The treatment of HIV infection continues to change as new drugs are introduced. The four currently FDA-approved protease inhibitors saquinavir mesylate (Invirase, Hoffmann-LaRoche), ritonavir (Norvir, Abbott), indinavir sulfate (Crixivan, Merck) and nelfinavir mesylate (Viracept, Agouron Pharmaceuticals) represent a significant addition to the nucleoside reverse transcriptase inhibitors.

Protease inhibitors inhibit the human immunodeficiency virus (HIV) by selectively and competitively preventing the cleavage of large polypeptides into smaller, functional proteins. By preventing the formation of functional viral protein, protease inhibitors act to decrease the number of functional virions produced by each HIV-infected cell. Since this mechanism of action is distinctly different from the nucleoside reverse transcriptase inhibitors, the two classes of drugs used in combination should produce additive or synergistic effects. Saquinavir is FDA-approved only in combination with nucleoside analogs. Ritonavir, indinavir and nelfinavir are FDA-approved as monotherapy or combination therapy.

Resistance has been reported with all four of the protease inhibitors and may be associated with loss of therapeutic effect. Of clinical concern is the issue of cross-resistance between the protease inhibitors. However, cross-resistance between protease inhibitors and nucleoside reverse transcriptase inhibitors is not expected due to their different sites of action. Studies with saquinavir given alone or in combination with zidovudine have resulted in saquinavir-resistant strains, but no cross-resistance to either indinavir or ritonavir. Resistance with ritonavir used in combination with nucleoside analogs develops slowly; however, strains that are cross-resistant to indinavir and saquinavir have been reported. Indinavir also has shown cross-resistance to ritonavir and saquinavir. This information on cross-resistance will help to determine a logical sequence of protease inhibitors in treatment protocols. The full implications of cross-resistance are still under study...