Reports for NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment

July 7-11, 2001 Buenos Aires, Argentina

Clinical Trials Presentations:

Atazanavir (TAZ) (BMS-232632)

Study AI424-008: Phase II, 48 week, randomized, open-labeled as to Atazanavir or Nelfinavir but blinded as to the dose of Atazanavir. Atazavavir is a protease inhibitor in development from Bristol Meyers Squibb.

(Brief note from Jules Levin. This study was an initial comparison with nelfinavir which showed comparable results between the two arms. BMS232632 is being currently studied in Phase III to efavirenz. This new PI has utility for persons with some PI resistance but efficacy seems to fade with extensive PI resistance. The appeal for this Pi is that it’s once per day and the early data shows no increases in cholesterol and triglycerides. Anecdotal reports are of initial decreases in cholesterol and triglycerides in patients who switch from other therapies and have elevated lipids. These reports are preliminary and will have to be confirmed with more studies. For some patients an elevated bilirubin can occur about 4 weeks after starting therapy which may require interruption of therapy.)

Entry Criteria:

--VL > 2000 copies/ml
--T-cell > 100 or > 75 cells/mm3 without history of an AIDS defining OI.
--ARV naïve

Design:

3 arms randomized 2:2:1

Group 1 – TAZ 400 mg qd + 3TC bid + D4T bid
Group 2 – TAZ 600 mg qd + 3TC bid + D4T bid
Group 3 – NFV 1250 mg bid + 3TC bid + D4T bid

Baseline Characteristics (comparable across arms):

N = 467
Median VL = 4.74 log copies/ml
Median T-cells = 270 cells/mm3
Male = 63%
Prior AIDS treatment = 11%

Results (24 weeks):

--Median change from baseline in VL = -2.6 log copies/ml across regimens
--ITT <50% across all arms were undetectable to <50 copies/ml
--Triglycerides & Cholesterol for TAZ shows no change from baseline and significantly lower then NFV at week 32
--As Treated analysis not shown
--Genotypes of virologic failures not shown
--Grade 3-4 Total Bilirubin elevations: TAZ 400 qd = 32%, TAZ 600 qd 52%, NFV 2%

Commentary: This is a large study that took place in numerous countries in over 50 sites. The virologic efficacy using the protocol definition of below the level of detection shows modest results. It remains to be seen how significant is the hyperbilirubinemia. The lack of lipid elevation with this protease inhibitor is a significant advance in PI therapy. Once a day dosing without RTV is attractive. Resistance profile remains to be characterized. Early in vitro evidence suggests some ability to salvage some prior PI exposure but significant loss of activity among highly PI resistant isolates.