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  XVII International HIV Drug Resistance Workshop
June 10-14, 2008
Sitges, Spain
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Q148 Mutations Emerge as Primary Raltegravir Resistance Pathway
  XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
Mutations at integrase position Q148, rather than at N155, proved the predominant route to failure of raltegravir in a phase 2 study of people with triple-class resistance [1]. Q148 variants with additional mutations were more resistant to raltegravir than N155H plus additional mutations.
Michael Miller and Merck coworkers analyzed how resistant virus evolved over time in 35 people in whom raltegravir failed by week 48 of a phase 2 trial that combined the integrase inhibitor (or placebo) with an optimized background regimen. They used standard population sequencing to track genotypic changes in the integrase coding region compared with the pretreatment genotype, and they evaluated resistance levels of mutant virus by phenotypic analysis.
The Merck team identified integrase mutations in 35 of 38 failure samples (92%). Those 38 samples represented 28.6% of the 133-person study group. In the first genotype done at virologic failure, 20 of these 35 people had a mutation at Q148, 14 had the N155H mutation, and 1 had a Y143R mutation. N155H and Q148 mutations (Q148H, Q148R, and Q148K) never evolved in the same virus, a finding confirmed in a separate analysis of failure in the phase 3 BENCHMRK trials [2].
Q148 mutations-and especially Q148H plus G140S-tended to remain stable in viral populations, whereas populations initially harboring N155H tended to switch to Q148H/G140S. Specifically, viral populations from 7 patients evolved from N155H plus Q148R/H/K to populations dominated by Q148R/H/K alone. Viral populations in 5 patients evolved from N155H with no Q148 mutations to populations again dominated by only by Q148 mutations.
By themselves, Q148 mutations and N155H engendered similar degrees of resistance to raltegravir. But Q148 mutations plus secondary mutations proved more resistant to the integrase inhibitor than N155H plus secondary mutations. Of all the variants studied, Q148H/G140S attained the highest level of resistance to raltegravir and had the least impaired viral replication capacity.
An analysis of time to loss of virologic response involved 13 people with Q148 mutations and no N155H mutation and 7 people with N155H and no Q148 mutations. Those with N155H had a longer time to loss of response, but Millar emphasized this analysis rests on a limited number of patients and must be confirmed in larger groups.
Miller concluded that treatment with raltegravir after emergence of one mutation exerts continued selective pressure leading to evolution of secondary mutations. Does this mean raltegravir should be switched out of a failing regimen as soon as possible to prevent mutation pile-ups, as is done with a failing nonnucleoside? After noting that he is not a clinician, Miller told workshop attendees he saw no compelling reason to continue raltegravir in such cases. Merck has identified compounds that control raltegravir-resistant virus, he added. But developing those compounds into attractive clinical products is not simple, Miller cautioned, so he could not predict when a second-generation integrase inhibitor would be ready for testing in humans. (from Jules: Steve Deeks' poster here suggests that for some patients stopping raltegravir after resistance develops may increase viral load; in one patient viral load increased 1 log from 7,000 to 70,000 - but these needs further research and clarification).
1. 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.
2. 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.