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The makers of Quantiferon-TB were scheduled to ask the U.S. Food and Drug Administration (FDA) for a license to market their new diagnostic test for latent TB in this country on Oct. 12. The FDA was expected to base much of its answer to that request on data scheduled for publication in the Oct. 10 issue of the Journal of the American Medical Association (JAMA). The JAMA article was to have laid out the findings from a Phase 3 trial of Quantiferon in the United States in which Quantiferon was compared with the tuberculin skin test (TST).
Cellestis Ltd., the Australian firm that makes Quantiferon, has asked the FDA to approve the product for exactly the same indications as the TST, says Jim Rothel, PhD, chief scientific officer for Cellestis. The new test offers substantial logistical advantages over the TST, because it consists of only one step, not two, and because results are far less subject to subjective interpretation, says Rothel. Quantiferon uses an enzyme immunoassay to measure the amount of gamma-interferon, a cytokine produced by individuals whose immune systems have been primed to react to tuberculin.
Superior logistics notwithstanding, the FDA’s task will be to decide whether the test gives more accurate results than the much-maligned TST. To do that, the Phase 3 trials used people with no known history of TB exposure to gauge specificity and persons with culture-confirmed TB to assess sensitivity, says Rothel.
But to compare the two tests’ ability to detect latent TB infection, the only standard available is the TST. Clearly, the two tests don’t always agree. (Analysis of early data from the trials suggested they disagreed 70% to 90% of the time.) But given the well-known fallibility of the TST, is that good news or not? "It’s exactly what we’d hoped for — our test didn’t always agree with the TST," says Rothel. Whether the FDA agrees with his interpretation is, he concedes, the big question.
In tests in cattle, results suggest the difference is due to Quantiferon’s superior performance, he adds. Bovigam, also made by Cellestis, is used to detect latent TB in cattle by reacting to a cytokine produced by the animals. In side-by-side comparisons with the bovine equivalent of the TST, Bovigam disagreed with the skin test about 20% of the time. In those tests, it was easier to interpret the discrepancy, because cultures from the cattle provided a ready reality check. In the animal trials, Bovigam was clearly the winner, giving more accurate readings.
But Bovigam is testing for a different cytokine than Quantiferon, so it’s not accurate to say results from the Bovigam trials apply equally to Quantiferon, says Gerald Mazurek, MD, an epidemiologist at the Center for Disease Control and Prevention’s Division of TB Elimination who has overseen the Phase 3 trials.
Still, Quantiferon’s performance has looked promising in two other respects. Although it sometimes does react positively in people who have received a bacille Calmette-Guèrin (BCG) vaccination in the past, it appears to be flummoxed by BCG less often than TST, says Rothel.
When it comes to nontuberculous mycobacterial infections, such as Mycobacterium avium, Quantiferon seems a much cannier instrument, with early data showing it reacted to atypicals only one-third as often as TST. (See related story in TB Monitor, October 2000, p. 97.)
Both tests sometimes fall short when it comes to spotting TB in active cases, concedes Rothel. In the case of Quantiferon, that’s because levels of gamma-interferon plummet with onset of active disease and often don’t rebound until as late as a year later, he says. The fact that all patients in the Phase 3 trials had already begun treatment probably threw off Rothel’s test further, he says; the test would have performed better in pretreatment subjects, he adds.
In Australia, Quantiferon is already licensed for use and is being used in place of the TST in two hospitals in Perth, Rothel says. "But I won’t lie to you," he adds. "Most people here have been waiting before they switch to see the results of the Phase 3 trials in the U.S."
Even if the FDA gives full approval at the licensure hearing, Rothel says he doesn’t expect an overnight revolution in the way clinicians assess latent TB. "First we’ll have to dispel a certain amount of myth and folklore, I expect," he says.