Background: HIV entry inhibitors that block infection via CCR5 have shown efficacy in suppressing CCR5- (R5) but not CXCR4- (X4) or dual/mixed-tropic HIV. ACTG5211 was a phase IIb study of the CCR5 antagonist vicriviroc (VCV) in treatment-experienced subjects with R5 virus at study screen. Reduced virologic response was observed among subjects with R5 virus at screen but dual/mixed at baseline, and in subjects with CXCR4-using virus on study as determined by a standard tropism assay (Trofile, Monogram Biosciences, South San Francisco). An enhanced version of this assay has been developed with improved ability to detect low levels of CXCR4-using variants. We hypothesized these assay enhancements might better identify CXCR4-using virus in the screening samples from subjects enrolled into ACTG 5211.

Methods: The co-receptor tropism of virus populations obtained at screen and baseline from 116 subjects was determined with the enhanced assay and compared to original tropism results. The number of subjects reclassified with dual/mixed virus at screen and who would have been excluded from the study by the enhanced assay was determined and compared to the number of patients with CXCR4-using virus on-study by the standard tropism assay.

Results: Enhanced tropism results are available for 116 subjects. In the screening sample, 25 subjects were previously defined as having R5 virus by the standard assay and were reclassified as having dual/mixed virus by enhanced assay. On study, 15 of these 25 reclassified subjects received VCV with 12 of 15 demonstrating dual/mixed virus by the standard assay during follow-up. Conversely, 3 of 15 reclassified VCV recipients had R5 virus at all follow-up time points by the standard assay. In the screening sample, 12 subjects were previously defined as having R5 virus and dual/mixed virus at baseline by the standard assay. The enhanced assay detected dual/mixed virus in the screening sample in 7 of these subjects.
Conclusions: The enhanced sensitivity tropism assay identified CXCR4-use at screen in 12 of 15 VCV recipients with emergence of CXCR4-using variants on-study as determined by the standard tropism assay. This suggests that the enhanced assay may be an improved screening tool for determining eligibility for CCR5 antagonist therapy. Reanalysis of virologic response to VCV in light of enhanced tropism assay calls will determine if the enhanced assay may further optimize selection of patients who may benefit from CCR5 inhibitors.