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Improved Genotypic Algorithm for Predicting Etravirine Susceptibility: Comprehensive List of Mutations Identified Through Correlation with Matched Phenotype
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Reported by Jules Levin
CROI 2010 SF Feb
Mojgan Haddad, Eric Stawiski, Jamal Benhamida, Eoin Coakley
Monogram Biosciences, South San Francisco CA USA
Mojgan Haddad
Monogram Biosciences, Inc.
345 Oyster Point Blvd.
South San Francisco, CA 94080
mhaddad@monogrambio.com
Phone #: (650) 616-3645
Fax #: (650) 616-3652
RESULTS
Sensitivity to detect ETR FC ≥ 2.9 was 90.1% and discordance rate for all samples was 13.6% compared to 83.7% and 12% for the original MGRM weighted score, respectively. The improved sensitivity was accompanied by modest increase in number of samples with FC < 2.9 but a weighted score ≥ 4, from 11 by the original score to 14.5 by the enhanced algorithm.
AUTHOR CONCLUSIONS
Using this optimized genotypic score, sensitivity for detecting resistant viruses was improved by 6.4% thru inclusion of more mutations associated with phenotypic reduced susceptibility to ETR. Adversely, the rate of identifying ETR FC < 2.9 decreased by 3.5%.
Discordant cases with high genotypic score but phenotypically susceptible to ETR may be caused by increased sensitivity due to NRTI mutations.
Phenotype remains the reference methodology to optimally determine ETR susceptibility.
BACKGROUND
Etravirine (ETR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which has shown activity against many HIV-1 strains with multiple NNRTI resistance mutations.
Recent studies (Benhamida 2008 and Vingerhoets 2008) have shown that a weighted factor applied to more extensive list of mutations minimizes discordance rate of ETR susceptibility by phenotype versus genotype.
We evaluated a new weighting algorithm applied to the combined list of mutations within Monogram’s matched phenotype and genotype database from the most recent year of commercial patient testing.
METHODS
We studied phenotype and genotype results of 4,923 samples containing at least one NNRTI mutation from the following lists:
Expanded list of ETR muations derived from combining 2 studies [1, 2]: V90I, A98G, L100I, K101E/H/P, K103R, V106A/I/M, E138A/G/K/Q, V179D/E/F/I/L/M/T, Y181C/F/I/V, Y188L, V189I, G190A/E/Q/S/T, H221Y, P225H, M230L, K238N/T.
NNRTI resistance associated mutations: A98G, L100I, K101E/P, K103N/S, V106A/M, Y181x, Y188x, G190x, P225x, F227x, M230L, P236L, where x represents any amino acid substitution.
ETR reduced susceptibility as measured by fold-change of IC50 (FC) ≥ lower clinical cutoff (2.9) was compared to a weighted score applied to the
expanded list of mutations.
Weights for individual mutations and threshold for reduced susceptibility on overall score were optimized to minimize discordance rate between phenotype and genotype.
1. Purpose of the Study
To develop an enhanced genotypic algorithm for detecting resistance to ETR, by applying a combination of 2 weighted score
systems, and other resistance associated mutations identified thru correlation analysis with phenotypic response.
The 2 independent studies that reported extended lists of ETR resistance associated mutations and their weight factors are:
- MGRM: developed by Monogram Biosciences thru minimizing discordance to phenotypic susceptibility [1].
- TBTC: developed by Tibotec thru correlation with virologic outcome [2].
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