Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc.

Background: Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop.

Objectives: To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials.

Study Design: Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff.

Results: 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed.

Conclusions: In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.