17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

MUTATIONAL PATTERNS IN THE HIV-1 INTEGRASE RELATED TO VIROLOGICAL FAILURES ON RALTEGRAVIR-CONTAINING REGIMENS

Antivir Ther. 2008; 13(Suppl. 3):A14 (abstract no. 12)

D Da Silva^1,2, I Pellegrin^1,2, G Anies^1,2, D Breilh^1,2, L Wittkop³ , P Morlat¹, M Dupon^1,2, D Neau^1,2, JL Pellegrin^1,2, H Fleury^1,2 and B Masquelier^1,2
1CHU de Bordeaux, France; ²EA 2968, Université Victor Segalen, Bordeaux, France; ³INSERM U897, Bordeaux, France

BACKGROUND: We aimed to study the in vivo viral genetic pathways for resistance to raltegravir (RAL), an HIV-1 integrase inhibitor (INI), in antiretroviral-experienced patients with absence of complete inhibition of HIV-1 replication on RAL-containing regimens.

METHODS: We set up a prospective study including antiretroviral-experienced patients receiving RAL and an optimized background antiretroviral regimen as salvage therapy. The virological and immunological response was studied at months (M) 0, 1, 3 and 6 after initiation of RAL. Genotypic resistance analysis was performed at baseline of RAL by sequencing analysis of the HIV-1 pol gene (protease, reverse transcriptase and integrase). The integrase was also sequenced at the time of virological failure (VF; that is, the absence of decrease of viral load <50 copies/ml at month 3 and 6 or rebound of viral load >50 copies/ml). We used a list of mutations previously reported to be related to in vivo or in vitro resistance to INI for the description of mutations emerging between baseline and VF.

RESULTS: We included 46 patients of the ANRS CO3 Aquitaine Cohort. At baseline, the median plasma viral load (pvl) was 4.43 log₁₀ copies/ml and the median CD4+ T-cell count was 200 cells/µl. The proportion of patients with pvl <50 copies/ml was 48.8% at M3 (n=46) and 65.7% at M6 (n=35). Integrase sequences were obtained at baseline and at follow-up for 12 patients with VF. Four different patterns of mutations were observed: emergence of Q148H/R with secondary mutations V72I, L74M, G140A/S, E138A, K156N, K160N, V201I and T206S (five patients); emergence of N155S/H, in the following replaced by a pattern including L74M, T97A, Y143C/H/R, G163R, V151I, S230R (three patients); selection of S230N (one patient); and no selection of mutation but conservation of mutations from baseline to VF (V201I, E157Q+T206S and L74M with one patient each).

CONCLUSIONS: Complex and diverse genetic profiles can be associated to VF on RAL-containing regimens, including dynamics of replacement of mutational profiles. This genetic evolution deserves further molecular investigation in order to better characterize the resistance to RAL.

2008-06-10
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