CCR5 Antagonist Vicriviroc Demonstrates Greater Efficacy in Patients Identified Using More Sensitive CCR5 Tropism Test

		SUMMARY: The experimental CCR5 antagonist vicriviroc, currently under development by Schering-Plough, was found to be more effective than previously demonstrated when eligible patients were selected using the newer, more sensitive Trofile CCR5 tropism test, according to an analysis published in the December 1, 2009 Journal of Infectious Diseases.

By Liz Highleyman

Zhaohui Su from Harvard School of Public Health and colleagues used the enhanced-sensitivity Trofile assay (produced by Monogram Biosciences) to re-screen 118 treatment-experienced participants in AIDS Clinical Trials Group study A5211 who were previously classified as having exclusively CCR5-tropic HIV at study entry.

HIV can use 2 different surface co-receptors -- CCR5 and CXCR4 -- to gain entry into cells. CCR5 antagonists like the approved drug maraviroc (Selzentry) and the experimental candidate vicriviroc are intended to work against CCR5-tropic strains of the virus. For this reason, potential study participants were screened to ensure that they carried only CCR5-tropic virus, and not CXCR4-tropic or dual/mixed-tropic HIV strains.

Inhibition of virus entry of CCR5-utilizing (monocytotropic) and CXCR4-utilizing (T-cell tropic) HIV isolates by the natural ligands of the chemokine coreceptors CCR5 and CXCR4.

As previously reported, maraviroc demonstrated better efficacy in a retrospective analysis (called MERIT-ES) that excluded patients who initially were misclassified as having exclusively CCR5-tropic HIV using the original Trofile test, but later were found to have CXCR4-tropic or dual/mixed-tropic virus using the more accurate assay. In fact, using the new test shifted the results from failure to demonstrate non-inferiority to efavirenz (Sustiva) to statistical equivalence.

In the present study, investigators performed a similar reanalysis of participants in ACTG A5211, a randomized trial of vicriviroc versus placebo.

Among the 90 vicriviroc recipients, the 72 patients with confirmed exclusively CCR5-tropic HIV achieved a significantly larger mean reduction in HIV RNA than the 15 patients who were reclassified as having dual/mixed-tropic virus using the enhanced sensitivity test (-1.11 versus -0.09 log copies/mL at day 14, -1.91 versus -0.57 log copies/mL at week 24; P < 0.001).

These findings indicate that vicriviroc appears more effective than previously shown and, according to the study authors, "suggest that the enhanced-sensitivity assay is a better screening tool for determining patient eligibility for CCR5 antagonist therapy."

1/12/10

Reference
Z Su, RM Gulick, A Krambrink, and others. Response to Vicriviroc in Treatment-Experienced Subjects, as Determined by an Enhanced-Sensitivity Coreceptor Tropism Assay: Reanalysis of AIDS Clinical Trials Group A5211. Journal of Infectious Diseases 200(11): 1724-1728 (Abstract). December 1, 2009.