CDC changing position on anergy testing, therapy

Testing may be needed in high-risk areas

After years of debate, a revised set of recommendations for anergy testing of HIV- positive patients due this fall is expected to step back and take a less definitive approach. The guidelines also will address new evidence supporting the notion that preventive therapy for tuberculosis in this population also is unwarranted in most settings.

"Based on what I’ve seen, the CDC won’t mandate that it’s wrong to do anergy testing — just that it’s okay not to do it," says Charles Daley, MD, assistant professor of medicine at the University of California San Francisco (UCSF). He also is chief of the chest clinic at San Francisco General Hospital, and is one of the experts whose testimony on the subject will be incorporated into the new guidelines.

The new recommendations are expected to address what many experts see as the test’s biggest problem: It’s not standardized, says Daley.

"It’s standardized neither in terms of what antigens are used, nor in terms of what’s considered a positive reaction," he says. Some publications define a positive reaction as greater than 0 mm, some say greater than 2 mm, and some — including the CDC — say greater than 5 mm, he adds.

The situation with antigens is likewise confusing. Only recently have drug companies shown much interest in producing a product that’s consistent from one batch to the next, Daley also notes. "Within the last year, there’s a new Candida antigen that’s standardized. Tetanus [toxoid], coccidioidin, and Candida are starting to get there," he says. "But we need one company and one lot."

Anergy may prove so fickle a phenomenon that it’s not even worth assaying, some experts say.

One multi-center study has shown that anergy waxes and wanes over time. After a year’s time, a third of previously anergic patients in a cohort regained their ability to mount a delayed-type hypersensitivity response.

Thus, anergy tests in their present form give clinicians nothing of value, Daley says. At UCSF, "we don’t make any clinical decisions based on whether someone is anergic or not. We don’t provide them with preventive therapy; it doesn’t help us to know they’re anergic."

Theoretically, a standardized test could be useful, he says. But first, antigens must be standardized; how to read the test must be standardized; and the test itself must be tested, says Daley.

"That will all take a very long time," he says. "That means we’re not going to have an answer soon." It also means that for now, at least on the subject of anergy testing, "we’re still confused."

Revising position on preventive therapy

On the other end of the anergy testing debate is the controversy over whether preventive therapy is useful in HIV-positive patients who are anergic. Since 1991, the CDC has recommended that anergic patients should be considered for preventive therapy if they belong to groups in which the prevalence of tuberculosis is greater than 10%. While anergic HIV- positive patients are deemed high-risk for developing TB, no study has investigated the benefit they receive from prophylaxis — until now, that is.

In a large controlled trial conducted from 1991 to 1996, 517 patients with two or more risk factors for TB were treated with six months of isoniazid (INH) or placebo.1 The patients, three-quarters of whom were from New York City, were similar in both groups, with 23% diagnosed with AIDS and a mean CD4 count of 240. The only difference was that the placebo group had more patients who were unemployed for a year or more. In both groups, 63% of the patients completed therapy.

The study found that the treatment was safe, but offered no benefit in preventing TB or improving survival. In the treatment group, 3 of 260 patients developed confirmed TB, compared to six of 257 in the placebo group.

"The impact of INH was so light that it was really not statistically significant," says lead author Fred Gordon, MD, chief of infectious diseases at the VA Medical Center in Washington, DC. "This population has so little TB that you really shouldn’t invest your time and effort in providing prophylaxis."

As a result of this and other studies, the CDC is revising its 1991 guidelines on anergy testing and should publish them in September.

"We concluded that anergy testing, at least in the United States, was not very helpful in predicting which people would be at risk of tuberculosis," says Rick O’Brien, MD, chief of the CDC’s research and evaluation branch in the division of TB elimination. "Our revised guidelines are saying that anergy testing in program settings is no longer routinely recommended, but there are individual instances where anergy testing may be useful."

Clinicians who treated patients in areas at high risk for TB, particularly in New York, argue that INH preventive therapy is reasonable and will probably continue to recommend it, O’Brien says. The new guidelines don’t rule out the use of preventive therapy in anergic patients and will continue to recommend that any HIV-positive patient exposed to TB should receive preventive therapy, he says.

"The guideline doesn’t come out explicitly as saying we shouldn’t give preventive therapy [to anergic patients]," he says, adding that a meeting in early September on TB prevention issues in HIV infection will consider that question more definitively. In some high-risk environments, particularly correctional facilities, preventive therapy may still be warranted in anergic patients, he adds.

Reference

1. Gordin G, Matts J, Miller C, et al. A controlled trial of isoniazid in persons with anergy and HIV infection who are at high risk for tuberculosis. N Engl J Med 1997; 337:315-320.