February 26, 2002
Atazanavir (BMS-232632) is a once-daily protease inhibitor (PI) that is being developed by Bristol-Myers Squibb. It is currently in phase III trials and will likely be approved in the coming year. While atazanavir appears to be relatively potent when compared to nelfinavir, unlike the protease inhibitors currently available, studies have indicated that the lipid changes associated with atazanavir appear to be minimal. A poster presentation provided data regarding the lipid changes associated with atazanavir in two clinical trials, AI424-007 and AI424-008. These studies compared the efficacy and tolerability of atazanavir and nelfinavir in combination with two nucleoside reverse transcriptase inhibitors (NRTIs), and also evaluated lipid changes associated with each regimen.
In both studies, the regimens performed equally well at 48 weeks regarding viral suppression to less than 400 and less than 50 copies/mL and CD4+ T cell count rise, approximately 60 percent, 40 percent and 200 cells/mm3, respectively. Both regimens appeared to be relatively well tolerated, with roughly equal rates of discontinuation due to an adverse event, with diarrhea more common in the nelfinavir arm and jaundice more common in the atazanavir arm, especially at doses greater than 400 mg daily. The following table shows the lipid profile changes from baseline to week 48:
|Mean Change, Percentage (n) From Baseline|
|Total Cholesterol||Fasting LDL||Fasting Triglycerides|
|Trial AI424-007 at week 48 (n)|
|Atazanavir 400 mg qd (101)||7* (81)||-7* (35)||2* (44)|
|Nelfinavir 750 mg tid (100)||28 (82)||31 (39)||42 (46)|
|Trial AI424-008 at week 48 (n)|
|Atazanavir 400 mg qd (178)||5* (153)||5* (87)||7* (85)|
|Nelfinavir 1,250 mg bid (91)||25 (76)||23 (41)||50 (50)|
|* p<0.05, atazanavir vs. nelfinavir|
Using the ATP III, ACTG criteria for lipid-lowering therapy (LDL >160 mg/dL), of the patients on atazanavir and nelfinavir in study AI424-007 6 percent and 18 percent, respectively, and in study AI424-008 6 percent and 15 percent, respectively, met the criteria for starting that therapy.
These studies are encouraging. They indicate that atazanavir is a potent, once-daily, protease inhibitor with a favorable lipid profile. The primary problem is, of course, the benign increase in bilirubin levels and jaundice that may occur in some patients, but this appears to be dose related and occurs at a lower rate in the patients given 400 mg daily, the dose that is going forward in clinical trials.