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  International HIV and Hepatitis Drug Resistance Workshop
June 8-12, 2010,
Dubrovnik Croatia
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Over Half of European Raltegravir Failures Without
Apparent Integrase Mutations

  International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
More than half of patients in whom raltegravir failed in a multicenter European study had no detectable integrase mutations [1]. Among those with mutations, one major pattern differed between people with subtype B HIV-1 and people with other subtypes.
The Coronet project evaluates resistance to integrase inhibitors across Europe. This analysis involved 255 raltegravir-experienced people at nine centers and in two multicenter databases, the UK HIV Drug Resistance Database and the EuResist Database. Forty-five people (17.6%) were infected with a non-B subtype, usually CRF_AG, but also C, F, G, A, D, and CRF_AE. The investigators also searched for integrase mutations in 561 people beginning raltegravir with no integrase inhibitor experience.
Median viral load at genotyping was 3523 copies among raltegravir-experienced people and 21,476 copies among integrase inhibitor-naive individuals. Among 255 patients taking a failing raltegravir regimen, only 114 (45%) had one or more detectable integrase mutations. Median viral load did not differ significantly between raltegravir-experienced people with and without major integrase mutations (3420 versus 3834 copies, P = 0.30). N155H was the most common integrase mutation (18%), followed by G140A/S plus Q148H/R/K (14.1%), Y143R/C alone (4.7%), E92Q plus N155H (3.1%), and Q148H/R/K alone (2.4%). Seven people (2.7%) had one or more "nonclassic" mutations without one of the just-listed major mutations.
Looking at the three major raltegravir resistance pathways, the Coronet investigators found a significant difference in proportions with Q148H/R/K infected with subtype B (n = 43, 20.5%) and those infected with non-B strains (n = 2, 4.4%) (P = 0.02). But rates of two other major pathways did not differ between B and non-B viruses: N155H in 22.4% versus 22.2%, and Y143R/C in 5.2% versus 4.4%.
Other integrase mutations occurring in more than 1% of samples were L74I/M, T97A, T125A/V, E138D/K, V151I, M154I/L, E157Q, K160Q/T, G163E/R, I203M, and S230N. These mutations usually appeared with major integrase mutations. The investigators also identified three novel integrase mutation groups that they did not see in 591 integrase inhibitor-naive people starting raltegravir: K159Q/R, I161L/M/N/T/V, and E170A/G. As a result, the Coronet team suggested these substitutions may play a role in resistance to integrase inhibitors.
Why raltegravir-containing regimens failed so frequently without integrase mutations and why mutation patterns sometimes differ according to HIV-1 subtype remain to be elucidated. The Coronet researchers did not have data on raltegravir blood levels as an adherence gauge. Nor did they have data on the activity of antiretrovirals being taken with raltegravir.
The findings could have implications for use of second-generation integrase inhibitors. For example, other work presented at this Resistance Workshop (reviewed separately by NATAP) found that a Q148 mutation pattern in raltegravir-failing patients tended to make virus cross-resistant to S/GSK1349572, an investigational integrase inhibitor [2]. A French study of 11 people in whom raltegravir failed found that those with Q148H/R mutation patterns had virus highly resistant to both raltegravir and elvitegravir, another integrase inhibitor in clinical development [3]. In the French study only 2 of 11 people (18%) with virologic failure during raltegravir salvage therapy had no evidence of integrase mutations.
1. Geretti AM, Fearnhill E, Ceccherini-Silberstein F, et al. Prevalence and patterns of raltegravir resistance in treated patients in Europe. HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 51.
2. 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.
3. da Silva D, Van Wesenbeeck L, Breilh D, et al. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemoth. 2010;65:1262-1269.