Evaluation of the genotypic prediction of HIV-1 coreceptor use versus a phenotypic assay and correlation with the virological response to maraviroc: the ANRS GenoTropism study

Abstract

Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist.

FIG. 1.

Study design.

FIG. 2.

Sensitivity and specificity of the detection of X4 or dual/mixed isolates according to 14 genotypic algorithms or combinations of algorithms compared to Trofile (n = 189 patients). Geno2pheno5 and Geno 2pheno10, Geno2pheno algorithms with a false-positive rate set up at 10% or 5%, respectively; Geno2pheno10Clinic, Geno2pheno10 with “clinical” parameters (baseline HIV-1 RNA and nadir CD4⁺ cell count); Geno5PSSM or Geno10PSSM, combinations of Geno2pheno and PSSM algorithms; global, combination of all individual algorithms for detection of X4 or dual/mixed isolates.

FIG. 3.

Virological response to maraviroc-based regimens according to the baseline HIV-1 coreceptor use predicted by different genotypic algorithms (n = 112 patients). Geno10clin, Geno2pheno algorithm with false-positive rate set at 10% and with “clinical” parameters (baseline HIV-1 RNA and nadir CD4⁺ cell count); Geno5PSSM or Geno10PSSM, combinations of Geno2pheno (with false-positive rates set at 5% or 10%) and PSSM algorithms; M1, M2, and M3, date (in months) of follow-up.