Abstract
ObjectivesWe analysed the impact of different parameters on genotypic tropism testing related to clinical outcome prediction in 108 patients on maraviroc (MVC) treatment.Methods87 RNA and 60 DNA samples were used. The viral tropism was predicted using the geno2pheno[coreceptor] and T-CUP tools with FPR cut-offs ranging from 1%-20%. Additionally, 27 RNA and 28 DNA samples were analysed in triplicate, 43 samples with the ESTA assay and 45 with next-generation sequencing. The influence of the genotypic susceptibility score (GSS) and 16 MVC-resistance mutations on clinical outcome was also studied.ResultsConcordance between single-amplification testing compared to ESTA and to NGS was in the order of 80%. Concordance with NGS was higher at lower FPR cut-offs. Detection of baseline R5 viruses in RNA and DNA samples by all methods significantly correlated with treatment success, even with FPR cut-offs of 3.75%-7.5%. Triple amplification did not improve the prediction value but reduced the number of patients eligible for MVC. No influence of the GSS or MVC-resistance mutations but adherence to treatment, on the clinical outcome was detected.ConclusionsProviral DNA is valid to select candidates for MVC treatment. FPR cut-offs of 5%-7.5% and single amplification from RNA or DNA would assure a safe administration of MVC without excluding many patients who could benefit from this drug. In addition, the new prediction system T-CUP produced reliable results.
Highlights
To enter the host cell, the Human Immunodeficiency Virus type 1 (HIV-1) binds to the cellular receptor CD4 and one of the cellular coreceptors CCR5 or CXCR4
Concordance between single-amplification testing compared to ESTA and to next generation sequencing (NGS) was in the order of 80%
Concordance with NGS was higher at lower FPR cut-offs
Summary
To enter the host cell, the Human Immunodeficiency Virus type 1 (HIV-1) binds to the cellular receptor CD4 and one of the cellular coreceptors CCR5 or CXCR4. Since MVC binds exclusively to the CCR5 molecule, its administration must be preceded by a coreceptor usage (or tropism) phenotypic or genotypic analysis. The most-widely used is the Enhanced Trofile (ESTA) test, whose validity has been shown in the MOTIVATE, MERIT and A4001029 trials [1,2,3], other methods are currently available [4]. Several studies have demonstrated that the V3 bulk sequencing produces tropism results comparable to ESTA and is adequate for clinical purposes [5,6,7]. Sequences generated in genotypic testing (bulk and NGS) need to be interpreted by bioinformatics tools to produce a tropism prediction. For NGS, the geno2pheno[454] tool is freely-available within the geno2pheno system on the internet
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