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"Selective Advantage" Analysis Sees Low Risk of Cross-Resistance With Dolutegravir
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51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago
Mark Mascolini
Assessment of dolutegravir cross-resistance using "selective advantage" profiles yielded evidence that dolutegravir "is unlikely to promote emergence of viruses carrying resistance mutations selected by other integrase inhibitors," unless multiple mutations arise [1].
The analysis rests on a variable dubbed "selective advantage," which French virologist Francois Clavel argues is a better way to assess viral resistance to HIV drugs than 50% inhibitory concentration (IC50). Some research suggests IC50 does not always explain how likely drug-resistant virus will emerge in people taking the drug of interest [2,3].
Clavel's "selective index" expresses the ratio of mutant to wild-type (nonmutant) HIV infectivity as a function of drug concentration. This variable, which combines resistance and replication capacity, assesses the extent to which a mutant virus is likely to be selected at a particular concentration of a drug. A higher index indicates a greater likelihood that a mutation will emerge when HIV is exposed to a given drug.
Dolutegravir, a once-daily investigational integrase inhibitor originally called S/GSK1349572, retains activity against HIV resistant to other integrase inhibitors, and some evidence suggests it has a higher barrier to resistance than raltegravir [4].
To determine how avidly dolutegravir selects viruses resistant to other integrase inhibitors, Clavel (Hospital Saint-Louis, Paris) calculated dolutegravir selective index for an array of integrase mutations. To do this he used site-directed mutagenesis to construct viral clones carrying single or multiple mutations associated with resistance to other integrase inhibitors: E92Q, T97A, E138K, G140S, Y143C, Q148H, and N155H. IAS-USA resistance experts list E92Q, Y143R/H/C, Q148H/K/R, and N155H as raltegravir-related mutations [5]. Clavel determined dolutegravir and raltegravir IC50 and selective advantage for each of these single and multiple mutants.
None of the clones bearing a single integrase mutation had a selectivity advantage above 1 for any dolutegravir concentration ranging from 0 to 2000 nM. No mutations in the Y143C resistance pathway had a selective advantage above 1 when exposed to dolutegravir.
Two double mutants, E92Q + N155H and G140S + Q148H, had a low to moderate selective advantage (approximately 1.5) at dolutegravir concentrations of 10 to 100 nM. The analysis determined that the double mutants G140S + Q148R and G140S + G148K are not likely to emerge with dolutegravir. A clone carrying four integrase mutations (T97A + E138K + G140S + Q148H) had a high selective advantage (approximately 2.5) with dolutegravir concentrations ranging from 10 to 1000 nM.
The selective advantage of raltegravir-resistant mutants was always substantially higher and wider in clones exposed to raltegravir than in clones exposed to dolutegravir.
Clavel concluded that "single integrase mutants do not express measurable selective advantage in the presence of dolutegravir." He noted that one double mutant, G140S + Q148R, had a 5-fold increase in dolutegravir IC50 but expressed no selective advantage in his experiments, a finding suggesting "the inability of IC50 measures to give a full account of the escape potential of some mutants."
References
1. Dazza M, Clavel F. Selective advantage profiles of HIV-1 integrase mutants in the presence of dolutegravir. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H1-374.
2. Quercia R, Dam E, Perez-Bercoff D, Clavel F. Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J Virol. 2009;83:10245-10249. http://jvi.asm.org/cgi/content/full/83/19/10245?view=long&pmid=19605484.
3. Mammano F, Trouplin V, Zennou V, Clavel F. Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. J Virol. 2000;74:8524-8531. http://jvi.asm.org/cgi/content/full/74/18/8524?view=long&pmid=10954553.
4. Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55:813-821. http://aac.asm.org/cgi/content/full/55/2/813?view=long&pmid=21115794.
5. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: December 2010. Top HIV Med. 2010;18:156-163. http://www.iasusa.org/pub/topics/2010/issue5/156.pdf.
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