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Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret Fischl, Qiming Liao, Lisa Ross and

The ALERT Study: A Planned Week 24 Interim Analysis of Once Daily Boosted Fosamprenavir or Atazanavir with Tenofovir/Emtricitabine. Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret Fischl, Qiming Liao, Lisa Ross and Tracey Lancaster. Background.

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Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret Fischl, Qiming Liao, Lisa Ross and

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  1. The ALERT Study: A Planned Week 24 Interim Analysis of Once Daily Boosted Fosamprenavir or Atazanavir with Tenofovir/Emtricitabine Kimberly Smith, Winkler Weinberg, Edwin DeJesus, Margaret Fischl, Qiming Liao, Lisa Ross and Tracey Lancaster

  2. Background • IAS Guidelines recently added boosted FPV and ATV + 2 nucs as recommended initial therapy • FPV/r dose in US product label is 1400mg FPV + 200mg RTV once daily for naïve subjects • This study used a reduced FPV/r dose of 1400 mg FPV + 100 mg RTV once daily that has not been previously studied

  3. Objective • To compare the efficacy, safety, and tolerability of RTV-boosted FPV versus RTV-boosted ATV, both in combination with TDF/FTC

  4. Study Design Randomized (1:1), open-label, 48 week pilot study FPV 1400 mg QD + RTV 100 mg QD + TDF/FTC QD ART-naïve subjects, n=106 ATV 300 mg QD + RTV 100 mg QD + TDF/FTC QD Entry criteria: HIV-1 RNA >1000 c/mL No CD4 cell count restrictions Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL Baseline resistance testing was not done prior to entry

  5. Endpoints • Primary • Proportion of patients with plasma HIV-1 RNA <50 copies/mL at 48 weeks • Secondary • Proportion of patients with plasma HIV-1 RNA <50 copies/mL at 24 weeks • Proportion of patients with plasma HIV-1 RNA <400 copies/mL at 24 and 48 weeks

  6. Endpoints cont. • Secondary • Change from baseline in CD4 cell counts at 24 and 48 weeks • HIV treatment-emergent resistance patterns • Differences between treatment arms in incidence, type and severity of adverse events

  7. Definition of Virologic Failure • Confirmed plasma HIV-1 RNA ≥400 c/mL at Week 24 or later

  8. Baseline Characteristics FPV/r ATV/r Total (N=53) (N=53) (N=106) Median age, years 40 40 40 Male 79% 89% 84% Race-African American 34% 45% 40% -Causasian 64% 49% 56% -Other 2% 6% 4% Ethnicity- Hispanic 23% 23% 23% CDC Class C 9 (17%) 11 (21%) 20 (19%) Median HIV-1 RNA, log10 c/mL 4.88 4.88 4.88 HIV-1 RNA <100,000 c/mL 37 (70%) 36 (68%) 73 (69%) HIV-1 RNA 100,000 c/mL 16 (30%) 17 (32%) 33 (31%) Median CD4 count, cells/mm3 161 188 172 <50 cells/mm3 14 (26%) 9 (17%) 23 (22%) 50 - <200 cells/mm3 21 (40%) 19 (36%)40 (38%) 200 cells/mm3 18 (34%) 25 (47%) 43 (41%)

  9. Completion Status at 24 Weeks

  10. HIV-1 RNA <400 c/mL = 89% = 89% = 94% = 94%

  11. HIV-1 RNA <50 c/mL = 79% = 83% = 84% = 88%

  12. Mean CD4+ Cell Count with 95% Confidence Intervals FPV/r ATV/r

  13. Median Fasting Lipidsat Baseline and Week 24 Cholesterol Triglycerides Baseline n= 48 46 48 46 Week 24 n= 38 39 38 39

  14. Median Fasting Lipidsat Baseline and Week 24 LDL HDL Baseline n= 48 45 48 46 Week 24 n= 36 39 38 39

  15. Subject 1: TDF/FTC+FPV/r RT: S68G, K70T, V118I, L210W, T215C PRO: K20I,M46I,L63P, A71V, V77I TDF FC=0.95; APV FC= 3.8 FTC FC=1.5 Week 0 RT:S68G, K70T, V118I, L210W, T215C, M184V PRO:K20I,M46I, I54I/L/ML63P, A71V, V77I TDF FC= 0.61; APV FC= 13 FTC FC > 112.8 Week 20 Clade B

  16. Subject 2: TDF/FTC+FPV/r Week 0 RT: WT PRO: L10V, L63L/P, V77V/I No phenotypic resistance Week 24 RT: K65R PRO: L10V,V32I, M46M/I, I47V TDF FC= 2.2 APV FC= 8.6 FTC FC= 5.6 Week 12 RT: K65R PRO: L10V, L63L/P, V77V/I No phenotypic resistance Clade B

  17. Subject 3: TDF/FTC+ATV/r Week 0 RT: WT PRO: M36I, L63A TDF FC= 1.1 ATV FC= 0.9 FTC FC=1.04 Week 24 RT: WT PRO: M36I, L63A TDF FC= 1.08 ATV FC= 2.07 FTC FC=1.08 WD Clade B

  18. Adverse Event Related Study Discontinuations • One pt. DC’d FPV/r due to AE- Grade 3 Rash • One pt. DC’d ATV/r due to SAE- new onset Kaposi’s Sarcoma

  19. Adverse Event Related Study Drug Discontinuations • Two pts.* DC’d TDF/FTC (then switched to individual components of ABC/3TC) due to declining renal function, defined in protocol as: • eGFR change >25% below baseline, or • eGFR <50mL/min (confirmed) *61% of subjects had baseline GFR >50 and <90 mL/min by MDRD

  20. Treatment-Related AEs by Overall Frequency >4%

  21. Conclusions • Both arms provided similar rates of virologic suppression and immunologic improvement at Week 24 • Lipid changes were similar • Overall, fewer severe adverse effects occurred with FPV/r than with ATV/r; differences due primarily to bilirubin- associated AEs

  22. Acknowledgements ALERT was made possible by the contributions of patients and staff at the following US sites*: Cynthia Brinson- Austin, TX Cal Cohen- Boston, MA Edwin DeJesus- Orlando, FL Margaret Fischl- Miami, FL Joseph Horvath- Columbia, SC Ricky Hsu- New York, NY Lewis McCurdy- Charlotte, NC Cheryl McDonald- Ft. Worth, TX • Bruce Rashbaum- Wash., DC • Robert Scott- Oakland, CA • Kimberly Smith- Chicago, IL • Ford Kinder- Miami, FL • Winkler Weinberg- Atlanta, GA • Ben Young- Denver, CO *Also wish to thank the CRO, MediStaf Research, for their contributions. Support was provided by GlaxoSmithKline

  23. Backup Slides (Additional Data)

  24. Fasting Cholesterol 182 173 165 158

  25. Fasting Triglycerides 192 144 145 141

  26. Fasting LDL 105 101 98 94

  27. Fasting HDL 47 40 37 36

  28. Mean CD4+ Cell Count Change from Baseline with 95% CI Baseline mean: 176 Baseline mean: 205 Week 12 Week 24

  29. Fasting LipidsMedian Change from Baseline at Week 24 n= 36 37 36 37 34 36 36 37

  30. Treatment Emergent Fasting LipidToxicities by Intensity Grading Triglycerides Cholesterol LDL n= 40 39 40 39 38 38

  31. eGFR by MDRD (FPV/r) Wk 0 to Wk 24

  32. eGFR by MDRD (ATV/r) Wk 0 to Wk 24

  33. eGFR by MDRD (All Subjects) Wk 0 to Wk 24 Two pts. DC’d Truvada due to declining renal function, defined as eGFR change >25% below baseline or eGFR <50mL/min (confirmed)

  34. Subject 1: TDF/FTC+FPV/r RT: S68G, K70T, V118I,210W,T215C PRO: K20I,M46I,L63P, A71V, V77I TDF FC=0.95 APV FC= 3.8 FTC FC=1.5 Week 0 RT:S68G, K70T, V118I,M184V, L210W, 215C, K219K/Q PRO:K20I,M46I, I47I/V, F53F/L,I54I/L,L63P,A71V, V77I TDF FC= 0.61 APV FC= 2.98 FTC FC > 78.3 Week 12 RT:S68G, K70T, V118I,M184V, L210W, 215C, PRO:K20I,M46I, I54I/L/ML63P, A71V, V77I TDF FC= 0.61 APV FC= 13 FTC FC > 112.8 Week 20 Clade B

  35. Subject 2: TDF/FTC+FPV/r Week 0 Week 24 RT: WT PRO: L10V, L63L/P, V77V/I No phenotypic resistance RT: K65R PRO: L10V,V32I, M46M/I, I47V TDF FC= 2.2 APV FC= 8.6 FTC FC= 5.6 Week 4 RT: WT PRO: L10V, L63L/P, V77V/I No phenotypic resistance Week 28 RT: K65R, D67D/N, PRO: L10V,V32I, M46I, I47V TDF FC= 1.8 APV FC= 19 FTC FC= 8.5 Week 12 RT: K65R PRO: L10V, L63L/P, V77V/I No phenotypic resistance Clade B

  36. Subject 3: TDF/FTC+ATV/r Week 0 RT: WT PRO: M36I, L63A TDF FC= 1.1 ATV FC= 0.9 FTC FC=1.04 Week 12 RT: WT PRO: M36I, L63A TDF FC= 1.08 ATV FC= 2.07 FTC FC=1.08 WD Clade B

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