Overcoming Obstacles to the Success of Protease Inhibitors in Highly Active Antiretroviral Therapy Regimens

Success with current protease inhibitors (PIs) is limited by substantial variability in pharmacokinetics, onset of adverse metabolic effects that include sustained lipid elevations and insulin resistance, and increased risk of lipodystrophy. Additionally, poor adherence to the often complex regimens can lead to emergence of PI-resistant human immunodeficiency virus (HIV) variants and treatment failure. Boosting blood levels of current PIs through coadministration of ritonavir can improve the pharmacokinetic characteristics of these agents, increasing the chances of success, but often at the price of additional adverse effects. New PIs in development have the potential to overcome at least some of these obstacles. Tipranavir, mozenavir, and atazanavir have favorable and unique resistance profiles, making them potentially effective in new treatment strategies in both PI-naïve and PI-experienced patients. Atazanavir does not cause the lipid elevations seen with current PIs, and it may improve adherence through once-daily dosing.