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Monogram Devises Weighted Genotypic Score to Predict Etravirine Response
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Assigning weights to etravirine-related mutations yielded a scoring system that allowed a more accurate forecast of response to etravirine regimens by people with antiretroviral experience, according to a 2700-sample analysis by Neil Parkin and Monogram colleagues [1].
Earlier work suggested that three or more etravirine-specific mutations (V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S) correlated with a poor response to an etravirine rescue regimen. To get a better fix on how resistance mutations affect viral susceptibility to etravirine and potential response, Parkin analyzed 2756 viral isolates carrying any one of a long list of nonnucleoside mutations, including gene changes not linked to nonnucleoside therapy (polymorphisms). He also considered a separate set of 1006 samples that did not bear nucleoside-induced mutations known to increase susceptibility to etravirine.
Using a 2.9-fold change in susceptibility to etravirine as a lower clinical cutoff [2], Parkin found an overall 16.8% discordance between the 3-mutation formula and phenotypic susceptibility. When Monogram eliminated samples with confounding nucleoside mutations, discordance improved to only 15.7%.
Next the Monogram team refigured genotype-phenotype discordance rates when assigning each mutation a weight of 4, 3, 2, or 1, with each higher value representing an incremental drop in susceptibility to etravirine. Starting with the mutation yielding the highest mean fold change in susceptibility to etravirine and working their way through the whole list, Parkin's crew kept mutations that worsened the overall score and threw out mutations that improved the score. With a total score of 4 as the cutoff for reduced susceptibility to etravirine, the weighted scoring system had an overall phenotype-genotype discordance of 5.9% and, after excluding samples with nucleoside mutations, a discordance of only 3.2%.
Four mutations, all of them on the original etravirine mutation list, merited a weighting factor of 4: L100I, K101P, Y181C, and Y/181/I. Mutations with a weighting factor of 3 were E138A/G, V179E, G190Q, M230L, and K238N. Weighting scores of 2 were assigned to K101E, V106A, E138K, V179L, and Y188L. And mutations at 11 sites got a score of 1: V90I, K101H, V106M, E138Q, V179D/F/M, Y181F, V189I, G190E/T, H221Y, P225H, and K238T. Mutations at three sites formerly installed as signature etravirine mutations--A98G, V106I, and G190A/S--ended up off the weighted mutation list entirely. The revised genotype system lowered the chance of unexpected reduced susceptibility to 2.4%.
Parkin and colleagues concluded that current genotype rules underestimate reduced susceptibility to etravirine. They called for validation studies of their revised model in separate patient populations.
References
1. Benhamida J, Chappey C, Coakley E, Parkin NT. HIV-1 genotype algorithms for prediction of etravirine susceptibility: novel mutations and weighting factors identified through correlations to phenotype. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 130.
2. Coakley E, Chappey C, Benhamida J, et al. Biological and clinical cut-off analysis or etravirine in the PhenoSense HIV assay. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 122.
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