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Prevalence of genotypic and phenotypic susceptibility to etravirine in US samples received for routine resistance testing
Presented by Gaston Picchio (United States).
G. Picchio1, J. Vingerhoets2, L. Tambuyzer3, E. Coakley4, M. Haddad4, J. Witek5
1Tibotec Inc., Titusville, United States, 2Tibotec BVBA, Clinical Virology, Mechelen, Belgium, 3Tibotec BVBA, Mechelen, Belgium, 4Monogram Biosciences, South San Francisco, United States, 5Tibotec Therapeutics, Titusville, United States
Background: In the Phase 3 DUET trials of the NNRTI etravirine (TMC125), 77.0% and 74.1% of etravirine-treated patients with a Tibotec susceptible etravirine weighted genotypic score (WGS) ≤2 or an Antivirogram fold-change (FC) ≤3 at baseline, respectively, achieved < 50 HIV-RNA copies/mL at Week 48. The prevalence of etravirine susceptibility was investigated in clinical samples referred for routine resistance testing (RT) using Monogram Biosciences (MGR) etravirine WGS and PhenoSense assay.
Methods: 14,940 samples submitted to MGR for RT from June 2008 to June 2009 were analysed. Samples were defined as NNRTI-resistant if they carried at least one of the following mutations: A98G, L100I, K101E, K101P, K103N, K103S, V106A, V106I, Y181x, Y188x, G190x, P225x, F227x, M230L, and P236L where x represents any amino acid substitution. MGR's etravirine WGS consisting of 30 mutations (Benhamida 2008) was used to define viral susceptibility to etravirine, with a genotypic score ≤3 denoting full susceptibility. Phenotypic susceptibility to etravirine was determined using 2.9 and 10 as low and high clinical cutoffs, respectively. The impact of K103N on genotypic susceptibility to etravirine was also investigated.
Results: Among 5,482 (36.7%) NNRTI-resistant samples, 67.2% were classified as genotypically susceptible and 76.4% as phenotypically susceptible (median FC 0.8) to etravirine, with 10.7% having FC≥10. Using Tibotec's WGS, 67.4% of NNRTI-resistant samples were etravirine-susceptible (WGS≤2). Among NNRTI-susceptible samples (n=9,458), 99.5% had etravirine FC< 2.9 (median 0.8) and 0.5% had FC≥2.9 and < 10 (median 3.5). In a subset of NNRTI-resistant samples (n=4,514), with (n=3,598) or without (n=916) K103N mutation, the proportion of etravirine genotypically-susceptible samples (average median FC 1) was 76.9% and 48.6%, respectively.
Conclusions: Using different interpretation systems, most samples received for RT with or without evidence of NNRTI resistance were susceptible to etravirine. Among NNRTI-resistant samples, more were etravirine-susceptible phenotypically than genotypically, and more were etravirine-susceptible among those with K103N.
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