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17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008)

17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27, 2008. 17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27, 2008. Adapted from the Presentation Nucleoside Analogue Spring 2008 Update on

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17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008)

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  1. 17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27, 2008 17th Annual Canadian Conference on HIV/AIDS Research (CAHR 2008) Montreal, Quebec / April 24-27, 2008 Adapted from the Presentation Nucleoside Analogue Spring 2008 Update on Friday, April 25, 2008

  2. Is the Risk of MI Increased With HAART? 8 7 6 5 4 Incidence (events per 1,000 person-yr) 3 2 1 0 None <1 1–2 2–3 3–4 >4 Exposure to combination antiretroviral therapy (yr) No of events 3 19 14 22 31 47 No of person-yr 5714 4140 4801 5847 7220 8477 D.A.D. N Engl J Med 2003.

  3. 6 5 4 Relative Risk (%) 3 2 1 0 Total cholesterol (per 1-mmol/l increase) Exposure to combination ART (per additional yr) Age (per additional 5 yr) Triglycerides(per doubling) Hypertension Current or former smoker Diabetes Male sex 25 20 15 Relative Risk (%) 10 5 0 Total cholesterol (per 1-mmol/l increase) Exposure to combination ART (per additional yr) Age (per additional 5 yr) Triglycerides(per doubling) Hypertension Current or former smoker Diabetes Male sex Prior CV disease Is the Risk of MI Increased With HAART? D.A.D. N Engl J Med 2003.

  4. Is the Risk of MI Increased With PIs/NNRTIs? D.A.D. N Engl J Med 2007.

  5. Endpoints of the SMART Study, Including Cardiovascular Disease SMART N Engl J Med 2006 .

  6. D:A:D Relative Rates of MI for ABC and ddI Recent use = still using or stopped within last 6 months Past use = last used more than 6 months prior Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008.

  7. D:A:D Rates of MI for Patients with Recent vs. No Recent ABC/ddI Use • Unadjusted Rates of MI per 1000 patient-years (overall incidence/1000 PY: 3.3 [95% CI: 3.0,3.6]): P>0.02 for interaction among groups P=0.04 for interaction in Mod/High risk and ABC Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008.

  8. VA Event Rates in the 1993- 2003 VA Cohort Bozzette S, et al. J Acquir Immune Defic Syndr 2007.

  9. Median Lipid Changes from Baseline to Week 48 mg/dL

  10. Little change in glucose tolerance or insulin sensitivity was seen after 96 weeks of initial ART with ABC + Combivir, COM/NFV, or d4T/3TC/NFV (ESS40002) JE Hernandez, V Williams, P Wannamaker & K Pappa, GSK R&D, RTP, NC, USA CAHR Meeting, Montreal, April 2008 Poster # P-171

  11. Median Change in Fasting Glucose (mg/dL) from BL By Regimen Assignment (N=245) ESS40002 mg/dL * n= 78,86,8166,72,6864,71,7059,73,6556,62,5755,59,5545,49,4843,44,44 Study week * P>0.8 among groups (LSMean, ANCOVA)

  12. Median Change in Insulin (uIU/mL) from BL By Regimen Assignment (N=245) ESS40002 uIU/mL * n= 78,86,8161,70,6850,56,5642,47,5041,44,45 Study week * P>0.4 among groups (LS Mean, ANCOVA)

  13. Median Change in HOMA-IR from BL By Regimen Assignment (N=237) ESS40002 * n= 76,83,7858,69,6350,56,5342,47,4741,42,44 Study week * P>0.5 among groups (LS Mean, ANCOVA)

  14. Markers of impaired thrombolysis and inflammation in subjects treated with ABC+APV-based regimens for 8 weeks (N=14) *P-value by Wilcoxon rank-sum test BL vs wk 8 + One outlier with marked increase in CRP and pneumonia; if removed: BL: 3.86 ± 3.73 ng/mL; wk 8: 2.90 ± 2.72 (P=0.045). All values means ± SE Young DB, Hernandez JE, et al. Cardiovasc Toxicol 2004;4:179-86 and CAHR Meeting 2008.

  15. BL Characteristics in Naïve Subjects(ABC-containing CART, n=5700) Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.

  16. BL Characteristics in naïve subjects (non-ABC-containing CART, n=2406) Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.

  17. Proportion of Subjects on ART +/- ABC Reporting MI or Acute MI among 14682 Subjects Percent Subjects 0.139% 0.129% 0.125% Non-ABC 7/5043 Total 19/14682 ABC 12/9639 n/N= ART Regimen Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.

  18. Relative Rate of Events Per 1000 Person Years of Exposure to ABC Compared with No Exposure to ABC Cutrell A, Hernandez J, Brothers C et al, Submitted and Lancet 2008.

  19. Incidence of Serious CV Events D:A:D Study, VA Study & GSK Data Repository Sabin C, et al. 15th CROI 2008 Poster 957c and Lancet 2008. Bozzette S, et al. J Acquir Immune Defic Syndr 2007;0:1-4. Cutrell A, et al. Submitted and Lancet 2008.

  20. Rates of MI, stratified by predicted 10 year risk of CAD & recent use of ddI or ABC D.A.D. Study Group. The Lancet. Published online April 2, 2008 DOI:10.1016/S0140-6736(08)60423-7.

  21. ACTG5202 Study Design Phase IV, randomized (1:1:1:1), double blind, 96-week study conducted at US ACTG sites Kivexa QD + Truvada placebo + Efavirenz QD (n=~450) or Atazanavir/r QD (n=~450) ART-naïve subjects, n=1858 Truvada QD + Kivexa placebo + Efavirenz QD (n=~450) or Atazanavir/r QD (n=~450) Entry criteria: No CD4 cell count restrictions HIV-1 RNA >1000 c/mL Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL

  22. Clinical Trials with Third Drugs (N>100) ABC+3TC (BID, QD, or Kivexa) NNRTI PI NRTI EFV CNA30021CNA30024 CLASS ABCDE ESS30008 ESS30009 CAL30001 ACTG5202 ASSERT 908 NEAT SOLO CLASS ESS30008 KLEAN LPV/r KLEAN HEAT NFV NEAT SOLO ESS30008 ATVARIES SHARE ACTG5202 MERIT d4T CLASS ZDV CNA3005 CNA3014 NZTA4006 ACTG5095 etc. Completed trials Trials in progress Trials with same arms as in ACTG5202

  23. Subject Disposition by Week 48 HEAT There were 7 deaths during the study, 1 (<1%) in the Kivexa arm and 6 (2%) in the Truvada arm; none were attributable to study drug. Smith K, et al. 15th CROI 2008: Poster 774.

  24. HEAT HIV-1 RNA <50 c/mL at Week 48 % Point difference 12 -12 Smith K, et al. 15th CROI 2008: Poster 774.

  25. ABC/3TC 100 TDF/FTC 80 71 69 68 67 65 63 60 Proportion of Subjects 40 20 0 <100,000 c/mL =>100,000 c/mL Total HIV-1 RNA <50 c/mL at Week 48 by Baseline HIV-1 RNA (ITT-E, M=F) n = 188 205 155 140 343 345

  26. Median Change from Baseline in CD4 Cell Count (ITT-E, Obs) HEAT 201 173 Median CD4, 214429 cells/mm3 193370 n (obs) KIVEXA = 343 317 310 294 294 285 275 272 Truvada = 345 318 306 297 287 277 270 267 Smith K, et al. 15th CROI 2008: Poster 774.

  27. CNA30024 Study Design Phase III, randomized, double-blind, multicenter1 study ABC 300mg BID + ZDV 0mg BID + 3TC BID + EFV QDITT-Exposed = 324 N = 654 ART naïve adults2 ZDV 300mg BID + ABC 0mg BID + 3TC BID + EFV QDITT-Exposed = 325 48 wk • Screening HIV-1 >400 copies/mL, CD4+ >50 cells/mm3 • Enrollment was stratified by screening HIV-1 strata (100K and >100K). 1. 78 sites: 48 in US, 17 in Europe, 13 in Latin America2. 5 subjects (3-ABC, 2-ZDV) randomized never took drug (ITT-Exposed=649)

  28. CNA30024 Response 50 c/mL through Wk 48 ITT Exposed* 95% CI: (-6.3%, -7.9%) ABC: 70%ZDV: 69% * Using TLOVR Algorithm

  29. CNA30024 Response 50 c/mL at Wk 48ITT Exposed* * Using TLOVR Algorithm

  30. CNA30024

  31. CNA30024

  32. ESS40013 Time to vRNA <50 c/mL by BL vRNA Trizivir + EFV

  33. CNA30024

  34. ATV 300mg QD RTV 100mg QD ATV 300mg QD RTV 100mg QD ART-naïve subjects, N=500 ABC/3TC FDC (600mg/300mg) QD ABC/3TC FDC (600mg/300mg) QD ARIES Study Design Phase IIIb, randomized (1:1), open-label, non-inferiority, international, 84-week study ATV 400mg QD ABC/3TC FDC (600mg/300mg) QD Entry criteria: HIV-1 RNA 1000 c/mL No CD4 cell count restrictions Appropriate genotype HLA-B*5701 negative Stratified at randomization by baseline HIV-1 RNA < or  100,000 c/mL Day 1 Week 84 Week 36Randomization Young B, et al. CAHR 2008, Poster # P-159.

  35. ATV 300mg QD RTV 100mg QD ATV 300mg QD RTV 100mg QD ART-naïve subjects N=516 ABC/3TC FDC (600mg/300mg) QD ABC/3TC FDC (600mg/300mg) QD ARIES Preliminary Data Enrollment between 28Mar07 and 07Sep07 ATV 400mg QD ABC/3TC FDC (600mg/300mg) QD 4 cases of suspected HSR, all SPT neg. Entry criteria: HIV-1 RNA 1000 c/mL No CD4 cell count restrictions Appropriate genotype HLA-B*5701 negative Stratified at randomization by baseline HIV-1 RNA < or  100,000 c/mL Day 1 Week 84 Week 36 Week 24 Young B, et al. CAHR 2008, Poster # P-159.

  36. HIV-1 RNA <400 c/mL at Week 48 According to BL Viral Load (ITT-E, TLOVR) <100,000 c/mL 100,000 c/mL M=F M/S=F Percentage of Patients EPZ+ATV/r EPZ+LPV/r EPZ+FPV/r ABC+3TC ABC+3TC BID ABC+3TC QD ABC+3TC BID +EFV +EFV +EFV +EFV n = 49 62 209 235 197 237 123 46 217 167 217 169 198 126 Data on file, GlaxoSmithKline.

  37. HIV-1 RNA <50 c/mL at Week 48 According toBL Viral Load (ITT-E, TLOVR) <100,000 c/mL 100,000 c/mL M=F M/S=F Percentage of Patients EPZ+ATV/r EPZ+LPV/r EPZ+FPV/r ABC+3TC ABC+3TC BID ABC+3TC QD ABC+3TC BID +EFV +EFV +EFV +EFV n = 49 62 209 235 197 237 123 46 217 167 217 169 198 126 Data on file, GlaxoSmithKline.

  38. Lack of Virologic failure (ACTG Definition) in GSK Studies by Study Week (% Survival) All Subjects

  39. Lack of Virologic failure (ACTG Definition) in GSK Studies by Study Week (% Survival) > 100000 VL

  40. KIVEXA is Preferred/Recommended on the DHHS & IAS-USA Guidelines Please see guidelines for full information on considerations for choice, major toxic effects, cautions, and resistance considerations http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf: Jan 2008. Hammer S, et al. JAMA 2006;296:827-43.

  41. ABC & KIVEXA, Next Steps… • Manuscript of GSK MI analysis submitted for publication • Groups with large observational cohorts to repeat DAD analysis (VA, Kaiser) • Further analysis of markers of inflammation, impaired thrombolysis and endothelial dysfunction ongoing (HEAT) • DSMB review of ACTG 5202 to be repeated in June • Additional analysis of ACTG5202 ongoing

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