Atazanavir (Reyataz) is an effective and well-tolerated first-line anti-HIV therapy, according to Phase III trial results published in the August 15th edition of the Journal of Acquired Immune Deficiency Syndromes. Atazanavir is currently the only protease inhibitor approved for once-daily dosing and - unlike other drugs in its class – it is not associated with significant blood fat elevations or insulin resistance.
Kathleen Squires, MD, from the University of Southern California and an international team of colleagues compared atazanavir against efavirenz (Stocrin or Sustiva) in a randomized, double-blind trial of 805 treatment-naive participants. The study was conducted at 91 sites in Europe, North America, South America, Asia, and South Africa. Baseline characteristics were similar in the atazanavir and efavirenz arms; the median age was 33 years, 65% were men, and 67% were non-Caucasian. At study entry, subjects had viral load levels of at least 2,000 copies/ml (median 4.88 log10), and CD4 counts of at least 75-100 cells/mm3 (median 282).
Participants received either 400mg atazanavir (404 patients) or 600mg efavirenz (401 patients) once daily, along with twice-daily fixed-dose AZT/3TC (Combivir). After 48 weeks, 70% of subjects receiving atazanavir and 64% in the efavirenz arm had HIV RNA levels below 400 copies/ml in an intent-to-treat analysis (95% confidence interval 5.2% (-1.2%, 11.7%)). The corresponding as-treated rates were 81% and 84%.
However, when using a more sensitive viral load assay, just 32% in the atazanavir arm and 37% in the efavirenz arm had viral loads below 50 copies/ml (as-treated: 44% and 51%). It is expected that more people will be classified as ‘undetectable’ using a less sensitive viral load test, but the difference is usually not so great. The researchers thus conducted a further exploratory analysis to examine the unexpected discrepancy. They found that most subjects who were undetectable on the
CD4 cell increases were comparable in the atazanavir and efavirenz arms (176 vs 160 cells/mm3, respectively).
Overall rates of adverse events were similar in both arms (41% in the atazanavir group, 45% in the efavirenz arm), as were the rates of serious (grade 3 or 4) adverse effects (less than 10% in both arms); 6% and 8%, respectively, discontinued due to adverse events. Nausea was the most common side effect in both arms (13-14%). Elevated bilirubin (a byproduct of the breakdown of red blood cells) occurred more often in the atazanavir arm, and jaundice and scleral icterus (yellowing of the eyes) were significantly more common among atazanavir recipients (p
Participants receiving atazanavir had more favorable lipid profiles than those taking efavirenz, with smaller increases in total cholesterol, fasting low-density lipoprotein (LDL, a type of cholesterol associated with atherosclerosis), and fasting triglyceride levels (p
“Atazanavir is comparable in efficacy and safety to efavirenz in the initial treatment of HIV infection,” the researchers concluded. “Unlike other [protease inhibitors], atazanavir does not produce clinically significant increases in total cholesterol, fasting LDL cholesterol, fasting triglycerides, insulin, or glucose, thus potentially reducing the use of lipid-lowering agents and the risk for future cardiovascular disease events that may be associated with treatment in HIV-infected patients.”
Atazanavir was licensed in 2003 on the basis of these results at a dose of 400mg once daily in the United States for use in first-line or subsequent antiretroviral regimens. However the European Medicines Agency decided to license ataznavir for use only in treatment-experienced patients and only when boosted with 100mg of ritonavir due to concerns about the low trough levels of the drug that might lead to resistance.
Squires K et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. JAIDS 36: 1011-1019, 2004.