Use of HIV protease inhibitors as pharmacoenhancers

Short- and long-term therapy with many protease inhibitors (PIs) at standard dosing may be limited by inconvenient dosing regimens, high tablet volumes, and variable drug exposure. Booster agents, such as low (or "baby") doses of ritonavir, and codosing with the nonnucleoside analogue delavirdine are increasingly used to maintain high PI trough exposures. Combinations of HIV PIs, either alone or coadministered with nucleoside analogues, have demonstrated substantial virologic and immunologic responses sustained over long periods of follow-up. This approach is rapidly becoming the standard of care with PI use. The advantages of the boosted PI approach include raising trough drug concentrations, diminishing interpatient variability, prolonging drug half-life to allow twice-daily and possibly once-daily dosing, and diminishing food requirements and tablet volume. In addition, increases in drug exposure may potentially enable inhibition of the virus in the presence of reduced sensitivity to PIs. Using a boosted PI, in the absence of comparative data on resistance profiles of boosted regimens, should be considered differently from dual-PI combinations, where there is exposure to 2 active PIs. Some physicians are now using a booster agent plus 2 PIs in the salvage therapy setting in an attempt to achieve effective, yet less toxic, concentrations of 2 PIs to overcome different resistant populations in a patient's viral quasispecies.