Background:  Approximately 10% of treated patients with drug-resistant viremia transition from detectable CCR5-tropic virus (R5) only to dual/mixed-tropic virus when followed on a stable antiretroviral regimen for 1 year. R5 to DM tropism changes between study screen and baseline have been associated with subsequent virologic failure of CCR5 inhibitor-based therapy. A pre-existing clinically significant minority CXCR4-using virus population, present below assay detection limits at screen, may account for these changes.
Methods:  HIV-infected patients with drug-resistant viremia >1000 copies/mL on a stable CCR5 inhibitor-sparing antiretroviral regimen for >4 months were sampled from a clinic-based cohort study (SCOPE). Viral co-receptor tropism was measured every 4 months until treatment change with a standard tropism assay (Trofile, Monogram Biosciences) and a new modified version of the assay with enhanced sensitivity for detecting minor CXCR4-using viruses.
Results:  In 57 patients with drug-resistant viremia, median baseline values were: plasma HIV RNA level, 3.9 log₁₀ copies/mL and CD4 count, 236 cells/mm³. Using the standard assay, 40 (70%) had R5, 15 (26%) had dual/mixed-tropic virus, and 2 (4%) had X4 virus at baseline. 40 patients, 6 (15%) with R5 at baseline according to the standard assay were reclassified with dual/mixed-tropic virus virus according to the high sensitivity assay. There was a median of 3 tropism observations/patient over a median of 8 months. Using the standard assay, 15% of those harboring R5 at baseline (95%CI 5% to 28%) had apparently changed to dual/mixed-tropic virus at 1 year. Of these apparent R5 to dual/mixed transitions on the standard assay, 60% were persistently dual/mixed by the high sensitivity assay. Using this enhanced assay, 15% of those harboring R5 at baseline (95%CI 7% to 32%) also changed to dual/mixed and 15% of those harboring dual/mixed at baseline (95%CI 5% to 41%) transitioned to R5 by 1 year.
Conclusions:  The majority of apparent R5 to dual/mixed-tropic virus transitions detected with the currently available tropism assay among treated patients are due to pre-existing minority CXCR4-using populations. While R5 to dual/mixed tropism changes can still occur with the enhanced assay, these changes remain relatively uncommon in this population. The clinical significance of these presumably low-level shifts in CXCR4-using virus populations remains to be established in clinical trials.