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Quantiferon, a one-step blood test for latent TB infection, got a thumbs-up from a Food and Drug Administration (FDA) advisory panel on Oct. 12. TB researchers hailed the Microbiology Devices Panel’s approval, saying the favorable judgment clears the way for the fine-tuning needed to show how the test can best be used. Though the FDA is not bound by recommendations of advisory panels, the agency generally abides by them.
"For the first time in a hundred years, we have a new test to aid in the diagnosis of latent TB infection," says Gerald Mazurek, MD, an epidemiologist at the Division of Tuberculosis Elimination (DTBE) at the Centers for Disease Control and Prevention, and the principal investigator of the CDC’s Phase III trials of Quantiferon. "It’s not a perfect test yet, but this gives us the framework in which it will evolve."
The fact that results of Quantiferon tests don’t always agree with results from the tuberculin skin test (TST) didn’t trouble panel members. "We felt that given the limits of the tuberculin skin test, [Quantiferon] offers advantages," says Roxanne Shively, MS, senior scientific reviewer in the FDA’s bacteriology branch, and a member of the FDA review team that presented a summary of findings to the panel. "We felt the concordance issue wasn’t as important as being able to get results."
The challenge now, Shively adds, is for the CDC to figure out how best to interpret the results in clinical settings and for TB control purposes. "We want guidelines in place from the CDC on how to use this test, and how to incorporate the test into a meaningful clinical algorithm," Shively says. Most panel members felt it would be better for the CDC to provide physician training than for the company that manufactures the device, Cellestis Ltd. of Melbourne, Australia, to set up educational components, she notes.
The FDA panel placed no restrictions on how the test could be used, other than to note that data are still lacking for test performance in certain groups, including HIV-positive people, transplant patients, pregnant women, and children, Shively says. As one condition attached to its approval, the panel added that the test should not be used within 30 days of applying a TST. TB experts at the CDC say that’s because the tuberculin antigen in the TST sometimes can provoke a transient immune reaction that might yield a false positive result from Quantiferon.
The panel’s favorable decision opens the doors for new trials that may produce the next generation of Quantiferon, says Mazurek. Researchers now plan to substitute more specific antigens for the tuberculin presently used in the assay, a step that has the potential to eliminate false positives due to cross-reactions with BCG or atypical mycobacteria, says Mazurek. Quantiferon already has been found to outperform the TST when discriminating between subjects infected with latent TB and those either infected with an atypical mycobacterium or who have been vaccinated with BCG, according to results from Mazurek’s first round of studies.1
Once the CDC has provided appropriate guidelines, anyone equipped to perform an ELISA test can start using Quantiferon, Mazurek notes. Most likely, the first large-scale users will be the U.S. military, jails, or other entities that currently use the TST to get baseline screenings on large groups of people. The U.S. Navy (which participated in a second group of Phase III trials conducted in the United States) is said to be eager to substitute Quantiferon for the TST as a screening device for naval recruits.
Some TB experts at the CDC say Quantiferon might also work as a back-up test for situations in which TST screenings have resulted in suspected false positives. Waiting for 30 days until after the TST has been placed — the period of time suggested by the FDA panel — might remedy the problem of transient false-positive reactions from the tuberculin, some DTBE experts say.
As a condition of its approval, the FDA panel listed five tasks that Cellestis must first perform. They include:
Complying with these conditions should not prove difficult, say Shively and Mazurek. The "new studies" requirement means Cellestis must retest the assay in different settings using the blood samples already collected, Mazurek says. As for resorting and revalidating data by a different cut-point, that step is meant to reduce the number of positives in low-risk populations while making sure that raising the cut-point doesn’t change results across other populations, says Shively. Like the skin test, the results of Quantiferon are read quantitatively, with cut-off points established to designate whether the test is read as positive or not.
It’s not yet possible to say how much the test will cost on the American market, says Mazurek. Whatever the cost, the test offers a substantial logistical advantage over the TST in that subjects don’t have to return a second time for a reading.
The test was first developed by an Australian veterinarian to detect latent TB infection in cattle. It measures the amount of the cytokine gamma-interferon produced in response to the tuberculin antigen. The assay was purchased by Cellestis, which has been collaborating with the CDC to shepherd the assay through its Phase III trials in the U.S.
1. Mazurek GH, LoBue PA, Daley CL, et al. Comparison of whole-blood interferon assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA 2001; 286:1740-1747.