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Routes to Cross-Resistance With Raltegravir and Elvitegravir
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Lab studies by Olivia Goethals and Tibotec colleagues delineated different mutation profiles that confer varying degrees of cross-resistance to raltegravir, elvitegravir, and experimental integrase inhibitors [1]. Q148R appeared to be the prime mutation conferring resistance to both raltegravir and elvitegravir. Certain mutation sets making HIV resistant to elvitegravir engendered only moderate cross-resistance to raltegravir.
Tibotec investigators used classic in vitro selection experiments to prompt emergence of mutations conferring resistance to raltegravir or elvitegravir. They relied on site-directed mutagenesis to mint virus combining various mutations, then tested those site-directed mutants for susceptibility to raltegravir, elvitegravir, and the structurally diverse integrase inhibitors L-870,810, L-731,988, PYRAZ, and PYCA.
As in a Merck study of resistance in people with raltegravir failure during a phase 2 trial [2], mutations at integrase position Q148 emerged as the primary pathway of resistance to raltegravir in the Tibotec selection experiments. N155H did not evolve in any of eight viruses analyzed. One selected mutant-Q148R plus E138K, G140A, and V54I-had more than 600-fold resistance to both raltegravir and elvitegravir, as well as reduced susceptibility to the other integrase inhibitors.
Viruses that evolved during in eight vitro selection studies with elvitegravir always included either Q148R, E92Q, or T66I, usually with one or more additional mutations-R20K, L74M, A128T, E138K, or S230R. All selected mutant viruses had significant reductions in susceptibility to elvitegravir and other integrase inhibitors, except for raltegravir, against whichh they had moderately reduced susceptibility.
Site-directed mutants bearing the Q148R mutation had 74-fold reduced susceptibility to elvitegravir and 10-fold resistance to raltegravir. The E92Q mutation conferred 54-fold reduced susceptibility to elvitegravir, but only a 3-fold drop in susceptibility to raltegravir. T66I mutants had 35-fold resistance to elvitegravir but retained almost full susceptibility to raltegravir. A site-directed mutant bearing N155H conferred a 32-fold drop in susceptibility to elvitegravir and an 8-fold drop to raltegravir.
The mutations R20K, V54I, L74M, A128T, E138K, G140A, and S230R also emerged in the selection experiments. But as single mutations in site-directed mutants they caused little or no loss of susceptibility to raltegravir, elvitegravir, or any other compound studied. Thus, Goethals proposed, these are probably compensatory secondary mutations.
The Tibotec team proposed that Q148R, N155H, E92Q, and T66I confer resistance to an array of integrase inhibitors. This is the first in vitro study in which both raltegravir and elvitegravir selected Q148R. A Merck study presented at this workshop found Q148 mutations the primary route to raltegravir resistance [2].
References
1. Goethals O, Clayton R, Wagemans E, et al. Resistance mutations in HIV-1 integrase selected with raltegravir or elvitegravir confer reduced susceptibility to a diverse panel of integrase inhibitors. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 9.
2. Miller MD, Danovich RM, Ke Y, et al. Longitudinal analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from P005, a phase II study in treatment- experienced patients. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 6.
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