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Screening for HIV tropism using population-based V3 genotypic analysis: a retrospective virological outcome analysis using stored plasma screening samples from MOTIVATE-1
Presented by P.R. Harrigan (Canada).
P.R. Harrigan1, R. McGovern1, W. Dong1, L. Swenson1, A. Thielen2, M. Jensen3, T. Mo1, D. Chapman4, M. Lewis5, I. James5, J. Heera6, S. Ellery6, H. Valdez4
1BC Centre for Excellence in HIV/AIDS, Vancouver, Canada, 2Max-Planck Institute for Informatics, Saarbrucken, Germany, 3Fortinbras Research, Buford, United States, 4Pfizer, Inc., New York, United States, 5Pfizer R&D, Sandwich, United Kingdom, 6Pfizer R&D, New London, United States
Background: MOTIVATE-1 compared maraviroc + Optimised Background (OB) vs placebo + OB in treatment-experienced (TE) patients with R5-HIV (standard Monogram Trofile). A subset screened with non-R5-HIV were followed in a sister safety trial, “A4001029”. This study retrospectively examined the performance of population V3-loop sequence-based tropism screening.
Methods: Triplicate V3-loop sequencing performed on stored screening plasma samples was processed without human intervention using custom software (“ReCall”), blinded to clinical data. 25% of the dataset was reserved for validation. Tropism was inferred using either geno2pheno ('g2P'; 5% false positive rate) or PSSM (-2.96 cut-off). Primary outcomes were a) concordance between the screening Trofile and genotype; and b) viral load (VL) changes after starting maraviroc.
Results: Compared to Trofile, genotype had sensitivities of 63% and 56% and specificities of 91% and 90% for detecting non-R5 virus using g2P and PSSM, respectively (n = 1230). Genotype and Trofile results were available for 572 subjects with virologic outcomes data (non-R5 N=116 by Trofile).
[Table 1]
VL responses were similar regardless of the assay used. Median placebo week 8 VL decreases were ≤ 1 log; ≤ 26% of placebo recipients had a virologic response (VL < 50c/mL) at week 24. The effect of triplicate sequencing was a change in tropism call from R5 to non-R5 in ~7.5% of samples.
Conclusions: Despite apparently poor sensitivity of standard genotyping for predicting non-R5 HIV relative to standard Trofile, early viral load reductions in this TE population were similar regardless of the assay used, suggesting the potential of genotyping as an accessible assay to select candidates for maraviroc.
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