REYATAZ 

1. REYATAZ Safety & Tolerability Issues for HIV‑Infected Patients Requiring Protease Inhibitor Therapy

2. Disclaimer This slide set has been developed by Reyataz Global Marketing for internal BMS use only. Utilization of this monograph, in whole or in part, for any promotional purposes requires regional and local legal, regulatory, and medical approval prior to use.

3. Evolution of HIV Therapy acute infection datapublished clinical use of viral load long latency period presumed current theory of viral dynamics published clinical use of genotyping phenotyping viral cause of AIDS isolated OraQuick ‘02 ‘03 ‘01 ‘98 ‘99 ‘00 1983 1987 ‘91 ‘92 ‘93 ‘94 ‘95 ‘96 ‘97 ATV T20 FTC EFV ABC NFV DLV AZT RTV, IDV NVP APV LPV/r TFV 3TC SQV ddl ddC d4T NNRTI’s firstARV AIDS deaths decline PIs introduced combo use triple ARV (HAART) monotherapy AIDS Timeline 1985-2004. http://www.projectinform.org/20/time.pdf. ; http://www.kff.org/hivaids/timeline/index.cfm Accessed 5.13.05

4. Patients are Living Longer in the Era of HAART Mortality and frequency of HAART including a PI among HIV-infected patients with CD4+ <100 cells/mm3 40 100 Deaths Therapy with a PI (% of patient-days) Deaths per 100 person-years 50 20 Use of PIs 0 0 1994 1995 1996 1997 Avoiding complications and optimizing treatment acceptance Treating the disease PI = protease inhibitors; HAART = highly active antiretroviral therapy Palella FJ et al. N Eng J Med. 1998; 338: 853–860

5. Therapeutic Goals of ART • Primary goals of ART include: • Reduce HIV-related morbidity and mortality • Improve quality of life • Restore and preserve immunologic function • Maximally and durably suppress viral load • Secondary goal: • Select a safe and effective regimen US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed May 11, 2005.

6. Reasons for ART Failure • Causes of treatment failure include: • Patient factors (CD4 nadir, VL, comorbidities, etc) • Suboptimal adherence • Toxicity and intolerance (adverse events) • Pharmacokinetic problems • Drug-drug interactions • Suboptimal drug potency • Development of viral resistance Hugen PWH et al. J Acquir Immune Defic Syndr. 2002;30:324-334. US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed May 11, 2005.

7. ICONA Study: Reasons for Failure of Initial HAART 8% n=25 20% n=61 58% n=182 14% n=44 d'Arminio Monforte A, et al. AIDS. 2000;14:499-507. Ammassari A et al. J Acquir Immune Defic Syndr. 2001;28:445-449.

8. ART and Adherence • “Adherence to antiviral medication is the key determinant in the degree and duration of virologic suppression.” — DHHS, 2004 • Factors affecting nonadherence include: • Complex dosing schedules • Heavy pill burden • Adverse effects • Nonadherence can lead to the development of resistance to ARV medications, which may result in treatment failure and limit future therapeutic options for the management of HIV US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf . Accessed May 11, 2005. Yun LWH et al. J Acquir Immune Defic Syndr. 2005;38:432-438.

9. How Much Adherence is Enough? P<0.001 90-95 80-90 70-80 <70 ≥95 Adherence, % Paterson DL et al. Ann Intern Med. 2000;133:21-30.

10. Medication-Related Factors and Adherence • Adverse effects (AEs) have been reported with virtually all ARV medications and are among the most common reasons for switching or discontinuation of therapy and for medication nonadherence • “Minor” common side effects may be as important to the patient as major grade 3/4 events • Nausea, vomiting, abdominal discomfort or cramping, and diarrhea are common reasons why patients stop their medications • Most patients are asymptomatic when treatment is started • Development of even minor symptoms can therefore be distressing Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124. O’Brien ME et al. J Acquir Immune Defic Syndr. 2003;34:407-414. http://clinicaloptions.com/04nrti.

11. Common Adverse Events Associated with ART • Short-term (acute) • Usually occur within hours or days of beginning treatment • Rash, CNS disturbances, nausea, vomiting, diarrhea • Long-term (chronic) • Lipodystrophy • Diabetes • Hyperlipidemia • Cardiovascular (CV) risk • Life-threatening • Liver failure, renal failure Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

12. Adverse Events in PI-Based ART • Most common PI AEs: • GI intolerance • Nausea • Headache • Hyperlipidemia • Insulin resistance and diabetes • Lipodystrophy US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005. Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

13. Some PIs are Known for Specific Adverse Events • IDV  nephrolithiasis, hyperbilirubinemia, GI intolerance • SQV  diarrhea • LPV/r  diarrhea • NFV  diarrhea • RTV  GI intolerance, hepatitis • f-APV  rash, diarrhea • ATV  indirect hyperbilirubinemia, PR interval prolongation US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005. Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

14. Impact of PI-based ART on GI System

15. ART-related GI Disturbances • Common occurrence with all ART • Generally not life threatening • Includes dyspepsia, nausea, vomiting, diarrhea • Can usually be controlled with OTC drugs or prescription drugs Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

16. Common PI-Related GI Adverse Events Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

17. BMS-008: Naïve ATV vs NFV in Treatment-Naïve Patients:GI Adverse Event Profile* P<0.0001 ATV 400 mg QD (n=178) NFV 1250 mg BID (n=91) Grade 1-4 Related AEs in % *Reported with a frequency of >20% in any treatment group Murphy RL et al. AIDS 2003; 17: 2603–2614

18. BMS-043: PI experienced (unboosted vs boosted PI) ATV vs LPV/r in Treatment-Experienced Patients:GI Adverse Event Profile* ATV 400 mg QD (n=144) LPV/r 400/100 mg BID (n=146) Grade 2-4 Related AEs in % Adapted from: Cohen C et al. 2nd IAS, Paris, July 2003. Oral presentation 117 * =  2% of Patients

19. BMS-045: Experienced (boosted ATV vs boosted LPV) ATV/r vs LPV/r in Treatment-Experienced Patients:GI Adverse Event Profile* ATV/r 300/100 mg QD (n=119) LPV/r 400/100 mg BID (n=118) *5% of patients Johnson M et al.AIDS. 2005; 19:685-694

20. BMS-045: Experienced (boosted ATV vs boosted LPV) ATV/r vs LPV/r: Use of Antidiarrheal Agents P=0.001 P=0.04 • Antidiarrhea/Intestinal Antiinflammatory Agents • Antidiarrheal • Atropine/diphenoxylate (lomotil) • Attapulgite • Bismuth subsalicylate • Lactobacillus acidophilus • Loperamide • Nystatin • Sacchromyces cervislae • Sulfasalazine 24 P=0.0005 17 13 8 6 3 Antidiarrhea/Intestinal Antiinflammatory Agents Loperamide

21. Impact of PI-based ART on Hepatic System

22. ART-Related Liver Issues • Severe hepatotoxicity in 5-10% within the first 12 months • Risk increases with treatment duration • Risk factors – hepatitis, alcoholism, NVP or RTV regimens • Most cases resolve within months • Therapy should be stopped if liver enzymes are very elevated or there are symptoms of hepatitis. Dore G. J HIV Ther. 2003;8:96-100; US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005.

23. PI-Related Liver Issues • For the PIs, onset of hepatotoxicity generally takes weeks or months vs onset of hepatotoxicity with NRTIs, which takes months to years • Clinical manifestations • Generally asymptomatic • Some patients present with anorexia, weight loss, and/or jaundice associated with indirect hyperbilirubinemia US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf Accessed April 21, 2005; Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124

24. Common PI-Related Hepatic Effects Sax PE, Kumar P. J Acquir Immune Defic Syndr. 2004;37:1111-1124.

25. BMS-045: Experienced (boosted ATV vs boosted LPV) ATV/r vs LPV/r: Hepatic Effects* RTV 100 mg RTV 100 mg ATV 300 mg QD LPV 400 mg BID ATV 400/SQV Grade 2-4 related adverse events in % n=119 n=118 n=110 Jaundice 6 0 2 Scleral icterus 3 0 0 Grade 3-4 Laboratory parameter in % Total bilirubin 49 <1 20 ALT/SGPT 4 3 4 AST/SGOT 3 3 2 *5% of patients,No patients withdrew treatment due to jaundice or bilirubin elevations Johnson M et al.AIDS. 2005; 19:685-694

26. PI-Related Hyperbilirubinemia • IDV causes hyperbilirubinemia in <25%1 • Most common lab abnormality seen with ATV2 • Dose dependent • 62% of patients • Grade 1 or 2 • Discontinuation of either PI results in ↓ bilirubin levels 1. Zucker S et al. DDW 2001. Abstract 233; 2. Squires K et al. CROI 2001. Abstract 15.

27. Steps at Which Bilirubin Metabolism is Effected RBC 2. Transport 1. Hemolysis B Sinusoid B*ALBUMIN 5. Glucuronidation 3. Uptake GST + B UGT-1A1 enzyme 4. IC Transport* B  G1 or  G2 hepatocyte 6. Export MRP2 Canaliculus *Intracellular transport

28. Indirect Bilirubin Elevations With ATV: Mechanism Meaning • Elevated indirect (unconjugated) bilirubin • ATV inhibits UGT-1A1 • Decreased UGT-1A1 activity similar to the effect observed with Gilbert’s syndrome and mechanistically similar to that seen with IDV • No evidence of a hepatotoxic process: Grade 3-4 elevations in total bilirubin were rarely associated with grade 3-4 elevations in ALT/AST • Readily reversible upon discontinuation of ATV • No difference in frequency of bilirubin elevations or virologic suppression in HBV/HCV co-infected patients • <1% discontinuation in clinical trials due to bilirubin increases in studies 034 and 043

29. BMS-034: Naïve HBV/HCV: Liver Function and Bilirubin Elevations in bilirubin seen with ATV treatment are not associated with hepatotoxicity, and are not influenced by HBV or HCV co-infection 100 Hepatitis co-infected Not co-infected 80 60 AST/SGOT ALT/SGPT Bilirubin % with Grade 3-4 Lab Changes 40 33 29 20 14 12 10 5 2 2 <1 <1 0 <1 0 ATV EFV ATV EFV ATV EFV Adapted from: Cahn P et al. 6th ICDTHIV, Glasgow, Nov 2002. Poster P281

30. Impact of PI-based ART on Lipids

31. Contribution of PI Therapy to Dyslipidemia • Most PIs have demonstrated association with dyslipidemia • Lipid abnormalities associated with PI therapy include: • Hypercholesterolemia •  LDL-c • Hypertriglyceridemia • Up to 80% of HIV+ patients on a PI regimen may experience elevated plasma lipid concentrations • Clinical consequences of PI-associated dyslipidemia: •  risk of CAD in younger HIV+ patients • Peripheral atherosclerosis • Abnormalities of glucose homeostasis • Pancreatitis •  risk long-term CVD Dubé MP et al. Clin Infect Dis 2003; 37: 613–627 Calza L, et al. Int J Antimicrob Agents. 2003;22:89-99. Kannel WB, Giordano M. Am J Cardiol. 2004;94:901-906.

32. Comparative Lipid Profiles of Different PIs Lipid profiles associated with different antiretroviral drugs: data from two German outpatient clinics Data presented in mg/dLAll highlighted segments are at least p<0.05 Presumably negative differences Mauss S et al. 6th International Conference on Adverse Drug Reactions and Lipodystrophy in HIV patients. Washington 2004. Poster presentation

33. ATV SQV IDV NFV APV LPV/r RTV* Little, if any Fewest Intermediate Most markedIncludes cross-study comparisons; direct comparisons for all PIs are not available *At therapeutic doses2 Dyslipidemia in Adults on ART Effects of PIs on Lipids • CV subcommittee of ACTG summarized effects of PIs on ‘lipids’ by degree of abnormality:1 • Further data now available: • ATV/r has less effect than LPV/r on TC and fasting TG (p0.005)3 • FosAPV/r and LPV/r associated with similar increases in TC and TG levels4 • SQV/r has less effect than LPV/r on TG (p=0.0004), but similar effect on TC; LDL-cholesterol could not be reliably assessed5 ATV = atazanavir; SQV = saquinavir; IDV = indinavir; NFV = nefinavir; APV = amprenavir; LPV/r = lopinavir/ritonavir; RTV = ritonavir; fosamprenavir/ritonavir; ATV/r = atazanavir/ritonavir 1. Dubé MP et al. Clin Infect Dis 2003; 37: 613–627; 2. Hsu A et al. Antimicrob Agents Chemother 1997; 41: 898–905; 3. Johnson M et al.AIDS. 2005; 19:685-694; 4. DeJesus E et al. 10th CROI, Boston 2003, #178; 5. Walmsley S et al. 11th CROI, 2004; Poster 90

34. 50 40 p<0.0001for both 30 20 10 0 TC Effects of ATV and NFV on Lipids in Naïve Patients at Week 48 p<0.001 p<0.0001 NRTI backbone: d4T + 3TC bid 49.5 ATV 400 mg qd (n=181) p<0.001 p<0.01 NFV 1250 mg bid (n=91) 24.6 23.2 Mean change frombaseline to 48 weeks (%) ATV 600 mg qd (n=195) 7.6 7.2 7.1 5.9 5.1 5.2 Baseline mean 168/ 165/ 169 99/ 97/ 102 128/ 108/ 121 value (mg/dL) LDL-C TGs P<0.01 for all comparisons to baseline Murphy RL et al. AIDS 2003; 17: 2603–2614

35. Fasting TGs HDL-C TC LDL-C Minimal Effect of ATV/r on Lipid Metabolism:ATV/r vs LPV/r in Treatment-Experienced Patients Censoring: patients on lipid-lowering therapy excluded 40 p0.005 for both 30 20 p0.005for both Mean % change from baseline at Week 48 2 1 6 4 0 -3 -4 -4 -7 -8 -10 -14 ATV/r (n=119) LPV/r (n=118) ATV/SQV (n=110) -20 Baseline median 183/ 178/ 166 100/ 103/ 96 38/ 37/ 40 164/ 163/ 153 value (mg/dL) Johnson M et al.AIDS. 2005; 19:685-694

36. Additional Safety Issues with ATV-based ART

37. ATV-Related Cardiology Issues • ATV can prolong PR interval • AV conduction abnormalities are asymptomatic and limited to 1º AV block • In clinical trials, 1º AV block was seen in: • 5.9% of ATV-treated patients (n = 920) • 5.2% of LPV/r-treated patients (n = 252) • 10.4% of NFV-treated patients (n = 48) • 3.0% of EFV-treated patients (n = 329) • Use ATV with caution in patients with pre-existing conduction diseases (marked 1º, or 2º or 3º AV block) Reyataz [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2004.

38. Drug Interactions • Didanosine (Videx-EC) • No interaction • Famotidine (Pepcid) • Coadministration  the AUC and Cmin of ATV • Methadone (Dolophine) • Omeprazole (Prilosec) • Coadministration  the AUC and Cmin of ATV • Rifampin (Rifadin) • Coadministration  AUC of rifampin; a dosage reduction of rifampin is recommended. • Tenofovir (Viread) • Coadministration  the AUC and Cmin of ATV Reyataz [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; 2004.

39. Pregnancy and ART • ATV is a pregnancy category “B” drug in the US • All other FDA-approved ART agents are in category “B”, “C”, or “D” • “B” – No risk to fetus but not studied in pregnant women • “C” – Animal studies show risk to fetus and not studied in pregnant women (benefits must outweigh the risks) • “D” – Human data show no risk, benefit may outweigh risk • Women should not breast feed while on a PI Dore G. J HIV Ther. 2003;8:96-100; US DHHS. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf ; Accessed April 21, 2005.

40. ART and Adherence • Medication adherence is key to obtaining optimal benefit from ART • Recognition of the factors that influence nonadherence, and selection of regimens that can strengthen adherence, are therefore key issues for the long-term success of ART • There is increasing emphasis on choosing patient-friendly regimens to which patients can readily adhere

41. ATV Tolerability Summary • ATV is safe and generally well tolerated in naïve and experienced patients • ATV and ATV/r are associated with significantly less diarrhea than are other PIs (LPV/r or NFV) • Improved GI tolerability may improve adherence • The most noticeable lab value change seen with ATV is  bilirubin • Not associated with hepatotoxicity, even in hepatitis co-infected patients • ATV has demonstrated a distinctly minimal effect on lipid levels in PI-naive and PI-experienced patients

42. Back-up Slides

43. Body Systems Affected by ART • ART can affect a number of different body systems including: • GI • Liver • Bilirubin • Lipids • Heart • Kidney • CNS Not affected by ATV

44. AEs Have Different Severities • Grades were developed using the following general guidelines: • 0: No adverse event or within normal limits • 1: Mild adverse event • 2: Moderate adverse event • 3: Severe adverse event • 4: Life-threatening or disabling adverse event • 5: Fatal adverse event

45. What is atazanavir (ATV)? • Protease inhibitor (PI) • Azapeptide • Dosed as 2 capsules daily • Can be boosted with ritonavir 100 mg to enhance the pharmacokinetics Reyataz [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

46. ATV Pharmacokinetics • Absorption • Rapidly absorbed (Tmax ~2.5 hours) • Food:  exposure,  intersubject variability • Distribution • Measurable concentrations in CSF and semen • Protein binding ~86% (albumin and 1-AG) • Metabolism • Primarily metabolized by CYP3A4 • Inhibitor of CYP3A4 (Ki ~ 2 M) and UGT 1A1 (not 2B7) • Elimination • Primarily eliminated in bile • Urinary excretion—7% unchanged drug • T½ ~7 hours Reyataz [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.

47. Efficacy of ATV • Treatment-naïve patients • ATV is as effective as EFV in treatment-naïve patients1 • Both regimens are teamed with zidovudine and lamivudine • Treatment-experienced patients • ATV/r is as effective as LPV/r in treatment-experienced patients2 1. Squires K et al. J Acquir Immune Defic Syndr. 2004;36:1011-1019. 2. Johnson M et al. AIDS. 2005;19:685-694.

48. Metabolic Profile of ATV • In naïve patients • No effect on blood lipids or glucose1 • In experienced patients • Reduction in LDL, triglycerides, and total cholesterol/HDL2 1. Squires KE et al. ICAAC 2002; 2. Johnson M et al. AIDS. 2005;19:685-694.

49. Improved Tolerability with ATV • In naïve patients: • ATV associated with less diarrhea than NFV1 • In experienced patients: • ATV/r associated with less diarrhea than LPV/r2 • Less diarrhea could lead to improved adherence 1. Panteleo G et al. ECCATHI, 2001; 2. Cohen C et a. IAS, 2003

50. Excellent Resistance Profile • Resistance in naive patients: • Rare (2%) and, if present, always associated with I50L mutation] • I50L mutation does not confer cross-resistance to other PIs Colonno R et al. J Infect Dis. 2004;189:1802-1810.