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ESS100327: ACTION Study

Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine vs. Atazanavir & Lamivudine/Zidovudine in Antiretroviral Naïve Subjects.

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ESS100327: ACTION Study

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  1. Safety, Tolerability & Efficacy of Abacavir/Lamivudine/Zidovudine vs. Atazanavir & Lamivudine/Zidovudine in Antiretroviral Naïve Subjects Kumar PN, Salvato P, DeJesus E, LaMarca A, Patel P, Sutherland-Phillips D, McClernon D, Florance A, Sall J, Wannamaker P, and Shaefer M for the ACTION study group ESS100327: ACTION Study No. H-1058

  2. Acknowledgements Investigators: C Aneziokoro N Bellos J Boghossian J Brand G Coodley P Cook E DeJesus R Dretler F Felizarta T File F Garcia E Godofsky S Green P Greiger-Zanlungo J Hernandez M Hill M Hoffman-Terry J Horvath A Huang R Jones Study Coordinators Patients GlaxoSmithKline J Royall J Weidner K Frusciante D Sutherland-Phillips J Sall P Wannamaker D McClernon A Florance M Moore M Watson B Matthews C Brothers S Chriscoe M Shaefer P Patel P Kumar P Lackey A LaMarca H Lampiris F Lutz A Mills J Morales-Reyes R Nahass D Parks R Peskind D Pitrak R Poblete J Ramos-Jimenez A Rodriguez J Rodriguez P Salvato J Schrank R Schwartz R Scott CB Small D Sweet E Tedaldi J Torres M Tribble W Weinberg R Wilcox D Wright

  3. Background • Abacavir/Lamivudine/Zidovudine (ABC/3TC/ZDV, Trizivir) & Atazanavir (ATV, Reyataz) are alternative options in ARV-naïve patients • ABC/3TC/ZDV should be reserved for those who cannot receive an NNRTI or PI-based regimen1 • ATV without ritonavir is an alternative to the preferred PI-based regimen, Lopinavir/ritonavir • Both regimens are used in clinical practice in select patient populations as they are well-tolerated and convenient therapies. 1DHHS Guidelines, May 2006.

  4. Study Design Phase IV, randomized (1:1), multicenter, open-label, 48 week study Conducted at 46 sites in US and Mexico ABC/3TC/ZDV 1 tablet twice daily N=139 ARV Naïve Subjects Screen HIV-1 RNA <200,000 c/mL CD4+ Count ≥ 100 cells/mm3 Stratified by HIV-1 RNA < or ≥ 100,000 c/mL Atazanavir 400mg daily + 3TC/ZDV 1 tablet twice daily N=140 Non-Inferiority established if the lower limit of the two-sided 95% CI was ≥ -0.12 Switch allowed for ABC HSR (TDF) or jaundice or scleral icterus (FPV)

  5. Study Endpoints Primary Endpoint • Proportion of subjects with HIV-1 RNA <50 c/mL at Week 48 • Subjects must not have met any definition of virologic failure • ITT-E, Missing/Switch = Failure Analysis Key Secondary Endpoints • Efficacy • Proportion of subjects with HIV-1 RNA <50 c/mL, switch ≠ failure • Change in HIV-1 RNA and CD4 cell counts from BL • Treatment-emergent genotype mutations • Safety • Drug-related adverse events (Grade 2-4) and serious adverse events • Changes in lipid parameters, insulin sensitivity and resistance

  6. Virologic Failure Criteria Virologic failure was defined as any of the following: • Failure to have ≥ 1 log HIV-1 RNA drop by Week 12 • Failure to have HIV-1 RNA <400 by Week 24 • Confirmed HIV-1 RNA <50 then ≥ 400 confirmed prior to Week 24 • Confirmed HIV-1 RNA ≥ 400 after Week 24 • HIV-1 RNA ≥ 400 at Week 48 without confirmation *Virologic responders could not have met any virologic failure criteria

  7. 1% 4% 6% 7% 0 <1% Baseline Demographics ABC/3TC/ZDV ATV+3TC/ZDV N=139 N=140 Median age, years 38 36 22% 20% Female, n (%) Race, n (%) White Black Hispanic 47% 41% 32% 35% 19% 21% Hepatitis B positive Hepatitis C positive Hepatitis B & C co-infection

  8. 0% 5% 24% 26% 47% 44% Baseline Characteristics ABC/3TC/ZDV ATV+3TC/ZDV N=139 N=140 CDC Class C (%) 4% 4% 4.48 4.64 Median HIV-1 RNA log10 c/mL 83% 82% HIV-1 RNA <100,000 c/mL (%) Median CD4+ (cells/mm3) 274 262 <100 100 - <200 200 - <350 ≥ 350 28% 25%

  9. Subject Disposition ABC/3TC/ZDV ATV+3TC/ZDV N=139 N=140 Completed 48 Weeks 103 (74%) 98 (70%) Premature Withdrawal 36 (26%) 41 (29%) Reasons for Discontinuation Virologic Failure* Lost to Follow-Up Adverse Event Other Investigator Decision Subject Decision Protocol Violation 16 (12%)16 (11%) 12 ( 9%) 14 (10%) 6 ( 4%) 11 ( 8%) 6 ( 4%) 0 6 ( 4%) 0 3 ( 2%) 1 (<1%) 0 2 ( 1%) *As reported on Study Conclusion Page. Note: subjects with VL<1265 c/mL were allowed to stay on study.

  10. Virologic RespondersHIV-1 RNA <50 c/mL at Week 48 Switch = Failure Analysis 95%CI (-7.5, 16.4) 95% CI (-6.7, 9.4) 95%CI (-46.2, 15.8) 95% CI (-5.6, 19.5) 95% CI (-49.2, 27.4) 95% CI (-5.9, 10.4) Proportion of Subjects Overall Observed S=F Overall ITT-E M/S=F HIV-1 RNA <100,000 c/mL HIV-1 RNA ≥100,000 c/mL HIV-1 RNA <100,000 c/mL HIV-1 RNA ≥100,000 c/mL ABC/3TC/ZDV n = 138 115 23 112 94 18 ATV+3TC/ZDV n = 140 115 25 112 89 23

  11. Virologic RespondersHIV-1 RNA <50 c/mL at Week 48 Switch ≠ Failure 95%CI (-7.4, 13.9) 95% CI (-7.8, 7) 95% CI (-50.1, 11) 95% CI (-5.3, 19.2) 95%CI(-52.9, 3.1) 95% CI (-6.4, 9.5) Proportion of Subjects Overall ObservedS≠F Overall ITT-E HIV-1 RNA <100,000 c/mL HIV-1 RNA ≥100,000 c/mL HIV-1 RNA <100,000 c/mL HIV-1 RNA ≥100,000 c/mL S≠F ABC/3TC/ZDV n = 138 115 23 111 93 18 n = 140 115 25 110 87 23 ATV+3TC/ZDV

  12. Median Change from Baseline in CD4+ Cell Count + 147 Median 274 CD4+ 262 434 419 ABC/3TC/ZDV n= 138 128 122 117 110 104 101 ATV+3TC/ZDV n=140 125 123 118 106 98 96

  13. Virologic Failure Outcomes ABC/3TC/ZDV ATV+3TC/ZDV N=138 N=140 Virologic Failures, n (%)18 (13%) 17 (12%) 10 12 HIV-1 RNA <100,000 c/mL HIV-1 RNA ≥ 100,000 c/mL 8 5 Reasons for Virologic Failure*, n 1. Fail to have ≥1 log RNA drop by Week 12 3 3 3 4 2. Fail to have VL <400 c/mL by Week 24 2 2 3. Two VL <50 then confirmed ≥400 c/mL by Wk 24 6 11 4. Two ≥400 c/mL after Week 24 7 3 • VL ≥400 c/mL after Week 48 without • confirmation * Subjects could have met multiple virologic failure criteria

  14. Treatment Emergent Resistance ABC/3TC/ZDV ATV+3TC/ZDV N=138 N=140 18 (13%) 17 (12%) Protocol-Defined Virologic Failure, n (%) 17 16 Paired BL and Failure GT/ PT Results 1011 Treatment-Emergent Mutations at VF NRTI* (M184V) (L210W, D67N, L74V, F77L) 9 ( 90%) 9 (82%) 1 ( 10%) 0 PI Major Minor 0 0 7 (70%) 6 (55%) (L10I, I13V, I13L/V, G16E,K20M, L24I, I31L/V, L33V, E35G, I54I/L, I62I/V, L63L/P, A71A/V, V77I/V, I85I/V, I93I, I93L) 1 (10%) 1 ( 9%) NNRTI(K103N)

  15. Treatment-Related Grade 2-4 Adverse Events in >2% of subjects N=138 N=140 ABC/3TC/ZDV ATV+3TC/ZDV % (% Grade 3/4) Hyperbilirubinemia 0 21% (16%) Nausea 11% (<1%) 4% (0) Neutropenia 5% (4%) 6% (4%) Fatigue 5% (0) 2% (0) Headache 4% (<1%) 4% (0) Suspected Abacavir HSR* 5% (0) 0 Anemia <1% (<1%) 3% (3%) Scleral Icterus 0 4% (3%) * Includes 1 Suspected ABC HSR reported as grade 1

  16. Percent Change in Fasting Lipids from Baseline to Week 48 % Change in Fasting Lipids

  17. Summary • In an ITT(E) M/S=F analysis, 62% vs. 59% of subjects achieved HIV-1 RNA <50 copies/ml in the overall population (ABC/3TC/ZDV vs. ATV+3TC/ZDV, respectively) • Protocol-defined virologic failure occurred in 13% of subjects and were balanced between arms • No treatment-emergent primary PI mutations in the ATV+3TC/ZDV arm were observed through 48 weeks and the majority of NRTI mutations were attributed to M184V

  18. Conclusion • In this study, ABC/3TC/ZDV and ATV+3TC/ZDV were well-tolerated and had comparable efficacy • In select patients naïve to therapy with HIV-1 RNA <100,000 c/mL, ABC/3TC/ZDV remains a viable option as an initial regimen

  19. Back-Up Slides

  20. Efficacy of ABC/3TC/ZDV Compared to Unboosted PIs and Efavirenz HIV-1 RNA <50 c/mL over 48 Weeks EFV+COM EFV+TZV Comparator: ABC/3TC/ZDV ABC/3TC/ZDV + IDV+COM PBOS IDV+ COM NFV+ COM IDV+COM + TZV PBO 83% 61% 60% 55% 55% 50% 46% Proportion of Subjects 40%

  21. Efficacy Outcomes TZV ATV+COM N=138 N=140 Week 48 n (%) HIV-1 RNA<50 c/mL, ITT-E, M/S=F All Responders85 (62%) 83 (59%) Response by Strata, n/N (%) 76 / 115 (66%) 68 / 115 (59%) HIV-1 RNA < 100,000 c/mL 9 / 23 (39%) 15 / 25 (60%) HIV-1 RNA ≥ 100,000 c/mL HIV-1 RNA <400 c/mL, ITT-E, M=F All Responders 93 (67%) 95 (68%) * Protocol-defined virologic failure was based on multiple criteria

  22. Adverse Events N=138 N=140 ABC/3TC/ZDV ATV+3TC/ZDV Serious Adverse Events 14 (10%) 17 (12%) Treatment-Related SAEs 7 ( 5%) 3 ( 2%) ABC HSR 7 ( 5%) 0 Anemia 0 3 ( 2%) Abdominal Pain 0 1 (<1%) Study Drug Discontinuation (G2-4 AE) 12 ( 9%) 13 ( 9%) Drug Hypersensitivity* 7 ( 5%) 0 Scleral Icterus 0 4 ( 3%) Hyperbilirubinemia 0 4 ( 3%) Jaundice 0 2 ( 1%) Anemia 1 (<1%) 2 ( 1%) Nausea 2 (1%) 0 Abdominal Pain 2 ( 1%) 0 Drug Eruption 0 2 ( 1%) *Includes 1 subject with Grade 1 HSR

  23. HIV-1 RNA <50 c/mL at Week 48 Subjects without protocol-defined virologic failureITT-E, CD4 Subgroup Analysis Percent of Subjects Overall Observed Overall M=F CD4+ <200 cells/mm3 CD4+ ≥ 200cells/mm3 CD4+ <200 cells/mm3 CD4+ ≥ 200 cells/mm3 TZV n = 138 34 104 101 22 79 ATV+COM n = 140 43 97 99 33 66

  24. Median Fasting Lipids (mg/dL) at Baseline and Week 48 Cholesterol Triglycerides NCEP III NCEP III 162 176 160 171 113 126 117 110 Baseline n= 131 137 131 137 Week 48 n= 93 93 93 93 NCEP ATP III Guidelines consider TC <200 mg/dL and TG <150 mg/dL as desirable

  25. Median Fasting Lipids (mg/dL) at Baseline and Week 48 LDL HDL NCEP III 97 102 98 99 NCEP III 36.5 44 33 44 Baseline n= 127 133 130 135 Week 48 n= 89 92 93 93 NCEP ATP III Guidelines consider LDL <100 mg/dL and HDL > 40 mg/dL as desirable

  26. The ACTION Study • Phase IV, randomized, multicenter, open-label study evaluating the safety and efficacy of ABC/3TC/ZDV vs. ATV + 3TC/ZDV in ART-naïve subjects over 48 weeks • 279 subjects were enrolled from 46 sites in the U.S. & Mexico between May 2004 – March 2005. • 95% from U.S. sites. • Subjects experiencing toxicity from randomized treatment were permitted to switch medications • Suspected ABC HSR reaction  3TC/ZDV + Tenofovir • Atazanavir-related jaundice or scleral icterus  Fosamprenavir + 3TC/ZDV • Virologic failure was based on multiple criteria

  27. Study Discontinuation Due to Grade 2-4 Adverse Events N=138 N=140 TZV ATV+COM Study Discontinuation from AEs, n (%) 6 (4%) 8 (6%) Rash 0 3 (2%) Anemia 1 (<1%) 2 (1%) Abdominal pain 2 (1%) 0 Nausea 2 (1%) 0 Dyspepsia 0 1 (<1%) Enteritis 0 1 (<1%) Vomiting 1 (<1%) 0 Fatigue 1 (<1%) 0 Headache 1 (<1%) 0 Hyperbilirubinemia 0 1 (<1%) Jaundice 0 1 (<1%)

  28. Toxicity Switches N=138 N=140 TZV ATV+COM 7 (5%) 9 (6%) Toxicity Switches Abacavir – Related Suspected Abacavir HSR 7 (5%) 0 Atazanavir - Related Jaundice Scleral Icterus Hyperbilirubinemia** 0 2 (1%) 0 4 (3%) 0 3 (2%) Grade 3 (>2.5-5x ULN) 3 **Although hyperbilirubinemia was not a protocol allowable toxicity switch reason, 3 subjects switched off ATV+COM due to ATV-related hyperbilirubinemia

  29. HIV-1 RNA <400 c/mL at Week 48 Proportion of Subjects Week 24 Week 24 Week 48 Week 48 M=F Obs

  30. 84 86 Virologic Response HIV-1 RNA <50 c/mL 62 61 ITT-E, M/S=F ITT-E, S=F n (obs) TZV = 138 130 122 117 111 104 101 ATV+CO M = 140 128 123 118 109 100 99

  31. 88 91 Virologic Response HIV-1 RNA <50 c/mL 65 64 ITT-E, M=F,S≠F ITT-E, S≠F n (obs) TZV = 138 130 122 117 111 104 101 ATV+CO M = 140 128 123 118 109 100 99

  32. 88 91 Virologic Response HIV-1 RNA <400 c/mL 65 64 ITT-E, M/S=F ITT-E, S=F n (obs) TZV = 138 130 122 117 111 104 101 ATV+CO M = 140 128 123 118 109 100 99

  33. 92 96 Virologic Response HIV-1 RNA <400 c/mL 67 68 ITT-E, M=F,S≠F ITT-E, S≠F n (obs) TZV = 138 130 122 117 111 104 101 ATV+CO M = 140 128 123 118 109 100 99

  34. Time to Loss of Virologic Response HIV-1 RNA<50 c/mL (TLOVR)

  35. Time to Loss of Virologic Response HIV-1 RNA<50 c/mL (TLOVR)M/S=F

  36. Median Changes in Metabolic Parameters at Baseline & Week 48 HOMA-IR QUICK1 3 2.9 2.4 2.2 0.59 0.54 0.58 0.54 Baseline n= 110 112 110 112 Week 48 n= 83 87 83 87

  37. Subject 855: TZV RT: L74V, F77L, V118I PRO: D30N, L63P, N88D ABC FC= 1.19 ATV FC =4.79 3TC FC= 1.33 ZDVFC= 0.85 WD RT: L74V, F77L, V118I, L210W PRO: D30N, M36I, L63P, N88D ABC FC=5.90 ATV FC = 11 3TC FC= 8.59 ZDV FC = 115

  38. Subject 573: TZV RT: WT PRO: L63P ABC FC= 0.82 ATV FC = 0.72 3TC FC= 1.22 ZDV FC= 0.59 RT: WT PRO: L63P ABC FC= 0.95 ATV FC = 0.58 3TC FC= 1.27 ZDV FC=0.65

  39. Subject 668: TZV RT: WT PRO: L63P ABC FC= 0.72 ATV FC = 0.92 3TC FC=1.03 ZDV FC=1.10 RT: M184V PRO: L63P ABC FC= 3.00 ATV FC = 0.80 3TC FC= 104 ZDV FC= 0.48

  40. Subject 852: ATV/COM RT: WT PRO: L63P ABC FC= 0.76 ATV F = 0.83 3TC FC=1.05 ZDV FC= 0.63 RT: K103N PRO: L63P ABC FC= 0.84 ATV FC =1.05 3TC FC= 1.21 ZDV FC= 0.60 3.2 log 3log

  41. Subject 918: ATV/COM RT: K103N PRO: L63P ABC FC= 0.57 ATV FC = 0.95 3TC FC=1.01 ZDV FC= 0.22 RT: K103N, M184V PRO: K20M, L24I, L63P ABC FC= 2.99 ATV FC = 0.58 3TC FC= 104 ZDV FC= 0.43

  42. Subject 592: ATV/COM RT: L74V, M184V, P225H PRO: L10I, K20I, I54L, A71V, L90M ABC FC= 2.85 ATV FC = 1.83 3TC FC= 87 ZDV FC= 0.91 RT: L74V, P225H PRO: L10I, K20I, A71V, L90M ABC FC= 0.99 ATV FC = 1.59 3TC FC= 1.06 ZDV FC=1.27

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