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HIV protease inhibitors

Amy L Graziani, PharmD
Section Editor
John G Bartlett, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Protease inhibitors (PIs) are potent antiretroviral drugs recommended as part of the "preferred regimen" for patients in the guidelines of the International AIDS Society-USA (IAS-USA) and the Department of Health and Human Services (DHHS) [1,2].

It is important to understand the pharmacology of the protease inhibitors since exposure to low doses of PIs for relatively short periods of time is associated with the development of HIV drug resistance [3,4]. As a result, underdosing, intermittent dosing, non-adherence, and drug malabsorption should be avoided during PI therapy [5]. In addition, these drugs should be taken in combination with other antiretroviral agents.

This topic review will provide information that will highlight the relevant dosing and administration differences between these agents. Some of the information is intended for the prescriber, while patient information and the important drug interactions that can occur are presented elsewhere. (See "Patient information: Tips for taking HIV medications (Beyond the Basics)".)


Serum concentrations and drug resistance — It is essential to dose the PIs correctly to avoid low serum drug concentrations, which can lead to the development of resistance to an individual agent or cross-resistance to other members of this class. Significant differences in absorption, serum half-lives, routes of metabolism, and dosing frequency exist among the protease inhibitors. For detailed information about PI dosing, see the DHHS Antiretroviral Guidelines for Adults and Adolescents, which can be accessed at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf (see Appendix B, Table 3).

The early dose-ranging studies with indinavir, for example, showed maximum antiretroviral effect with ≥2.4 g/day; lower doses were associated with a reduced response, increased resistance, and diminished effectiveness of dose adjustment [3]. Only newly enrolled patients who started therapy at 2.4 g/day showed a sustained, good viral load response, while those who started at too low a dose and later increased their dose did not achieve viral suppression. Subsequent trials have shown that all patients treated with PIs should receive combination antiviral regimens, usually consisting of one to two PIs and two nucleoside reverse transcriptase inhibitors [1,6].


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