Although raltegravir has exhibited substantial efficacy in clinical trials, it is expected that over time a significant number of individuals in clinical practice will exhibit incomplete viral suppression on this drug and will generate raltegravir-resistant variants. Hence, there is an obvious need for drugs in the integrase inhibitor class that retain activity against isolates containing clinically relevant raltegravir-associated mutations. Elvitegravir (EVG, GS-9137), another integrase inhibitor that is in clinical development, has a resistance profile similar to that of raltegravir.5,13–16 Preliminary cross-resistance data for the prototype second-generation integrase inhibitor MK-2048, designed to retain activity against HIV with resistance to raltegravir, indicate that it has a distinct resistance profile17–19; however, MK-2048 remains in very early clinical development. In vitro data have demonstrated that dolutegravir retains substantial activity against Y143 and N155H pathway virus with additional secondary mutations and against virus with Q148 mutations alone.5 Dolutegravir activity has a broader range of FC resistance against Q148 pathway virus with additional raltegravir secondary mutations; resistance generally increases with increasing number of mutations.5,6 Using clinically derived samples, we report that dolutegravir often retains full or near-full activity against variants that possess genotypic and phenotypic resistance to raltegravir. This is particularly true for isolates containing common raltegravir-associated mutations at positions 143 and 155 in the integrase open-reading frame. Single mutations at Q148 apparently conferred small but measurable susceptibility to dolutegravir. Isolates containing combined mutations at 140 and 148 have less susceptibility to dolutegravir than those isolates with mutations at positions 143 and 155, although in both cases, there is substantially greater susceptibility to dolutegravir than to raltegravir.
From a theoretical perspective, the problem of cross-resistance within the class of strand-transfer–specific integrase inhibitors has been considered a major concern because of the overlapping binding orientation of key pharmacophore elements in the integrase active site of the integrase inhibitors currently in development.20 However, a close structural comparison of the scaffolds for raltegravir, elvitegravir, and dolutegravir indicates that dolutegravir has a more “streamlined” scaffold.21,22 A comparison of the position of raltegravir, elvitegravir, and dolutegravir within the catalytic pocket of an HIV-1 model demonstrates that dolutegravir occupies less space between the Mg2+ metals at the base of the catalytic pocket and the Y143 at the top of the catalytic loop compared with both raltegravir and elvitegravir.21–23 This model renders dolutegravir more independent of the signature mutations that typically impact both of these integrase inhibitors. Overall, the data reported here indicate that although dolutegravir FC resistance is substantially lower than that of raltegravir for all clinical isolates obtained from subjects failing raltegravir-based therapy, there is a decrease in dolutegravir susceptibility for some HIV-1 virus, particularly with mutations at Q148 plus at least one additional raltegravir secondary mutation.
All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors would like to thank the subjects from the SCOPE study. The authors wish to acknowledge the following individuals for their editorial assistance during the development of this manuscript: Christine Levesque and Chris Lawrence.
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