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Novel Integrase Mutation Boosts Resistance to Elvitegravir and Raltegravir
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
L68V and L68I, two newly described integrase mutations, emerge with the primary elvitegravir mutation E92Q, according to an analysis of mutations evolving upon failure of elvitegravir in a phase 2 trial [1]. L68V made HIV more resistant to both elvitegravir and raltegravir when combined with E92Q or Q148R, another primary integrase mutation. (Gilead announced during the workshop that phase 3 trials of elvitegravir will begin later this year.)
Damian McColl and Gilead colleagues tracked the emergence of integrase mutations in 28 patients who endured virologic failure within 24 weeks while taking an elvitegravir-containing salvage regimen. E92Q arose in 11 of them (39%), and L68V/I evolved in 6 of those 11 (55%). N155H emerged in 7 people (25%), none of whom had E92Q or L68V/I. Q148R/H/K evolved in 9 people (32%), none of whom E92Q or L68V/I.
Single-genome sequencing of virus from people with the E92Q mutation showed that E92Q and L68V share the same viral genome. In viral populations that included E92Q and either N155H or Q148R, single-genome sequencing demonstrated that E92Q and N155H could also evolve on the same genome, but E92Q and Q148R could not. On the basis of this evidence, McColl proposed that E92Q and Q148R are mutually exclusive primary mutations, as are Q148R and N155H.
The Gilead team then constructed site-directed mutants to evaluate susceptibility of various single, double, and triple mutants to elvitegravir and raltegravir. Although L68V did not evolve with Q148R in the phase 2 trial participants, the site-directed mutants showed that L68V greatly amplified resistance to both elvitegravir and raltegravir compared with Q148R alone. L68V had the same effect on E92Q. But L68V had a more modest impact on resistance of virus already bearing N155H:
Mean fold change in susceptibility of site-directed mutants to elvitegravir and raltegravir:
· L68I alone: 0.9 for elvitegravir (susceptible), 0.9 for raltegravir (susceptible)
· L68V alone: 1.6 for elvitegravir (susceptible), 1.0 for raltegravir (susceptible)
· E92Q alone: 40 for elvitegravir (resistant), 6.0 for raltegravir (intermediate)
· E92Q + L68I: 43 for elvitegravir (resistant), 7.6 for raltegravir (intermediate)
· E92Q + L68V: 67 for elvitegravir (resistant), 14 for raltegravir (resistant)
· N155H alone: 36 for elvitegravir (resistant), 21 for raltegravir (resistant)
· N155H plus L68V: 51 for elvitegravir (resistant), 24 for raltegravir (resistant)
· Q148R alone: 109 for elvitegravir (resistant), 35 for raltegravir (resistant)
· Q148R + L68V: 139 for elvitegravir (resistant), 53 for raltegravir (resistant)
All integrase inhibitor-resistant constructs studied had significantly reduced replication capacity compared with wild-type (nonmutant) virus, except for L68V plus S147G. Among the three primary mutations analyzed, replication capacity was least impaired with E92Q, more impaired by N155H, and most impaired by Q148R/K/H. Although L68V furthered resistance to both elvitegravir and raltegravir, it did not improve fitness in virus already carrying any of these three primary mutations. In contrast, the secondary mutations G140S and S147G did partially compensate for reduced fitness with primary mutations at Q148.
Reference
1. Goodman D, Hluhanich R, Waters J, et al. Integrase inhibitor resistance involves complex interactions among primary and secondary resistance mutations: a novel mutation L6V/I associated with E92Q and increases resistance. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 13.
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