Monitoring safeguards considered for 2RZ guidelines
Firewall against hepatoxicity, trial suggests
Stepped-up biochemical monitoring may prove critical to preventing liver injury resulting from use of the new regimen for treating latent TB infection, TB experts say.
Revised guidelines for use of the regimen, two months of rifampin and pyrazinamide (2RZ), will probably call for laboratory monitoring at baseline and at two, four, and six weeks, says Rick O’Brien, MD, chief of the research and evaluation branch of the Division of TB Elimination (DTBE) at the Centers for Disease Control and Prevention in Atlanta.
The proposed revisions are in line with preliminary findings from the first randomized controlled trial using the new regimen in HIV-negative people. In that trial, subjects receiving 2RZ experienced "significantly" higher rates of both moderate and severe hepatotoxicity compared to patients taking INH, says the study’s principal investigator, Robert Jasmer, MD, assistant professor of medicine at the University of California in San Francisco. But preliminary analysis of trial results also strongly suggests that biochemical monitoring can head off trouble, he adds.
"We did find significantly higher rates of hepatotoxicity with 2RZ," says Jasmer. "But we also showed that by using intensive laboratory monitoring, we could pick up hepatitis, rather than waiting for patients to develop symptoms and require hospitalization."
About 90% of patients with hepatotoxicity were spotted before they became symptomatic, he adds. "Had we continued therapy, I’m convinced they’d have progressed to symptoms and possibly to hospitalization," adds Jasmer.
Instead, using one blood draw at baseline and a second after one month of treatment, serious problems were averted, and not a single patient required hospitalization.
Unlike Jasmer’s trial sites, public health programs trying out the new regimen haven’t made consistent use of laboratory monitoring, because original guidelines didn’t call for it. In some instances, programs have had problems with the new regimen, ranging from mild to severe, including several fatalities. Yet it’s hard to determine how often problems are occurring, because no denominator exists yet for field reports.
Factors linked to trouble
Reported problems with 2RZ appear to be concentrated among specific groups, O’Brien says: patients ages 50 or older; those with underlying liver disease or a history of alcohol abuse; and those with intolerance to INH. In several instances, patients also appear to have kept taking their medication after the onset of symptoms, he adds. In addition, patients getting the higher end of the dose range for pyrazinamide — over 20 mg/kg — seem to be having trouble.
It’s important for clinicians to recognize that 2RZ is neither risk-free nor less risky than INH, O’Brien adds. "This regimen is not innocuous," he said last month, addressing a meeting of the Advisory Council for the Elimination of Tuberculosis (ACET) in Atlanta. ACET members agreed that it’s crucial for TB control programs
to get this message out to hospitals and private providers who may be using the new regimen.
That applies doubly to health care providers, some at the ACET meeting said. That’s because health care workers often get skin-tested to meet federal or employer regulations, and not because they’re at substantial risk for TB infection — a fact that increases the likelihood of false-positive reactions. Such reactors certainly shouldn’t regard 2RZ as a quick and easy way to treat apparent latent TB infection, the ACET members agreed.
Revised guidelines are also expected to call for more intensive clinical monitoring, with visits at two, four, six, and eight weeks, O’Brien says. As in the first guidelines, the revised guide is expected to underscore — this time with an even heavier emphasis — the importance of teaching patients about symptoms and of making sure they know to stop taking the medicines immediately if symptoms occur, says O’Brien.
The new guidelines are also expected to recommend that the same provider see the patient throughout the course of treatment and that no more than two weeks’ worth of medications be handed out at a clinic visit.
Neither the regimen’s rocky start nor the expected stiffer monitoring requirements should scare people off, say TB experts. "There may be populations where [2RZ] will prove especially useful, like captive settings where you can do intensive monitoring," says Jasmer. "That’s the goal in the next few years: to find out in what settings and in what populations this will be most useful."
Faced with the prospect of four needlesticks, many patents will still probably opt for 2RZ over nine dreary months of INH, says Lee Reichman, MD, MPH, director of the National TB Center at the New Jersey Medical School in Newark. "Plus, INH still has such a bad reputation," Reichman notes. "Half the calls we get on our hotline are about INH."
As of mid-July, DTBE investigators were still working to finish on-site investigations of reports of liver injury apparently linked to use of 2RZ. When the DTBE conducted a "rapid survey" of public health jurisdictions across the country, they garnered 81 reports of adverse events associated with 2RZ, says John Jereb, MD, a medical epidemiologist at the DTBE. Those events were "uncharacterized," he adds, meaning they spanned the gamut from pruritis to insomnia to hepatitis.
In a second survey, callers to a hotline set up at the CDC in early summer had reported 54 instances of apparent liver injury linked to latent infection (with either INH or with 2RZ) by mid-July.
In 28 of the events — about 54% of the total — hepatotoxicity was severe enough that patients required hospitalization. Of those 28 severe events, 16 resulted from use of either daily or twice-weekly 2RZ. Four were linked to the use of INH only, with three of the four tied to daily INH and the fourth to thrice-weekly INH, Jereb says. The 28 events included seven deaths and one liver transplant either from use of INH or 2RZ (or, in two cases, both).
Categorization of fatalities
Here is the CDC’s breakdown of the seven deaths, as of last month:
— two linked to use of 2RZ only;
— two in which patients were started on INH, developed INH intolerance, and were switched to 2RZ;
— one linked to ethambutol/pyrazinamide;
— one linked to INH alone;
— one in which a suspect case got four-drug therapy and was switched to INH once TB was ruled out.
The patient who got a liver transplant had been treated with INH only, Jereb adds. Though he survived, CDC investigators classified his case with the other deaths, because without the transplant he likely would have died.
"Clearly, more data and more research on
the regimen are needed," says O’Brien. Adds Reichman: "Once we characterize these toxicities, we’ll have to do a decision analysis. People will have to decide for themselves whether or not the risks and the costs are worth the benefits."
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