2RZ may get new grade; MMWR guide best bet

Prospect of C’ rating has loyalists upset

If a new Public Health Service ratings table were issued today for treatment of latent TB infection (LTBI), the problem kid in the class — two months of rifampin/pyrazinamide (2RZ) — could wind up with a grade of "C." That grade would reflect one of two demotions under consideration for the regimen. The less-controversial proposal under consideration is to lower the strength of the recommendation for HIV-positive patients from "A" to "B." The other proposal would demote the strength of the recommendation for HIV-negative patients from a "B" to a "C."

The prospect of that "C" grade left some TB experts at a September meeting of the Advisory Council for the Elimination of Tuberculosis (ACET) sounding as upset as protective parents eying a bad report card. "We haven’t had any problems with 2RZ. Please, don’t make it a C,’" said James McAuley, MD, MPH, medical director for Cermak Health Services in Chicago, and ACET liaison for Cook County Correctional Services, also in Chicago.

Several of McAuley’s colleagues agreed. "A C’ says don’t use it,’" said Henry Blumberg, associate professor of medicine in the Division of Infectious Diseases at Emory University School of Medicine in Atlanta. "If you downgrade it to a C,’ you’ve essentially eliminated it."

Why no problems in some settings?

Recently, the new regimen has been linked to reports of severe hepatotoxicity, resulting in deaths in six instances. But McAuley says he’s had no trouble at all, and a Centers for Disease Control and Prevention trial of the regimen in Atlanta-area jails turned up only minimal trouble. Why the difference? Perhaps, McAuley speculated at the ACET meeting, it’s because being incarcerated precludes the chance for alcohol abuse, ensures good meals, and includes regular monitoring.

That leaves the second question of why HIV-positive patients seem to do just fine with 2RZ. Like incarcerated subjects, they are also frequently monitored, noted Blumberg; or maybe HIV-positive patients absorb the medications less efficiently, suggested Mike Tapper, MD, chief of infectious diseases at Lenox Hill Hospital in New York City. A third possibility, submitted by Michael Iademarco, MD, an epidemiologist with the CDC’s Division of TB Elimination, is that the hepatoxicity is linked to an immune response, and HIV-positive patients’ immune systems are not up and running at full force.

However clinicians perceive a "C," the grade (if it’s actually assigned) shouldn’t be taken to mean the regimen is no longer acceptable, adds Iademarco. "People think a C’ means you can’t use a regimen, but there are plenty of regimens with a C’ rating," he says. "They don’t become unacceptable until you get a D’ or an E.’"

Instead of worrying about letter grades, what clinicians need to do is focus on revised guidelines for using 2RZ published in recent CDC Morbidity and Mortality Weekly Reports (MMWR), Iademarco says. "These recommendations are appropriate, and they’re very clear," he says.

Tables, by comparison, can muddy the water when there are too many choices with too many different ratings, he notes. "That’s really what we have [with LTBI options]," he adds. "You’ve got HIV-positive, HIV-negative, isoniazid, twice weekly, daily . . . and it’s hard to fit all that clearly into one table."

Assuming that experts eventually do try to reconstruct a table, 2RZ’s final grade will depend on two things, says Iademarco. First, more evidence needs to collected on rates of hepatotoxicity; second, time must be allowed for a clear consensus among experts to develop. To assemble data on rates, Iademarco is planning retrospective cohort studies and is also contemplating the collection of data from pharmacy records.