Efficacy and Safety of Atazanavir-based therapy in Antiretroviral Na ve HIV Subjects-BMS 089

1. Efficacy and Safety of Atazanavir-based therapy in Antiretroviral Naïve HIV+ Subjects-BMS 089 Background: Efficacy and safety of ATZ boosted (300mg/100mg) or ATZ (400mg) with 3TC and d4T QD in naïve HIV+ patients. Methods: 96 week randomized, open label trial. Primary endpoint was =400 copies/mL through week 48. Secondary endpoints <50 copies/mL and CD4. N = 95 ATZ/r N = 105 ATZ unboosted. Responders: ATV/r = 82(86%) ATV = 89(85%) Median Baseline VL: 4.83/5.02 Median CD4 T-cell count: 201/194 Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, USBackground: Atazanavir (ATV) is a potent, generally well tolerated once-daily protease inhibitor that has been extensively studied without ritonavir (RTV) in ART-naïve, and when boosted with RTV, in treatment-experienced patients; however, data on the use of ATV with RTV (ATV/r) in ARV-naïve subjects are limited. Methods: Study AI424-089 is a 96-week, randomized, open-label, prospective study comparing the efficacy and safety of ATV/r 300 mg/100 mg with ATV 400 mg, both in combination with lamivudine (3TC) and extended-release stavudine (d4T), all given once daily, in ART-naïve subjects. The primary endpoint was the proportion of subjects with HIV RNA<400 copies/mL through week 48; planned secondary assessments included proportion with HIV RNA <50 copies/mL, CD4 count change, and safety parameters.Results: We randomized 200 subjects, of whom we treated 199. At baseline, the mean CD4 count was 235 cells/mm3, the mean HIV RNA 4.95 log10 copies/mL, the mean total cholesterol 161 mg/dL, and the mean triglyceride level 145 mg/dL. Discontinuations prior to week 48 were few: ATV/r, 12%; ATV, 10%. The rate of drug-related adverse events of at least moderate intensity was comparable between arms. Adverse events-related discontinuations occurred more commonly in the ATV/r arm (8%) than the ATV arm (1%); these were primarily protocol-mandated for persistent hyperbilirubinemia. Jaundice and scleral icterus (all grades) were more common in the ATV/r arm (22%; 23%) than the ATV arm (7%; 13%). Mean increase in total cholesterol was 15% for the ATV/r arm vs 6% for the ATV arm (p <0.01); mean increase in triglycerides was 26% for ATV/r vs –3% for ATV (p <0.01); a shift of ?1 NCEP triglyceride category occurred in 16% for ATV/r vs 11% for ATV.Week 48 Efficacy ResultsATV/rATV 400Difference Estimate (95% CI)(ATV/r - ATV400)HIV RNA (Intent to Treat, TLOVR)n = 95n = 105% with <400 copies/mL86851.5 (–8.2, 11.1)% with <50 copies/mL75705.0 (–7.0, 17.0)HIV RNA (On Treatment)n = 84n = 94% with <400 copies/mL93930.2 (–7.4, 7.8)% with <50 copies/mL877611.2 (–0.2, 22.6)Mean CD4 ? from Baseline (cells/mm3)189224–21.1 (–48.9, 6.6)**Time-averaged difference through Week 48Conclusions: In this study in ART-naïve HIV+subjects, ATV, with or without RTV, demonstrated a high rate of virologic response through 48 weeks. Both arms were generally safe and well tolerated, although subjects on ATV/r had a higher rate of hyperbilirubinemia. These results support additional studies using ATV/r in ART-naïve subjects.Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, US

2. Efficacy and Safety of Atazanavir-based therapy in Antiretroviral Naïve HIV+ Subjects-BMS 089 Results: Week 48 ITT efficacy results were- HIV RNA =400 (86%), =50 (75%) - ATZ/r HIV RNA =400 (85%), =50 (70%) - ATZ Safety- All grade of jaundice and scleral icteris more common in the ATZ/r arm than ATZ arm ATZ/r had a higher rate of Grade 3-4 hyperbilirubinemia Mean increase in triglycerides was 26% for ATZ/r Virologic failure greater in ATZ arm (10% vs 3%) CD4 increases +189 ATZ vs. + 224 ATZ/r arm Conclusions- Both doses of ATZ were equally efficacious, generally safe , and well tolerated, although ATZ/r had a higher rate of hyperbilirubinemia. Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, USBackground: Atazanavir (ATV) is a potent, generally well tolerated once-daily protease inhibitor that has been extensively studied without ritonavir (RTV) in ART-naïve, and when boosted with RTV, in treatment-experienced patients; however, data on the use of ATV with RTV (ATV/r) in ARV-naïve subjects are limited. Methods: Study AI424-089 is a 96-week, randomized, open-label, prospective study comparing the efficacy and safety of ATV/r 300 mg/100 mg with ATV 400 mg, both in combination with lamivudine (3TC) and extended-release stavudine (d4T), all given once daily, in ART-naïve subjects. The primary endpoint was the proportion of subjects with HIV RNA<400 copies/mL through week 48; planned secondary assessments included proportion with HIV RNA <50 copies/mL, CD4 count change, and safety parameters.Results: We randomized 200 subjects, of whom we treated 199. At baseline, the mean CD4 count was 235 cells/mm3, the mean HIV RNA 4.95 log10 copies/mL, the mean total cholesterol 161 mg/dL, and the mean triglyceride level 145 mg/dL. Discontinuations prior to week 48 were few: ATV/r, 12%; ATV, 10%. The rate of drug-related adverse events of at least moderate intensity was comparable between arms. Adverse events-related discontinuations occurred more commonly in the ATV/r arm (8%) than the ATV arm (1%); these were primarily protocol-mandated for persistent hyperbilirubinemia. Jaundice and scleral icterus (all grades) were more common in the ATV/r arm (22%; 23%) than the ATV arm (7%; 13%). Mean increase in total cholesterol was 15% for the ATV/r arm vs 6% for the ATV arm (p <0.01); mean increase in triglycerides was 26% for ATV/r vs –3% for ATV (p <0.01); a shift of ?1 NCEP triglyceride category occurred in 16% for ATV/r vs 11% for ATV.Week 48 Efficacy ResultsATV/rATV 400Difference Estimate (95% CI)(ATV/r - ATV400)HIV RNA (Intent to Treat, TLOVR)n = 95n = 105% with <400 copies/mL86851.5 (–8.2, 11.1)% with <50 copies/mL75705.0 (–7.0, 17.0)HIV RNA (On Treatment)n = 84n = 94% with <400 copies/mL93930.2 (–7.4, 7.8)% with <50 copies/mL877611.2 (–0.2, 22.6)Mean CD4 ? from Baseline (cells/mm3)189224–21.1 (–48.9, 6.6)**Time-averaged difference through Week 48Conclusions: In this study in ART-naïve HIV+subjects, ATV, with or without RTV, demonstrated a high rate of virologic response through 48 weeks. Both arms were generally safe and well tolerated, although subjects on ATV/r had a higher rate of hyperbilirubinemia. These results support additional studies using ATV/r in ART-naïve subjects.Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, US

3. Efficacy and Safety of Atazanavir-based therapy in Antiretroviral Naïve HIV+ Subjects-BMS 089 Limitiations: Viral load stratification data was not shown. Clinical Utility: Although ATV/r failures has no primary PI mutations and few NRTI mutations, safety concerns in the entire cohort were far greater : Increases in triglycerides and cholesterol ALT elevations Liver abnormalities (sclera icterus, hyperbilirubinemia, jaundice) Starting with NFV vs ATZ eliminates concern for long term treatment planning and has a similar safety profile in terms of lipids, with better safety data for liver function. NFV is safe in pregnancy, so this is one less concern to worry about, as safety with ATZ in pregnancy is unknown. CD4 increases with NFV are comparable to boosted PI’s. Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, USBackground: Atazanavir (ATV) is a potent, generally well tolerated once-daily protease inhibitor that has been extensively studied without ritonavir (RTV) in ART-naïve, and when boosted with RTV, in treatment-experienced patients; however, data on the use of ATV with RTV (ATV/r) in ARV-naïve subjects are limited. Methods: Study AI424-089 is a 96-week, randomized, open-label, prospective study comparing the efficacy and safety of ATV/r 300 mg/100 mg with ATV 400 mg, both in combination with lamivudine (3TC) and extended-release stavudine (d4T), all given once daily, in ART-naïve subjects. The primary endpoint was the proportion of subjects with HIV RNA<400 copies/mL through week 48; planned secondary assessments included proportion with HIV RNA <50 copies/mL, CD4 count change, and safety parameters.Results: We randomized 200 subjects, of whom we treated 199. At baseline, the mean CD4 count was 235 cells/mm3, the mean HIV RNA 4.95 log10 copies/mL, the mean total cholesterol 161 mg/dL, and the mean triglyceride level 145 mg/dL. Discontinuations prior to week 48 were few: ATV/r, 12%; ATV, 10%. The rate of drug-related adverse events of at least moderate intensity was comparable between arms. Adverse events-related discontinuations occurred more commonly in the ATV/r arm (8%) than the ATV arm (1%); these were primarily protocol-mandated for persistent hyperbilirubinemia. Jaundice and scleral icterus (all grades) were more common in the ATV/r arm (22%; 23%) than the ATV arm (7%; 13%). Mean increase in total cholesterol was 15% for the ATV/r arm vs 6% for the ATV arm (p <0.01); mean increase in triglycerides was 26% for ATV/r vs –3% for ATV (p <0.01); a shift of ?1 NCEP triglyceride category occurred in 16% for ATV/r vs 11% for ATV.Week 48 Efficacy ResultsATV/rATV 400Difference Estimate (95% CI)(ATV/r - ATV400)HIV RNA (Intent to Treat, TLOVR)n = 95n = 105% with <400 copies/mL86851.5 (–8.2, 11.1)% with <50 copies/mL75705.0 (–7.0, 17.0)HIV RNA (On Treatment)n = 84n = 94% with <400 copies/mL93930.2 (–7.4, 7.8)% with <50 copies/mL877611.2 (–0.2, 22.6)Mean CD4 ? from Baseline (cells/mm3)189224–21.1 (–48.9, 6.6)**Time-averaged difference through Week 48Conclusions: In this study in ART-naïve HIV+subjects, ATV, with or without RTV, demonstrated a high rate of virologic response through 48 weeks. Both arms were generally safe and well tolerated, although subjects on ATV/r had a higher rate of hyperbilirubinemia. These results support additional studies using ATV/r in ART-naïve subjects. Efficacy and Safety of Atazanavir-based Therapy in Antiretroviral Naive HIV-1 Infected Subjects, Both with and without Ritonavir: 48-week Results from AI424-089Niel Malan*1, E Krantz2, N David3, K Kastango4, D Frederick4, M Matthew4, S Schnittman4, J Hammond4, and the -089 Study Group1Triple M Res, Port Elizabeth, South Africa; 2Quinta-Res, Bloemfontein, South Africa; 3Cape Town, South Africa; and 4Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, US