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  International HIV and Hepatitis Drug Resistance Workshop
June 8-12, 2010,
Dubrovnik Croatia
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GSK Integrase Following Raltergavir Use: When Is It Risky to Use S/GSK1349572 After Raltegravir?
  International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik. Croatia
Mark Mascolini
Raltegravir-experienced patients screened for a study of the experimental integrase inhibitor S/GSK1349572 (called 572 for short) had more evolved raltegravir resistance patterns than in published reports of patients in whom raltegravir failed [1]. Viruses with the greatest resistance to 572, measured as fold-change in susceptibility to 572, had a mutation at integrase position Q148 with 2 or more other integrase substitutions. And that pattern was associated with the longest raltegravir use.
Primary raltegravir-related resistance mutations occur at positions Y143, Q148, and N155 in HIV integrase. Virus bearing these mutations generally has a low fold-change in susceptibility to 572, but resistance to this experimental integrase inhibitor grows with increasing numbers of substitutions associated with a Q148 mutation, according to results of S/GSK research. And in SCOPE cohort patients in San Francisco, people with G140S plus Q148H had 3.75-fold resistance to 572, and patients with G140S plus Q148R had 13.3-fold resistance to 572 [2].
To assess the frequency and patterns of these mutations in clinical practice, VIKING study investigators sequenced virus from people in whom a current or former raltegravir-containing regimen failed. VIKING is a pilot phase 2b study of 572 at a dose of 50 mg once daily plus other antiretrovirals after raltegravir failure with integrase mutations.
VIKING investigators screened 53 patients and enrolled 27 in the trial. Forty-three of the 53 screened people (81%) had raltegravir-related mutations, including 7 people with N155H, 13 with changes at Y143, 18 with changes at Q148, 2 with a mixture of Q148H and Y143H pathways, and 3 with rarely seen substitutions: T97A, V151I, and E138D plus V151I plus E157Q. Compared with the published results of the RAL P005 and BENCHMRK trials, in this screening population proportions of N155H were lower while proportions of Y143C/H/R or Q148H/K/R with two or more other mutations were higher.
All 7 patients with Q148H/K/R plus 1 or more other substitutions were taking a failing raltegravir regimen that had a phenotypic susceptibility score of 0 (meaning none of the drugs in the regimen had much activity). The 3 patients with Q148H/K/R plus 2 or more other substitutions had taken raltegravir for the longest time (median 31 months). Raltegravir duration was shorter for the 12 people with Y143C/H/R mutations (median 27.3 months), the 4 people with N155H (median 26.9 months), the 2 people with a Q148H-Y143H mixture (median 24 months), and the 4 people with Q148H/K/R plus 1 one substitution (median 22.6 months).
Fold-change in susceptibility to 572 indicated little or no resistance with substitutions at Y143 (fold-change 1.1) or N155 (fold-change 1.8). But the Q148-Y143 mixture induced a 7.8-fold change in susceptibility to 572, Q148 changes plus 1 other substitution induced a 5.5-fold change, and Q148 changes plus 2 or more substitutions induced a 21.0-fold change.
The VIKING team believes these findings argue that "prompt genotypic testing upon raltegravir virological failure and rapid regimen switch may preserve patients' future treatment options within the integrase inhibitor class." Caution must be exercised in interpreting the resistance pattern results since each defined resistance category contained only a small number of people.

1. Clotet B, Katlama C, Lalezari J, et al. HIV integrase resistance profiles and S/ GSK1349572 baseline phenotypic susceptibility for individuals experiencing virological failure on raltegravir and enrolling in the VIKING phase IIb pilot study (ING112961). HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik. Croatia. Abstract 50.
2. Underwood M, Johns B, Sato A, et al. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. 5th IAS Conference on HIV Pathogenesis and Treatment and Prevention. July 19-22, 2009. Poster WEPEA098.