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Steady Evolution of Integrase Mutations After Raltegravir Fails
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48th ICAAC,
October 25-28, 2008,
Washington, DC
Mark Mascolini
Analysis of resistance to raltegravir after failure of regimens containing this integrase inhibitor in the phase 3 BENCHMRK trials identified three pathways to resistance [1]. After follow-up, the Q148H mutation emerged as the primary raltegravir-induced mutation.
BENCHMRK 1 and 2 randomized people with triple-class resistance to raltegravir or placebo plus an optimized background regimen [2,3]. After 16 weeks of treatment, a noncompleter-equals-failure analysis determined that 355 of 458 people taking raltegravir (77.5%) versus 99 of 236 (41.9%) taking placebo had a viral load below 400 copies (P < 0.001). Respective proportions with a sub-50 load at week 48 were 62.1% and 32.9% (P < 0.001). Among people taking darunavir/ritonavir for the first time, 69% assigned to raltegravir and 47% assigned to placebo had a week 48-viral load under 50 copies [3].
In the new resistance study, Merck investigators used population sequencing to search for integrase mutations in 64 people whose raltegravir regimen failed [1]. They used standard assays to determine susceptibility of mutant virus to raltegravir and replication capacity of that virus.
The Merck team identified "signature mutations" at three integrase sites in most patients with virologic failure: N155, Q148, and Y143. Monitoring viral evolution in these people over time, Michael Miller and colleagues found that Q148H emerged as the principal resistance-conferring mutation, often replacing N155H in viral isolates. The first genotype after raltegravir failure determined that 45% of isolates from 64 patients had the N155H mutation, but only 18% of 51 people with a follow-up genotype had N155H. The first genotype detected mutations at position 148 in 27% of 64 people. Follow-up genotypes in 51 people found position 148 mutations in 53%. Mixed mutation populations declined from 19% of viral isolates in the first genotype to 10% of follow-up genotypes.
The study also documented steady emergence of resistance mutations when a failing raltegravir regimen continued. On the first genotype in 64 people, 30% had 1 mutation, 44% had 2 mutations, and 27% had more than 2 mutations. Follow-up genotypes in 51 people spotted 1 mutation in only 8%, 2 mutations in 45%, and more than 2 mutations in 47%.
Emergence of integrase mutations in people whose raltegravir regimen fails correlated with high-level resistance. In studies with site-directed mutants, Q148 mutations and N155H alone had similar impacts on HIV susceptibility to raltegravir and on replication capacity. Secondary mutations that evolved with these key mutations heightened resistance substantially more with Q148 mutations (several hundred-fold resistance) than with N155H (100-fold resistance).
Just before ICAAC, researchers at Belgium's Rega Institute reported that Q148R, E92Q, and T66I are the main mutations conferring resistance to elvitegravir, an investigational integrase inhibitor [4]. In these experiments all of these mutations also reduced susceptibility to raltegravir.
References
1. Miller M, Danovich R, Fransen S, et al. Analysis of resistance to the HIV-1 integrase inhibitor raltegravir: results from the Benchmrk 1 and 2. 48th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). October 25-28, 2008. Washington, DC. Abstract H-898.
2. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-3454.
3. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008;359:355-365.
4. Goethals O, Clayton R, Van Ginderen M, et al. Resistance mutations in HIV-1 integrase selected with Elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol. 2008;82:10366-10374.
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