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  XVII International HIV Drug Resistance Workshop
June 10-14, 2008
Sitges, Spain
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Mutually Exclusive Resistance Paths Seen With Raltegravir Failure
  XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Analysis of clones derived from virus of patients in whom raltegravir failed in phase 3 trials demonstrated that (1) the N155H mutation and mutations at integrase position Q148 do not appear in the same viral variant, (2) distinct secondary mutations appear with these primary mutations, and (3) viral replication capacity varies depending on which primary and secondary mutations emerge.
Monogram and Merck investigators scrutinized clones of virus from 11 people whose raltegravir salvage regimen faltered in one of the phase 3 BENCHMRK trials. They also created site-directed mutants to analyze the impact of N155H, Q148R/H/K, E92Q, and G140S/A alone and in combination.
Although 9 of 11 patients had viral populations including mutations at N155 and Q148, clonal analysis showed that no viral population harbored single viral variants with mutations at both positions. Resistance pathways stemming from these primary mutations do not appear to overlap, as a second raltegravir study at this workshop confirmed [2]. These primary mutations alone and, occasionally, solitary secondary mutations reduced susceptibility to raltegravir as measured by the PhenoSense assay. Although N155H and Q148R/H/K proved the dominant initial pathways to failure, a small number of failure samples featured the Y143C/R mutation, either alone or with N155H or N155H plus Q148R/H/K.
The secondary mutation E92Q appeared in clones with N155H, but never with Q148 mutations. On the other hand, the secondary mutations G140A and G140S appeared in clones containing Q148 mutations, but not with N155H.
Analysis of site-directed mutants showed that E92Q plus N155H lowered susceptibility to raltegravir and decreased replication capacity much more than N155H alone. E92Q alone could also confer reduced susceptibility to raltegravir. G140A and G140S usually increased resistance when combined with G148 mutations. The exception to this rule was G140S plus G148K: G140S suppressed resistance conferred by Q148K alone. G140S plus Q148H or Q148K had lower replication capacity than Q148H or Q148K alone. But G140S plus Q148R did not have lower replication capacity than Q148R alone.
Together these findings disclose subtle differences in measures of resistance and replication capacity with separate mutation sets. But this study could not address whether these differences have any clinical relevance.
Another study by Merck investigators, reported separately by NATAP, found evidence that Q148 mutations, rather than N155H, paved the primary route to resistance among people taking raltegravir in a phase 2 trial [2]. In people who had two or three genotypes after raltegravir failure, N155H populations faded and Q148 mutations rose to dominance, while additional mutations accumulated.
1. Fransen S, Gupta S, Danovich R, et al. Loss of raltegravir susceptibility in treated patients is conferred by multiple non-overlapping genetic pathways. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 7.
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.