Detecting viral tropism: impact of a more sensitive Trofile (ES) assay

It is unfortunate that the viral tropism assay available to screen patients for maraviroc and vicriviroc studies was insufficiently sensitive to identify patients with clinically important R5/X4 mixed populations, and treatment failure in these patients impacted on the trial efficacy results.

Trofile is still the only FDA approved test, but sensitivity has now been improved and a reanalysis of results from the ACTG 5211 vivriviroc study using the new assay (Trofile ES) was presented at the workshop.

Jacqueline Reeves and colleagues from Monogram presented screen and entry samples for the 118 patients, originally all classified as R5, and reported virological responses by the new tropism results. With the new test, 25 patients were now classified as mixed R5/X4. Four samples were not available, and the remaining 89 were all R5.

The virological results for R5 patients at day 14 and week 24 now improved to -1.10 and -1.85; -1.31 and -2.09; and -0.93 and -1.75 logs in the 5mg, 10mg and 15mg arms respectively. This was approximately a 0.2-0.3 log difference in the 5mg and 10mg arms, but did not affect the 15mg results.

While most patients are now thought to have a mix of R5/X4 viruses, the cut-off for the percentage of X4 that becomes clinical important clinical is still to be determined.

Treatment responses were significantly different in the 64 patients with confirmed R5 at screening and entry: -1.15 and -1.95 log reductions at day 14 and week 24. Responses in 5 patients who switched from R5 to mixed R5/X4 between screening and enrollment had reductions were -1.15 and -1.20; and in the 15 patients now identified with mixed tropism at screening of -0.66 and 0.57, at day 14 and week 24.

Several studies looking at determining tropism from genotyping the V3 and V2 loops showed that these results are improving and that using this faster and significantly less costly technology, with an X4 result screening out and an R5 result requiring confirmation, may be more likely in the next year or two. [2]

Comment

This more sensitive tropism test is welcome as accurate identification of tropism prior to using CCR5 inhibitors is clearly key to treatment outcome. Trofile ES will routinely replace Trofile from July 2008.

One important aspect of the genotype V3 approach is the potential to use this as a screening test for patients who are virally suppressed on their current treatment, but who wish to switch to CCR5 inhibitors due to tolerability issues on their current regimen. While phenotype tests require detectable viral load (>500 copies/mL) the genotype tests can work with plasma RNA and proviral DNA.