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

NUCLEOSIDE-ASSOCIATED MUTATIONS CAUSE HYPERSUSCEPTIBILITY TO ETRAVIRINE

Antivir Ther. 2008; 13(Suppl. 3):A25 (abstract no. 23)

G Picchio¹, J Vingerhoets², N Parkin³, H Azijn² and MP de Bethune^2
1Tibotec Inc, Yardley, PA, USA; ²Tibotec BVBA, Mechelen, Belgium; ³Monogram Biosciences, South San Francisco, CA, USA

BACKGROUND: Nucleoside associated mutations (NAMs) have been implicated in hypersusceptibility (HS) to first-generation non-nucleoside reverse transciptase inhibitors (NNRTIs); HS has been associated with better clinical responses to NNRTIs. In vitro HS to etravirine was investigated.

METHODS: A panel of 29 HIV-1 recombinant clinical isolates with well-characterized HS to nevirapine and efavirenz was tested for etravirine phenotypic susceptibility (PhenoSense, Monogram Biosciences). The panel consisted of four groups: a) isolates with no mutations in RT (n=8), b) isolates with M184V alone (n=6), c) isolates with NAMs plus M184V (n=8) and d) isolates with NAMs (n=7). NAMs included amino acid changes at positions 41, 65, 67, 69, 70, 115, 118, 151, 210, 215 and/or 219. In addition, isolates carrying the K103N mutation (n=11), with or without NAMs and other NNRTI mutations, as well as 1,023 wild type routine clinical samples with no known nucleoside reverse transciptase inhibitors-, NNRTI- or protease inhibitor-resistance mutations were tested. HS was defined as a fold change (FC) in EC₅₀ =0.4.

RESULTS: The proportion of samples with HS to etravirine, efavirenz and nevirapine, respectively, in each group was a) 0%, 62.5% and 100%; b) 100%, 100% and 100%; c) 87.5%, 87.5% and 100%; and d) 100%, 71% and 87.5%. Median FC values to etravirine, efavirenz and nevirapine, respectively, in each group were a) 0.53, 0.4 and 0.3; b) 0.27, 0.25 and 0.25; c) 0.29, 0.27 and 0.26; and d) 0.26, 0.33 and 0.34. In addition, one sample with K103N and NAMs showed HS to etravirine (FC=0.24). However, none of 10 samples with K103N alone (n=4) or with K103N plus other NNRTI mutations but no NAMs (n=6) showed HS to etravirine. The median FC among samples with K103N was 1.18 (range 0.49–2.22) for etravirine in contrast to >100 for efavirenz and nevirapine. Among wild type samples, 2.8%, 3.1% and 9.0% showed HS to etravirine, efavirenz and nevirapine, respectively.

CONCLUSIONS: Among the HIV-1 isolates studied, HS to etravirine was mainly observed among those carrying NAMs and/or M184V. K103N-containing isolates did not exhibit HS to etravirine; nevertheless, FC values were below the PhenoSense clinical cut-off for etravirine (2.9). The potential effect of HS on response to etravirine deserves further investigation.

2008-06-10
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