American Foundation for AIDS Research, August 2003
Kristen Kresge

The second anti-HIV drug to hit the market in 2003 is Bristol-Myers Squibb’s protease inhibitor atazanavir (or Reyataz). It may not be as groundbreaking as the introduction of this year’s first drug, T-20 (Fuzeon). But the drug, which received FDA approval June 20, will continue the trend toward simplified HIV regimens due to its once-daily dosing.

Where’s the Advantage?

Atazanavir does not stand out from the other protease inhibitors in terms of efficacy. BMS conducted several phase II and III studies to establish the efficacy of atazanavir in relation to such approved drugs as nelfinavir, efavirenz and Kaletra. In persons without prior treatment, atazanavir’s efficacy appeared similar to fellow protease inhibitor nelfinavir.

More surprising were the results of the trial comparing atazanavir with efavirenz — Bristol’s potent once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI). That study enrolled 805 treatment-naive volunteers who received Combivir (AZT and 3TC) along with either atazanavir or efavirenz.

After 48 weeks, 37% of volunteers receiving efavirenz and 32% receiving atazanavir had undetectable viral loads (less than 50 copies/mL). Both groups had similar CD4 cell increases and adverse event rates. Although efavirenz looked slightly better than atazanavir, its success in this trial was unexpectedly low compared with previous studies. This does not speak highly for atazanavir’s potency.

But aside from potency, one clear advantage is atazanavir’s evident lack of effect on blood lipids. People on anti-HIV regimens usually experience increases in cholesterol and triglyceride levels, which may put them at risk for cardiovascular disease. Atazanavir thus promises to reduce one of the major long-term side effects of continued HIV treatment.

Another potential advantage is atazanavir’s resistance profile. HIV that develops resistance to atazanavir commonly has a mutation not seen after exposure to other protease inhibitors.

Atazanavir in Salvage Therapy

Once thought to be promising for salvage therapy, atazanavir has not shown well in treatment-experienced patients with resistance to the available protease inhibitors. One phase III trial compared atazanavir with Kaletra (a protease inhibitor combination of lopinavir plus ritonavir). This study enrolled 229 volunteers with an average of three years prior HIV therapy. Everyone had failed a drug regimen that included at least one protease inhibitor. The volunteers were randomized to receive either atazanavir or Kaletra in addition to two nucleoside analogs selected for maximum effect in each person.

An interim analysis at 24 weeks found that atazanavir was less effective than Kaletra. In the Kaletra arm, 52% of study participants achieved viral loads below 50 copies/mL, whereas only 41% did so in the atazanavir arm. Overall, the percentages with viral loads below 400 copies/mL were 80% in the Kaletra group and 60% in the atazanavir group. Atazanavir’s activity was significantly diminished in study volunteers with previous exposure to two protease inhibitors. In this group, the respective percentages with viral loads below 400 copies/mL were 85% for Kaletra and 39% for atazanavir.

Hopes for atazanavir in the treatment-experienced population are now pinned to a new study comparing ritonavir-enhanced atazanavir with Kaletra in persons who have failed two or more HIV regimens. Atazanavir is given at a reduced 300-mg dose (the standard amount is 400 mg) along with ritonavir, which greatly slows atazanavir’s breakdown in the body. Bristol could not explore using a higher dose of atazanavir because of the drug’s tendency to cause high bilirubin levels in the blood. High bilirubin results from a block on the liver’s ability to eliminate excess iron. It can lead to jaundice. Adding ritonavir, then, is the only strategy at hand to make the drug more effective against resistant HIV.

But adding ritonavir lessens the simplicity of atazanavir’s dosing. And ritonavir is also a strong booster of blood lipids and is toxic to the liver. These factors could obviate atazanavir’s lipid-stabilizing effect, while complicating the jaundice that atazanavir can induce.

At the last minute, Bristol included the 24-week preliminary results of the atazanavir/ritonavir trial as part of its FDA filing. The overall atazanavir results were similar to Kaletra’s — 39% in the atazanavir/ritonavir arm and 42% in the Kaletra arm achieved viral loads below 50 copies/mL. Kaletra seemed superior only in those whose HIV had four or more mutations conferring resistance to protease inhibitors. However, the FDA did not consider this data when it granted broad approval of the drug.

Bristol has not yet made any public announcement of atazanavir’s price, but many members of the HIV community hope to see it priced no higher than Kaletra, the top-selling protease inhibitor.

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