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  1. BMS Data Update Dr Keith Aizen and Victoria Adamson Bristol-Myers Squibb Prescribing and adverse event reporting information can be found at the end of this presentation Date of preparation: July 2009 Job Bag No: HIV/0709/2983 MC/HIV/ATR/0709/0008

  2. VIdex® Didanosine (ddI) Zerit® stavudine (D4T) BMS Virology Portfolio

  3. DDI and D4T safety update

  4. Topics • Peripheral neuropathy • CV risk • Hepatotoxicity

  5. Peripheral neuropathy

  6. TDF+3TC+EFV d4T+3TC+EFV Study 903% Patients < 50 Copies/mL Intent to Treat (Missing=Failure) 73% 69% % Patients with HIV-1 RNA < 50 c/mL Weeks Adapted from Gallant et al JAMA July 14 2004 vol 202 191-201

  7. Study 903Selected Toxicities Associated with Mitochondrial Dysfunction through Week 144 d4T+3TC+EFV (n=301) TDF+3TC+EFV (n=299) (All Grades) Week 48Week 144Week 48Week 144 Patients (%) with Events 9 (3%)* 17 (6%)* 30 (10%)* 82 (27%)* Peripheral Neuritis/Neuropathy 6 (2%)** 9 (3%)* 20 ( 7%)** 31 (10%)* Lipodystrophy + 3 (1%) 9 (3%)* 11 ( 4%) 57 (19%)* Lactic Acidosis + 0 0 3 ( 1%) 3 ( 1%) Pancreatitis 0 0 0 0 +Investigator Defined * p value < 0.001; ** p = 0.013 Adapted from Gallant et al JAMA July 14 2004 vol 202 191-201

  8. Do treatments for HIV drug induced peripheral neuropathy work ? Pregabalin1 Improved pain but no better than placebo Acetyl L Carnitine2 After 14 days no difference to placebo by ITT, but significant difference by EE analysis Simpson D IAC Aug 2008 abstract THAB0301 Youle et al HIV Medicine (2007),8, 241-250

  9. Morphological changes

  10. What do BHIVA Guidelines recommend ? Lipoatrophy • Replace D4T or AZT • Surgical intervention Lipohypertrophy • Metformin if insulin resistance is present • GH – long term data required Gazzard et al, HIV Medicine (2008) vol 9 563-608

  11. CV risk

  12. 1.9 1.5 1.2 1.0 0.8 0.6 NRTIs and Risk of MI: Recent* Exposure to Each Drug RRyes/no95% CI ** ZDV ddI ddC d4T 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 #MI: 523 331 148 405 554 221 139 * recent use = current or within the last 6 months ** not shown (low number of patients currently on ddC) Lundgren JD, et al CROI Oral Abstract 44LB

  13. Newly described • Unknown cause in HIV infected Patients • Postulated to be associated with DDI Kovari et al Clinical infectious diseases 2009:49 626-635

  14. Literature review of noncirrhotic portal hypertension Kovari et al Clinical infectious diseases 2009:49 626-635

  15. Study design • Nested case control study • 15 patients with NCPH and 75 controls in the Swiss HIV cohort study • Matched by HIV duration, no viral hepatitis and follow up to at least the date of NCPH diagnosis Kovari et al Clinical infectious diseases 2009:49 626-635

  16. Definition of NCPH in this study • Endoscopically confirmed varices • Presenting symptoms include increased liver enzymes, heamatamesis or ascites Kovari et al Clinical infectious diseases 2009:49 626-635

  17. Kovari et al Clinical infectious diseases 2009:49 626-635

  18. Bivariable odds ratios for the effect of DDI on NCPH and ORs for the covariables before and after adjustment for DDI Kovari et al Clinical infectious diseases 2009:49 626-635

  19. Study Conclusions • Strong association between prolonged DDI exposure and development of NCPH • “An important finding of this study is that long-term toxicity of antiretroviral drugs might emerge only after decades. As persons with HIV infection in industrialized countries live longer and ART exposure is prolonged, we need to be alert for novel clinical manifestations attributable to drug-related adverse events” Kovari et al Clinical infectious diseases 2009:49 626-635

  20. Naïve patients: BHIVA 2008: What to start with? “It is the Writing Group’s view that EFV should be considered first line in all patients. This is Based upon its efficacy, durability, toxicity profile, convenience and cost” A + + • NNRTI • EFVa preferred • NRTI • AZT> • ddI alternative aexcept in women who may wish to become pregnant *Only when CD4 <250 cells/mm3 in females, <400 cells/mm3 in males ~ Where established cardiovascular disease risk factors and a PI required > Co-formulated as Combivir® & Co-formulated as Kivexa® + Co-formulated as Truvada® Gazzard et al, HIV Medicine (2008) vol 9 563-608

  21. 100 EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r 90 80 70 Probability of no Virologic Failure (%) 60 50 EFV + 2 NRTIs vs LPV/r + 2 NRTIs : P=0.006 EFV + LPV/r vs EFV + 2 NRTIs : P=0.49 (NS) EFV + LPV/r vs LPV/r + 2 NRTIs: P=0.13 (NS) (threshold for significance P<0.014) 40 30 ║ ║ 0 ACTG 5142 Study: Co-Primary Endpoint: Time to Virologic Failure (VF) EFV + 2 NRTIs arm had a statistically significantly longer time to virologic failure than the LPV/r + 2 NRTIs arm 0 24 48 72 96 120 144 Number of Patients Weeks After Randomization Adapted from: Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

  22. 903E Study: The Safety and Efficacy of Tenofovir DF (TDF) in Combination with Lamivudine (3TC) and Efavirenz (EFV) in Antiretroviral-naïve Patients Through 7 Years • Methods • Patients in selected sites (Argentina, Brazil, and Dominican Republic) rolled over into a 7-year (336-week) open-label extension phase (903E) • Data obtained from patients originally randomized to TDF and participating in 903E were analyzed • Study Design n = 86 Study 903E 3 Years(144 Weeks) 7 Years(336 Weeks) Study 903 Adapted from Madruga JVR, et al , ICDT 2008, Poster P4

  23. Resistance 4 patients discontinued due to virologic failure 2 Wild type genotypes 1 T69N, M184V, K103N at Week 240 1 M184M/V, K103 K/N, V108V/I, P225P/H, T69A/T,K219K/R, K70K/E/G/R at Week 336 No K65R 100 80 81% n=86 60 % with HIV RNA <400 copies/mL 40 20 0 0 1 2 3 4 5 6 7 Years 903E Study: HIV-1 RNA, CD4, and Resistance Proportion with HIV-1 RNA <400 copies/mL through 7 Years (M=F) Proportion with HIV-1 RNA <50 copies/mL through 7 Years (M=F) 100 80 80% n=86 60 % with HIV RNA <50 copies/mL 40 20 0 0 1 2 3 4 5 6 7 Years Mean Change from Baseline in CD4 through 7 Years 500 +459 450 400 350 300 Mean Change in cells/mm3 250 200 150 100 50 0 0 1 2 3 4 5 6 7 Years Adapted from Madruga JVR, et al , ICDT 2008, Poster P4

  24. 903E Study:Median Total Limb Fat (IQR) Years 2-7 12 • aP-value for change from Year 2 using Wilcoxon Signed Rank test 10 8.0a 8 6.7 P<0.001a Median Limb Fat in kg 6 4 2 0 0 3 2 1 4 6 5 7 Year Adapted from Madruga JVR, et al , ICDT 2008, Poster P4

  25. 903E Study: Investigators’ Conclusions • Through 7 years of therapy in antiretroviral-naïve patients, TDF + 3TC+ EFV demonstrated the following: • Sustained, durable antiretroviral efficacy • Continued CD4 cell count increases • No discontinuations due to renal adverse events • No evidence of clinically relevant bone effects • Significant increases in limb fat from Years 2 through 7 Madruga JVR, et al , ICDT 2008, Poster P4

  26. Efficacy of boosted Reyataz ®Atazanavir (ATV/r)in naïve patients

  27. CASTLE study design Screening/enrolment HIV RNA 5000 c/mL, no CD4 cell count restriction Randomization (n=883) Stratified: HIV RNA <100000 c/mL vs 100000 c/mL; geographic region (1:1) ATV/r 300/100 mg QD (n=440) LPV/r 400/100 mg BID (n=443) TDF/FTC 300/200 mg QD TDF/FTC 300/200 mg QD • Primary endpoint: • Proportion of subjects with HIV RNA <50 c/mL at Week 48 • Principal analysis: ITT-confirmed virological response (CVR) – (NC=F) ATV/r, atazanavir/ritonavir; BID, twice daily; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; QD, once daily; TDF, tenofovir Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

  28. Primary efficacy endpoint: ITT-confirmed virological response (NC=F) ATV/r (n=440) LPV/r (n=443) 100 80 60 Responders, % (SE) 40 HIV RNA <50 c/mL: 78% ATV/r vs 76% LPV/rDifference estimate: 1.7 (95% CI, -3.8%, 7.1%) 20 0 BL 4 12 24 36 48 Time (weeks) ATV/r has noninferior antiviral efficacy compared with LPV/r Supporting analyses: ITT–TLOVR: HIV RNA <50 c/mL: ATV/r 78%, LPV/r 76%; 1.9 (-3.6, 7.4) OT–VROC: HIV RNA <50 c/mL: ATV/r 84%, LPV/r 87%; -3.5 (-8.7, 1.8) Adapted from Molina J-M, et al. Lancet 2008;372:646−655

  29. Week 96 ResultsHIV RNA <50 c/mL (CVR NC=F) ATV/r (n=440) LPV/r (n=443) 100 80 60 * p<0.05 Responders (%) 40 HIV RNA < 50 c/mL: 74% ATV/r vs 68% LPV/rDifference estimate: 6.1 (95% CI, 0.3%–12.0%)* 20 0 BL 4 12 24 36 48 60 72 84 96 Time (weeks) ATV/r has noninferior antiviral efficacy compared with LPV/r Supporting analyses: ITT–TLOVR: HIV RNA <50 c/mL: ATV/r 70%, LPV/r 63%; 6.6 (0.4, 12.7) OT–VROC: HIV RNA <50 c/mL: ATV/r 89%, LPV/r 88%; 1.6 (-3.1, 6.2) Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

  30. As randomised: Week 96 CD4 mean change from baseline 300 250 ATV/r (n=440) LPV/r (n=443) 200 CD4 mean change (cells/mm3) 150 100 Increase in mean CD4 cells/mm3: 268 ATV/r vs 290 LPV/r Estimated difference: -21.2 (95% CI: -43.3, 0.9) 50 0 BL 4 12 24 36 48 60 72 84 96 Time (weeks) Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

  31. Adverse events: Summary • 3 discontinuations on ATV/r due to jaundice/hyperbilirubinaemia • None between Weeks 48 & 96 • 7 subjects discontinued due to diarrhoea (all on LPV/r) • 2 between Weeks 48 and 96 • 39 (9%) of subjects on ATV/r versus 96 (22%) on LPV/r initiated antidiarrhoeal medications • Renal all grade AEs: 4% in both arms • 1 discontinuation due to renal AE in each arm aThrough 96 weeksbExcluding laboratory abnormalitiesreported as AEs Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

  32. Grade 2−4 diarrhoea through 96 weeks Patients (%) Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

  33. Fasting lipids: NCEP and ratios 2% of subjects on ATV/r versus 9% of subjects on LPV/r initiated lipid-lowering drugs on study Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

  34. Findings from CASTLE sub-analyses Boosted Reyataz was efficacious & generally well-tolerated irrespective of race Mc Grath et al, IAC 2008 August 2008, Poster # TUPE0058 Boosted Reyataz was efficacious & generally well-tolerated irrespective of gender Absalon J, et al. XVII IAC, Mexico City, 3−8 August 2008, Poster # TUPE0062 Boosted Reyataz was efficacious & generally well-tolerated irrespective of HBV/HCV status Perez-Elias MJ, et al. IAS 2005 Poster TuPe1.1C25 Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136 Boosted Reyataz resulted in improvements in patients’ quality of life Su et al, IAC 2008 August 2008, POSTER # TUPE0060 Boosted Reyataz was an effective and well-tolerated in advanced HIV-infected treatment-naïve patients Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008. Poster H-1250d

  35. Boosted Reyataz was efficacious & generally well-tolerated irrespective of race Mc Grath et al, IAC 2008

  36. Efficacy ATV/r QD demonstrated noninferior antiviral efficacy to LPV/r BID (both +TDF/FTC) in ARV-naïve patients Virological response rates were consistently high in men and women Both regimens were associated with robust increases in CD4 cell count regardless of gender Boosted Reyataz was efficacious & generally well-tolerated irrespective of gender Absalon J, et al. XVII IAC, Mexico City, 3−8 August 2008, Poster # TUPE0062

  37. Boosted Reyataz was efficacious & generally well-tolerated irrespective of HBV/HCV status CASTLE: ATV/r Liver Function and Bilirubin Bilirubin and ALT levels Coinfected Not coinfected 2.4 Median total bilirubin ALT >200 UI/mL or ALT>3.5 x baseline abnormal levels 5 1.9 md/dL 2.0 1.8 mg/dL 4 1.6 *†p=NS Subjects withmoderate-to-severe ALT elevation (%) 3 1.2 Total bilirubin (mg/dL) 1.90 %* 2 0.8 0.6 mg/dL 1.10 %* 0.4 mg/dL 1 0.4 0%† 0%† n=176 n=116 n=107 n=75 n=176 n=116 n=107 n=75 0 0 Baseline Month 6 Baseline Month 6 n=subjects with measurements Perez-Elias MJ, et al. IAS 2005 Poster TuPe1.1C25

  38. Virological and immunological responses at Week 48 were similar in hepatitis uninfected and coinfected patients in the ATV/r and LPV/r arms Responses were comparable in coinfected patients treated with ATV/r or LPV/r CASTLE: Efficacy by Hepatitis B/C coinfection Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136

  39. Grade 2–4 treatment-related AEs through Week 48: As-treated patients, n (%) CASTLE: Adverse Events by Hepatitis B/C Coinfection • Hepatitis uninfected and coinfected patients treated with ATV/r had a more favourable lipid profile compared with LPV/r-treated patients • Lipid profiles were similar in hepatitis uninfected and coinfected patients in both the ATV/r and LPV/r treatment arms Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136

  40. Summary: Role of ATV in Coinfected Patients • ATV hyperbilirubinaemia is common in clinical practice, particularly when ATV is used with RTV (boosting) and among patients with altered bilirubin levels at baseline1 • Pre-existing Gilbert’s syndrome predisposes patients to higher bilirubin levels with ATV2 • Severe hyperbilirubinaemia occurs in only a minority of patients1 • Neither HBV nor HCV co-infection seemed to increase the risk of hyperbilirubinaemia and hyperbilirubinaemia did not seem to increase risk of flares in liver transaminases1 • Results confirm that hyperbilirubinaemia is manageable in clinical practice and an ‘innocent’ phenomenon in most cases as far as liver tolerability is concerned1 • Patients with hepatic impairment: ATV/r should be used with caution in patients with mild hepatic impairment. ATV should not be used in patients with moderate to severe hepatic impairment3 1. Lapadula G, et al. EACS 2007, Poster 9.6/03; 2. Lankisch TO, et al. Hepatology 2006;44:1324–1332,3. http://www.emea.europa.eu/humandocs/Humans/EPAR/reyataz/reyataz.htm

  41. 2003–2005 • 42 countries, 176 sites,33 008 patients • Low CD4 count at start of treatment suggests that many patients have advanced disease Boosted Reyataz was an effective and well-tolerated in advanced HIV-infected treatment-naïve patients Egger M, 14th CROI, 2007, Abstract 62. ART Cohort Collaboration http://www.art-cohort-collaboration.org

  42. CASTLE: 96-Week Efficacy According to Baseline Viral Load ITT-confirmed virological response (NC=F) at Week 96 by qualifying HIV viral load 100 90 Responders (%) <50 c/mL 75 74 80 70 66 70 60 ATV/r 50 LPV/r 40 30 20 10 n=218 n=223 n=217 n=225 0 HIV RNA <100 000 copies/mL HIV RNA ≥100 000 copies/mL Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008, Poster H-1250d

  43. ≥200 cells/mm3 100–<200 cells/mm3 50–<100 cells/mm3 <50 cells/mm3 ATV/r LPV/r n= 222 106 45 58 228 134 29 48 CASTLE: 96-Week Efficacy by Baseline CD4 Cell Count p=ns p=ns 100 90 78 76 80 Responders (%) <50 c/mL 71 71 70 69 69 70 58 60 50 40 30 20 10 0 Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008. Poster H-1250d

  44. Treatment Experienced patients • Evolving goal of antiretroviral therapy for all HIV-positive patients regardless of the extent of previous treatment experience • Achieve and maintain an undetectable VL1,2 • Achievable for majority of patients with currently available agents • Patients with therapy options • Consider changing regimen sooner rather than later • Change ≥ 2 drugs in the regimen to active agents • The use of an agent from a new drug class is likely to be effective 1. Hammer SM, et al. JAMA. 2006;296:827-843. 2. BHIVA website: http://www.bhiva.org/files/file1030835.pdf (Pre-press version of 2008 BHIVA Guidelines for HIV Anti-Retroviral Treatment; on page 11-Accessed on 04 September 2008)

  45. Evolution of Once-daily ATRIPLA® Dosing Efavirenz (Sustiva®) ATRIPLA® Emtricitabine(Emtriva®) Truvada® Tenofovir DF (Viread®) Sustiva SmPC, September 2008 Viread SmPC, September 2008 Emtriva SmPC, September 2008 Truvada SmPC, December 2008 ATRIPLA SmPC, December 2008 The pills shown are not the actual size

  46. The ATRIPLA® Indication in Europe • ATRIPLA® is a fixed‑dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate • It is indicated for the treatment of HIV‑1 infection in adults with virological suppression to HIV‑1 RNA levels of <50 copies/mL on their current combination antiretroviral therapy for >3 months • Patients must not have experienced virological failure on any prior ART and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in ATRIPLA® before initiation of their first ART regimen • The demonstration of the benefit of ATRIPLA® is primarily based on 48‑week data from a clinical study in which patients with stable virological suppression on a combination ART changed to ATRIPLA® • No data are currently available from clinical studies with ATRIPLA® in treatment‑naïve or heavily pretreated patients ATRIPLA SmPC

  47. Efficacy of ATRIPLA®Study AI266073 Design Phase IV, multicentre (55 US sites), open-label study (N = 300) • Stable ARV Regimen • (PI or NNRTI + 2 NRTIs) for≥ 3 months • VL <200 copies/mL • No History of Virologic Failure EFV/FTC/TDF Once Daily Switch Randomisation 2:1 Stratify by PI or NNRTI Continue Stayed on Baseline Regimen* Week 24 0 48 Primary Endpoint: assess non-inferiority of EFV/FTC/TDF vs. SBR in terms of maintenance of HIV-1 RNA <200 copies/mL through Week 48 by TLOVR**analyses **Time to loss of Virologic Response Algorithm *SBR: stayed on baseline regimen Adapted from Young B, et al., Glasgow 2008; Poster #P061 ATRIPLA® is not indicated for treatment-naïve patients in the EU

  48. ARV Baseline Regimen PIs (53%) NNRTIs (47%) FPV (3%) IDV (2%) ATV (2%) NVP 11% ATV/r 15% NFV (7%) SQV/r (2%) LPV/r 13% FPV/r (9%) EFV 36% a. Most frequent NNRTI regimens were: EFV+AZT/3TC (16%), EFV+ABC/3TC (6%), EFV+TDF+3TC (5%) b. Most frequent PI regimens were: ATV/r + FTC/TDF (13%), LPV/r + FTC/TDF (6%), FPV/r+ABC/3TC (4%) Adapted from DeJesus EACS 2007, Madrid, Spain ATRIPLA® is not indicated for treatment-naïve patients in the EU

  49. Primary Endpoint Analysis: Percentage of Patients with HIV-1 RNA <200 copies/mL Through 48 Weeks (TLOVR) Treatment Difference (EFV/FTC/TDF – SBR) and 95% CI:1.1% (–6.7%, 8.8%) 89% 88% Percent with Virologic Response • The primary endpoint of non-inferiority of EFV/FTC/TDF to SBR was demonstrated ATRIPLA® is not indicated for treatment-naïve patients in the EU Adapted from Young B, et al., Glasgow 2008; Poster #P061

  50. Efficacy Analysis by Prior Treatment Stratum: Week 48 a. Time to loss of virologic response algorithm (NC=F) b. Missing data (for any reason) was excluded in this analysis P=NS for all comparisons in both strata ATRIPLA® is not indicated for treatment-naïve patients in the EU Adapted from Young B, et al., Glasgow 2008; Poster #P061