 LPV / RTV ATV 300 / RTV ATV 400 / SQV LPV / RTV Males (N = 103) (N = 30) (N = 226) (N = 224) (N = 107) (N = 116) (N = 93) (N = 80) (N = 84) 451 - 500 1 0 0 1 0 1 1 0 0 Females (N = 49) (N = 18) (N = 127) (N = 105) (N = 30) (N = 25) (N = 24) (N = 25) (N = 27) 471 - 500 0 0 0 0 0 0 0 0 0 Source: Updated Summary of Clinical Safety a Two cohorts, one each from Studies AI424007 and AI424009, rolled onto Study AI424041. ECG analyses were performed on the AI424007 cohort only due to the very limited sample size of the AI424009 cohort. 5-BU-14

  18. -043 -045 ATV 300 /RTV 100(N = 119) ATV 400 /SQV(N = 110) ATV 400(N = 144) LPV / RTV(N = 146) LPV / RTV(N = 118) 5% 18% 7% 12% 14% Concomitant Use of Lipid Lowering Therapy in ATV Phase III Studies Naïve Subjects -034 ATV 400 (N = 404) EFV (N = 401) 1% 3% Experienced Subjects 6T-9

  19. DAD – Baseline Risk Factors for CVD Family History of CHD Previous CVD Smoking Ever Hypertension Obesity Diabetes Mellitus Elevated Total Chol. Lowered HDL-c Elevated Triglyc. % 0 20 40 60 80 100 n = 23,468 6A-5

  20. 185 185 335 335 185 185 335 335 Risk of Cardiovascular Disease According to Total Cholesterol at Specified Levels of Other Risk Factors Framingham Study. 18-yr follow-up. Men aged 35 60.2 8-YearProbability(/1000) 34.6 23.2 3.9 Cholesterol GlucoseIntolerance Systolic BP Cigarettes LVH on ECG 0 105 0 0 + 195 0 0 + 195 + 0 + 195 + + Kannel. Am J Cardiol. 1983;22:9B. 6U-5

  21. 100% Treatment Naive ATV (23) 100% ATV + SQV (32) Emergence of ATV Resistance • All have anI50L • ATV-specific resistance • Increased susceptibility to other PIs ~21% (9) ATV (33) ~79% • All lack an I50L • Cross-resistance to several PIs Treatment Experienced 10B-1

  22. Emergence of ATV Resistance:Impact of I50L on PI Susceptibility ATV +I50L ATVno I50L ATV/SQVno I50L 10B-2

  23. Viral Evolution Beyond I50L? 10B-14

  24. Genotype at Baseline Responders • Resistance via I50L pathway related to presence of changesat residues 14R, 46I and 88D and absence of L90M at baseline 10D-2

  25. Growth Impaired Clinical Virus 810024D-1: 10, 13, 23, 30, 37, 41, 62, 63, 70, 71T, 88, 93 810024D-2: 50L, 10, 13, 30, 37, 41, 62, 63, 70, 71T, 88, 93 10C-10

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