RIF/PZA reconsidered: Is a third month better?
For HIV-negative patients, perhaps, Sbarbaro says
Two months of rifampin/pyrazinamide (RIF/PZA) may not be enough to prevent tuberculosis in HIV-negative patients infected with TB, says John Sbarbaro, MD, professor of medicine at the Health Sciences Center of the University of Colorado. In HIV-negative people, Sbarbaro reasons, mycobacteria may not be active enough to stand up, so to speak, and catch the bullets being fired by quick-draw rifampin.
Since the converse situation applies in HIV- positive people, the two-month regimen can be expected to work fine for them, Sbarbaro adds. "If more bugs are beginning to activate because the macrophage isn’t controlling them as well, my bet is that rifampin will kill them quickly — and two months will probably be enough," he says.
At the Centers for Disease Control and Prevention — which officially has approved the new regimen for HIV-positive patients and recently gave clinicians an unofficial go-ahead for using it on HIV-negative people as well — the response to Sbarbaro’s latest fraternal assault is philosophical.
"I’m actually a little surprised John has anything at all good to say about the regimen," says Rick O’Brien, MD, chief of the research and evaluation branch of the CDC. "You should see the e-mail that’s been flying back and forth."
Still, his friend in Colorado may have a point, O’Brien concedes, since there’s scant evidence as to how well RIF/PZA will work on HIV-negative co-infected patients. After all, HIV-negative patients weren’t among the subjects in landmark studies of the new regimen. "With the exception of a small pilot study done by the CDC, along with some related studies in Poland and Berlin in the late ’80s, there’s been little experience with the two-month regimen of RIF/PZA in HIV- negative people," O’Brien says.
He said, he said’
So for now, it’s one man’s hypothesis against another’s, he adds. "But there are intelligent people who’ve looked at the data and who say that recommending this regimen for HIV-negative people makes sense. Plus, it represents a considerable improvement in our ability to treat people with latent TB infection."
Sbarbaro says his misgivings derive not only from a lack of data about the use of the regimen in HIV-negative people, but also from adding up what’s known about competent immune systems and the way rifampin works.
"One thing that’s always interested me, and that I’ve tried to study for years, is how do macrophages contain and control TB," he says. "Whatever the macrophage does, it manages to control that growth for a long period of time. If you’re HIV-positive and not taking these fancy new antiretroviral drugs, your macrophages are probably becoming progressively weaker, since when your CD4 count drops below 400 you start getting TB."
Rifampin works well on an HIV-positive patient, he continues, but only because in an immunocompromised patient, the TB bacilli have begun actively metabolizing. Research carried out by Denny Mitchison, the eminent British TB expert, shows that this is how rifampin operates, he adds.
In that experiment, Mitchison inoculated two culture plates with TB, allowed the bacilli to grow at room temperature, and then chilled the plates to 8° C, Sbarbaro says. Once the cultures stopped growing, Mitchison anointed one plate with rifampin and the other with isoniazid.
He then re-warmed the culture plates and let the bacilli grow for six hours. He then re-chilled them, rinsed off the antibiotics, and warmed them back up. The results? Six hours of exposure had wiped out the TB bugs on both plates.
But in a second round of the same procedure, Mitchison altered one condition: After the first chilling, the initial warm-up was limited to only one hour. Then, as before, there followed another chilling, a washdown, and a second re-warming.
This time, the bacilli on the rifampin-dosed plate lay dead, as before; but on the isoniazid plate, bacilli continued to grow undaunted. "So we know rifampin kills more quickly than INH," concludes Sbarbaro.
O’Brien pronounces himself underwhelmed. "We have good data that says this regimen [is] equivalent [to the longer six-month course of INH] and that adherence is better," he says. "It makes sense to try it in HIV-negatives."
Sbarbaro chuckles, and allows himself a final don’t-say-I-didn’t-warn-you: "Okay, guys. If you’re gonna use this, implement it patiently. Really document what’s happening. And go cautiously."
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