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NLM AIDSLINE
HIV-1 protease inhibitors.
Al Emini E; Merck Research Laboratories, West Point, PA.
November 30, 1996
3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:166. Unique

HIV-1 protease enzyme mediates the cleavage of the viral polyprotein precursors during maturation of the newly produced infectious virion; inhibition of the enzyme results in the formation of non-infectious, immature viral particles. Intensive research efforts over the last decade have resulted in the discovery of many specific and potent inhibitors. Within the past several years, a number of these compounds have advanced to clinical evaluation. The in vivo antiviral activities exhibited by the inhibitors have been variable, with effects ranging from none to greater than 99% suppression of circulating HIV-1 RNA levels. These variations have proven to be predominantly the result of differences in bioavailability, pharmacokinetic and serum protein binding characteristics. The profound viral suppression engendered by the more potent inhibitors is usually accompanied by significant CD4 cell count elevations. These elevations are typically sustained even when the inhibitor-mediated antiviral suppression is lost. The loss of the suppression, when it occurs, is typically the result of selection for HIV-1 isolates exhibiting reduced inhibitor susceptibility. Considerable diversity has been noted in the frequency and timing of this selection. The genetic basis of reduced susceptibility has been extensively studied as has the potential for cross resistance among the available inhibitors. The understanding derived from these studies has important implications for the appropriate clinical use of protease inhibitors, particularly with regard to potentially forestalling the development of resistance.

Biological Availability CD4 Lymphocyte Count Drug Resistance, Microbial HIV Protease/METABOLISM HIV Protease Inhibitors/*PHARMACOLOGY/PHARMACOKINETICS HIV-1/DRUG EFFECTS/*ENZYMOLOGY/ISOLATION & PURIF Hydrolysis RNA, Viral/BLOOD ABSTRACT

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