Top Ten Research Reports of 2003
6. Efficacy and Safety of Atazanavir With Ritonavir or Saquinavir Versus Lopinavir/Ritonavir in Combination With Tenofovir and One NRTI in Patients Who Have Experienced Virologic Failure to Multiple HAART Regimens: 24-Week Results From BMS AI424-045
Badaro R., DeJesus E., Lazzarin A. et al. Efficacy and Safety of Atazanavir With Ritonavir or Saquinavir Versus Lopinavir/Ritonavir in Combination With Tenofovir and One NRTI in Patients Who Have Experienced Virologic Failure to Multiple HAART Regimens: 24-Week Results From BMS AI424-045. Presented at: 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 118.
BackgroundThe protease inhibitor field is a crowded one. At the beginning of 2003, there were half a dozen agents vying to be the one and only PI. To break into this pack, an agent must demonstrate some advantage compared to its competitors. Me-too drugs don't go very far and can be a drag on formularies (to say nothing about the poor drug reps who have to detail the stuff). The early buzz on atazanavir, one of the two PIs approved during this past year, was not always encouraging.
Atazanavir is administered once daily, although in clinical trials11 it had potency that appeared to be on par with nelfinavir (which is one of the weakest PIs, not necessarily something to boast about when positioning yourself against lopinavir/ritonavir). In addition, atazanavir caused hyperbilirubinemia in enough study subjects to lead some to recommend that atazanavir be renamed to "turns-you-yellow-avir."
The situation was not helped much by the results of a quirky study Kate Squires, M.D., and others presented at ICAAC that on the one hand showed atazanavir to be equivalent to efavirenz when combined with two nucleosides, but on the other hand demonstrated that both agents had surprisingly low (<40%) rates of virologic success as measured by a viral load <50 copies/mL at 48 weeks.12
Yet, something surprising has happened. Since its release, atazanavir has been embraced. This is largely due to its once-a-day administration and its lipid- and glucose-friendly side-effect profile. However, these advantages alone may not have sufficed if it were not for this trial presented by Dr. Badaro at last summer's IAS conference. It indicates that atazanavir's potency, when coupled with a single, 100-mg dose of ritonavir, is similar to that of lopinavir/ritonavir.
What Is New Here?In Badaro's study, 358 subjects who had failed two combination antiretroviral regimens -- which included drugs from each of the three treatment classes -- were randomized to tenofovir plus any NRTI and either one of three possible arms: A.) atazanavir 300 mg/ritonavir 100 mg QD versus B.) atazanavir 400 mg/saquinavir 1,200 mg QD versus C.) lopinavir/ritonavir at the standard dose BID.
Surprisingly, the atazanavir/ritonavir combination did very well, with 39% of patients on this regimen achieving a viral load <50 copies/mL at week 24, compared to 42% on lopinavir/ritonavir and only 23% on atazanavir/saquinavir. Importantly, the addition of low-dose ritonavir did not considerably abrogate the lipid-neutral effects of atazanavir.
The Bottom LineIt is extremely impressive that ritonavir-boosted atazanavir can hold its own against lopinavir/ritonavir, arguably the most potent antiretroviral around, and it has many clinicians and patients looking at the drug in a new light. Longer-term data will emerge from this ongoing study, but for those of us treating patients, the addition of a powerful once-daily protease inhibitor to our bag of RXs -- one that can also be readily combined with other once-a-day antiretrovirals -- is tremendously welcome.
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