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Clinical, Virological, and Immunological Characteristics of Patients With Discordant Phenotypic and Genotypic (Ultra-Deep Sequencing) Tropism Test Results: Analysis of Tropism Calls in MOTIVATE and 1029 - poster
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Reported by Jules Levin
International HIV & Hepatitis Virus Drug Resistance Workshop and Curative
StrategiesJune 8-12, 2010Dubrovnik, Croatia poster 13
D Chapman1, H Valdez1, M Lewis2, I James2, J Heera3, RA McGovern4, LC Swenson4, PR Harrigan41Pfizer Inc, New York, NY, USA; 2Pfizer Global Research and Development, Sandwich, UK; 3Pfizer PGRDNew London, CT, USA; 4BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada
BACKGROUND
The MOTIVATE 1 & 2 studies compared maraviroc (MVC) + optimized background therapy (OBT) vs placebo + OBT in treatment-experienced patients with R5 HIV, with tropism determined using the original Trofileassay (Monogram Biosciences). Patients with non-R5 HIV received MVC in the A4001029 safety study
Both phenotypic (Trofile) and genotypic (deep V3 loop and population sequencing) methods of determining tropism have been shown to predict clinical responses to MVC1,2
retrospective analysis in patients with paired phenotypic and genotypic tropism results that are either concordant or discordant may help ascertain whether some phenotypically non-R5 viruses can respond to MVC and improve predictions of co-receptor tropism and therapeutic outcomes
Objectives
To determine the concordance of phenotypic (original Trofile) HIV-1 tropism results with those obtained by genotype using a deep (454) sequencing methodology, in plasma screening samples from treatment-experienced patients in the MOTIVATE 1 & 2 and A4001029 studies
To characterize patients with concordant and discordant results by these two methods in terms of their clinical, virological and immunological parameters
To characterize virologic responses in patients with concordant and discordant results to determine whether patients with R5 virus by genotype but non-R5 virus by the phenotypic assay can respond to MVC
Figure 1. Most patients (84%) had concordant tropism results between phenotypic and deep genotypic testing
Figure 2. Absolute and relative abundance of non-R5 virus by454-genotype at screening
a0 copies/mL (untransformed).
b25th percentile = 0 copies/mL.
Figure 3. Trofile X4 RLUs were comparable in discordant R5 Trofile and concordant R5 samples
Figure 4. Trofile calls cluster on extremes of non-R5 distribution by 454-genotype
aIncludes all 7 patients with X4 virus by Trofile.
Figure 5. Population sequencing detects more non-R5 HIV-1 than Trofile when 454-genotype is used as the reference standard
Figure 6. In cases of discordance, 454-genotypic tropism results correlated better with virologic response than original Trofile results
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