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JR Arribas 1 , AL Pozniak 2 , JE Gallant 3 ,E DeJesus 4 , R Campo 5 ,

Superior Outcome for Tenofovir DF (TDF), Emtricitabine (FTC) and Efavirenz (EFV) Compared to Fixed Dose Zidovudine/Lamivudine (CBV) and EFV in Antiretroviral Naïve Patients. JR Arribas 1 , AL Pozniak 2 , JE Gallant 3 ,E DeJesus 4 , R Campo 5 ,

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JR Arribas 1 , AL Pozniak 2 , JE Gallant 3 ,E DeJesus 4 , R Campo 5 ,

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  1. Superior Outcome for Tenofovir DF (TDF), Emtricitabine (FTC) and Efavirenz (EFV) Compared to Fixed Dose Zidovudine/Lamivudine (CBV) and EFV in Antiretroviral Naïve Patients JR Arribas1, AL Pozniak2, JE Gallant3,E DeJesus4, R Campo5, B Gazzard2, MJM Hitchock6, B Lu6, D McColl6, J Enejosa6 and A Cheng6 for the Study 934 Team 1Univ Hospital La Paz, Madrid, Spain; 2Chelsea and Westminster Hosp., London, UK; 3Johns Hopkins Univ School of Medicine, Baltimore, MD; 4Orlando Immunology Center, Orlando, FL; 5Univ Miami, Miami, FL; 6Gilead Sciences, Foster City, CA 18th International Conference on Antiviral Research 10 April 2005 Barcelona, Spain

  2. Study 934Study Design 96 wks TDF QD FTC QD Efavirenz QD ART-naïve patients (n = 517) randomized 1:1 Any CD4 cell count HIV RNA > 10,000 c/mL 96 wks AZT/3TC BID Efavirenz QD Adequate Renal and Hepatic Function at baseline FTC/TDF Fixed dose combination tablet was not used

  3. Study 934Statistical Analysis • Non inferiority Trial • Primary Endpoint < 400 c/mL at Week 48 -Time to Loss of Virologic Response (TLOVR) • FDA-required endpoint • Similar to ITT Missing = Failure, Switch = Failure • Requires confirmation for success • Used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals

  4. Study 934 Baseline Characteristics (ITT) a. Median values

  5. Study 934Study Population Randomized Population (n=517) Never Dosed 6 Patients Safety Population (n=511) Treatment-experienced 2 Patients ITT (n=509) Baseline NNRTI-R 22 Patients Modified ITT n=487

  6. Study 934Baseline NNRTI Resistance (ITT) • 22 patients (11 FTC/TDF vs. 11 CBV) • Investigators notified if affected • FDA recommended excluding these patients for Week 48 primary endpoint analysis (n = 487) • Primary Efficacy Endpoint (HIV RNA < 400 c/mL) at Week 48 analyzed for both populations, excluding NNRTI-R (n = 487) and ITT (n = 509)

  7. Study 934Summary Outcomes at Week 48 a. p value = 0.002 b. p value = 0.016

  8. 100 80 60 % Responder 40 20 0 BL 8 16 24 32 40 48 Weeks Study 934Proportion with HIV-RNA <400 c/mL (TLOVR)ITT (n = 509) p = 0.005 FTC/TDF 81%*CBV 70%* *95% CI: (+3.4%, +18.1%) Exclude NNRTI-R (n=487): FTC/TDF 84%,CBV 73%, p=0.002 (+4.3%,18.6%)

  9. 90 80 70 60 50 % Responder 40 30 20 10 0 BL 8 16 24 32 40 48 Weeks Study 934Proportion with HIV-RNA <50 c/mL (TLOVR)ITT (n = 509) p = 0.034 FTC/TDF 77%*CBV 68%* *95% CI: (+0.9%, +16.2%) Exclude NNRTI-R (n=487): FTC/TDF 80%,CBV 70%, p=0.021 (+1.6%,16.6%)

  10. 225 ) 3 175 125 Mean Change (cells/mm 75 0 BL 8 16 24 32 40 48 Weeks Study 934CD4 Mean Absolute Change from BaselineAs Treated FTC/TDF 190CBV 158 p = 0.002 at Week 48 p < 0.001 by AAUCMB FTC+TDF+EFV 238 234 223 218 209 198 CBV+EFV 222 216 199 188 175 164

  11. Study 934 Resistance Development in all Patients with >400 HIV RNA Copies/mL (mITT) • 1.All patients (after wk 8) with confirmed >400 copies/mL of HIV RNA at Week 48 or early discontinuation analyzed. • Patients w/ baseline NNRTI-resistance excluded (n = 22). Genotyping of 1 Combivir patient failed. • 2.K103N developed in 21/25 patients. Other NNRTI mutations that developed included K101E, K103E, V108I, V179D, Y188H, G190A/S/E, P225H, M230L

  12. Study 934 Adverse Events Leading to Study Drug Discontinuation Through Week 48 • Occurring in more than 1 patient in either arm; patients may have > 1 event • p = 0.016

  13. 20 60 20 55 18 18 50 16 47 16.0 45 16 16.0 14 40 40 13.8 14 13.8 12 35 33 12 31 10.8 Hematocrit % 10 30 10.8 Hemoglobin (g/dL) 10 9.3 22 25 9.3 Hemoglobin (g/dL) 8 8 20 6.9 6 6.9 15 11 6 4 10 3.7 4 3.7 2 5 2 0 0 Nadir Baseline Nadir Baseline 0 Nadir Baseline Study 934Median (Range) Hemoglobin and Hematocrit ValuesDiscontinuations due to Anemia on CBV arm (n=14)

  14. Study 934Serum Creatinine a. Confirmed toxicity grade = two consecutive visits

  15. Study 934Week 48 Summary • Superior overall response in the FTC/TDF arm compared to CBV arm • No patient developed K65R • M184V developed less frequently in the TDF/FTC arm than in the Combivir arm • Significantly more CBV patients discontinued due to adverse events • Similar renal safety profile • No confirmed abnormalities in serum creatinine or phosphorus in FTC/TDF arm

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