All quiet on 2RZ front; experts wondering why
CDC launches surveys to assess evolving use
The tally of cases of hepatotoxicity linked to a two-month regimen of rifampin and pyrazinamide (2RZ) now stands at 35, including seven deaths, say TB experts at the Centers for Disease Control and Prevention’s Division of TB Elimination (DTBE) in Atlanta.
Both the pace at which cases are occurring and at which they are being reported has slowed considerably. "The question is, are we [no longer] receiving these reports because no one is using this regimen," asks the DTBE’s Peter McElvoy, PhDF, "or because people are monitoring its use more closely?"
The CDC defines a case as an event of liver injury serious enough to require hospitalization. Of 34 such cases where the date of onset of symptoms is now known, 21 cases (or 79% of the total) took place during a 13-month period starting in July 2000 — the month after the CDC’s new latent TB infection (LTBI) guidelines were released — and ending in July 2001, according to a report at a recent meeting of the Advisory Committee to Eliminate Tuberculosis (ACET). At press time, the last event of liver injury leading to death began last September; the last non-fatal case occurred in October.
Reporting curve drops off steeply
The pace at which cases are being reported has slowed even more. Of the 35 cases of hepatotoxicity reported, 29 (83% of the total) were reported during a seven-month period from April through October last year. At press time, one nonfatal case had been reported during the months of November and December last year, with one additional non-fatality reported this past January.
Eighty percent (28 of 35) of the cases have been subjected to site review by DTBE epidemiologists. One such review found that an additional case (which would have brought the total reported to 36) was not linked to 2RZ, but to another regimen, says McElroy.
Whether providers are still using the regimen — and if they are, how — is one question the DTBE is in the midst of answering. At the same time, the division is working to establish the denominator — that is, the total number of people who’ve started the regimen. Once that figure is in hand, CDC experts will be able to calculate the rate of serious liver injury and compare that rate with the rate for nine months of isoniazid, the standard treatment for LTBI. Earlier studies put the rate of INH-associated hepatitis between 0.5% and 2.0%; a newer study places it much lower, at 0.1%.1
With all 50 state TB controllers and all 10 big-city TB controllers having responded to a survey engineered with the help of the Atlanta-based National TB Controllers Association, the DTBE has already established that there are 600 cohorts of patients who have tried the regimen, spread out across 35 states, says McElroy. The size of the cohorts varies widely, from just a couple of people to over 400. Settings are equally varied, and include homeless shelters, local TB control programs, correctional settings, and infection control programs in hospitals, McElroy says.
Next, demographics and case dispositions
The next step is to contact medical personnel who oversaw the various cohorts and ask them for more details. Along with demographic descriptors, "we’ll be asking how many people started and how many completed," says Renee Ridzon, MD, head of the Outbreak Investigations section of the Surveillance and Epidemiology Branch at the DTBE. "We’ll also ask how many stopped due to elevated liver enzymes, who got really sick, and who was hospitalized."
The federal TB experts also want to find out whether provider practices have evolved as the guidelines for the regimen have changed. "We’ll be asking about the use of 2RZ over three specific time periods," says McElroy. "The first period extends from the point when the guidelines were first published to the point when the first Morbidity and Mortality Weekly Report came out; the second time extends from then until the publication of the second MMWR; and the third is from that point until the present."
The first MMWR to deal with this issue, published April 20, 2001, apprised clinicians of trouble with the new regimen. The periodical reported a single death and one case of severe hepatitis, and concluded with a warning to providers to educate patients about symptoms of liver trouble and about the importance of stopping the medication if symptoms arose.2 The second MMWR, appearing Aug. 31, 2001, described an additional 21 cases, including five deaths. That issue laid out more elaborate cautions and guidelines for using 2RZ, including an admonition to use the regimen "with caution," particularly in patients with a history of alcohol abuse, liver injury, or a history of INH intolerance.3
"We don’t have a denominator yet for patients who had trouble with INH, but did fine with 2RZ," notes Ridzon; "still, for now, it makes good clinical sense to recommend that patients who didn’t do well on INH not be re-challenged with 2RZ."
The guidelines were also amended to include explicit directions about biochemical and clinical monitoring at two, four, and six weeks, with a final clinical visit at eight weeks, and warned against issuing more than two weeks’ worth of pills at one time.
The DTBE is still seeking reports of serious hepatotoxicity associated with 2RZ, Ridzon adds. People who wish to make a report are advised to call (404) 639-8116 and ask for Lauren Lambert.
References
1. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281:1014-1018
2. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection — New York and Georgia, 2000. MMWR 2001; 50:289-291
3. Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society CDC recommendations — United States, 2001. MMWR 2001; 50:733-5.
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