Study AI424-045: Atazanavir once daily + ritonavir once daily compared to atazanavir once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir DF + one NRTI. Study AI424-045 was a randomized, multicenter trial comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to atazanavir (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm
3 (range: 14 to 1543 cells/mm
3) and the mean baseline plasma HIV-1 RNA level was 4.4 log
10 copies/mL (range: 2.6 to 5.88 log
Treatment outcomes through Week 48 for the atazanavir/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. Atazanavir/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that atazanavir/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of quantification [see Microbiology, Tables 24 and 25 (12.4)].
|Outcome||atazanavir 300 mg + ritonavir 100 mg once daily + tenofovir DF + 1 NRTI (n=119)||lopinavir/ritonavir (400/100 mg) twice daily + tenofovir DF + 1 NRTI (n=118)||Difference a (atazanavir- lopinavir/ritonavir) (CI)|
|a Time-averaged difference through Week 48 for HIV RNA; Week 48 difference in HIV RNA percentages and CD4+ mean changes, atazanavir/ritonavir vs. lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV RNA; 95% confidence interval otherwise. b Roche Amplicor ® HIV-1 Monitor TM Assay, test version 1.5. c Protocol-defined primary efficacy outcome measure. d Based on patients with baseline and Week 48 CD4+ cell count measurements (atazanavir/ritonavir, n=85; lopinavir/ritonavir, n=93). e Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48.|
|HIV RNA Change from Baseline (log 10 copies/mL) b||−1.58||−1.70||+0.12 c (−0.17, 0.41)|
|CD4+ Change from Baseline (cells/mm 3) d||116||123||−7(−67, 52)|
|Percent of Patients Responding e|
|HIV RNA <400 copies/mL b||55%||57%||-2.2% (−14.8%, 10.5%)|
|HIV RNA <50 copies/mL b||38%||45%||−7.1% (−19.6%, 5.4%)|
No patients in the atazanavir/ritonavir treatment arm and three patients in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.
In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for atazanavir 400 mg with saquinavir (n=115) was −1.55 log 10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm 3. Through 48 weeks of treatment, the proportion of patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of atazanavir and saquinavir did not provide adequate efficacy [see Drug Interactions (7)] .
Study AI424-045 also compared changes from baseline in lipid values. [See Adverse Reactions (6.1).]
Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing atazanavir (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to atazanavir (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log 10 copies/mL in the atazanavir treatment arm and −2.02 log 10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, atazanavir without ritonavir was inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.
Pediatric Trials with Atazanavir Capsules
Assessment of the pharmacokinetics, safety, tolerability, and virologic response of atazanavir capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily atazanavir capsule formulation, with or without ritonavir, in combination with two NRTIs.
One-hundred five (105) patients (6 to less than 18 years of age) treated with the atazanavir capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm 3 in antiretroviral-naive patients and 220 cells/mm 3 in antiretroviral-experienced patients.
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