Currently approved protease inhibitors include amprenavir and fosamprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

Resistance to protease inhibitors can occur due to mutations in the structure of the protease enzyme, which prevent PIs from binding to specific sites on the enzyme.

Unlike resistance to 3TC or the NNRTIs, resistance to the PIs usually requires the accumulation of several mutations. The first mutation is often distinctive to one particular protease inhibitor, and leads to some loss of sensitivity to that PI, but not generally to high level resistance or cross-resistance to other PIs.

Over time, multiple mutations which are common to the other protease inhibitors may develop. The initial mutation usually makes the virus considerably less fit. As subsequent or "secondary" mutations accumulate, they typically improve the fitness of the virus, leading to a much greater rebound in viral load ^[1], and contribute to cross-resistance.

The chance of benefiting from a second PI is therefore probably greatest if a switch occurs quickly when resistance is first identified, before the virus has accumulated enough secondary mutations to make it more fit and cross-resistant.