The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy

Having changed the landscape in the treatment of HIV infection, the functional efficacy of current protease inhibitors (PIs) remains limited by their pharmacokinetic and pharmacodynamic profiles. Complex metabolism by the cytochrome P450 system (particularly the 3A4 isoenzyme), action of membrane drug transporter elements (such as P-glycoprotein and multi-drug resistance-associated proteins) and activation of the nuclear receptor steroid xenobiotic receptor may alter exposures and compromise the antiretroviral activity of these drugs. These factors, as well as inadequate adherence, can facilitate the emergence of PI resistance and lead to regimen failure. Coadministration of ritonavir can enhance exposures of a primary PI by inhibiting CYP3A4 metabolism, P-glycoprotein activity and multi-drug resistance protein-1-mediated efflux. Adding ritonavir, however, is not without cost. Dyslipidaemia (possibly increasing the risk of cardiovascular events), gastrointestinal intolerance, multiple drug-to-drug interactions and activation of steroid xenobiotic receptor can all result and must be balanced against the pharmacokinetic improvement rendered by the addition of ritonavir. Understanding the pharmacological origins for the variations in exposures of PIs, both between and within patients, is important for the successful use of these agents.