The consequence of cross-resistance is to narrow quickly the number of drugs a patient can take and expect to have a potent antiviral effect. Experiencing virologic breakthrough with a drug with broad cross-resistance will have consequences that reach beyond the utility of that particular drug. Resistance to a protease inhibitor develops in stages. The first mutation selected is usually near the active site of the protease. If primary mutations were the only change and no further mutations developed there would be little cross-resistance between protease inhibitors.
Primary mutations have a direct effect on the efficacy of the drug.
Secondary mutations often do not have effect on the level of resistance, but instead are thought to improve protease's overall function and fitness. See Figure . Unlike primary mutations, secondary mutations overlap considerably between the different protease inhibitors. This large overlap of secondary mutations is what accounts for the broad cross-resistance that is generally seen with protease inhibitors. This broad cross-resistance was confirmed using phenotypic tests in a study reported by Hertogs, et al.