CDC expected to make changes in preventive therapy guidelines
Meeting will address short-course regimens, hepatitis monitoring
New data on the efficacy of short-course regimens are prompting the Centers for Disease Control and Prevention to consider changes in its recommendations for preventive therapy. However, issues regarding who should receive preventive therapy, what they should receive, and how they should be monitored won’t be easily resolved without more study, health officials say.
"It looks like we may have some information that will lead us to recommend some newer, shorter regimens," says Rick O’Brien, MD, chief of the CDC’s research and evaluation branch in the division of TB elimination, at a recent meeting of the agency’s Advisory Council for the Elimination of TB (ACET). "And it is clear we need to look again at our recommendations on screening with the idea of focusing preventive therapy on high-risk groups."
Next fall, the CDC plans to convene a major meeting jointly with the American Thoracic Society on preventive therapy. The meeting will focus primarily on the results of recent short-course therapy studies, including a large CPCRA/ACTG trial that was recently completed a year earlier than anticipated based on the recommendation from the trial’s drug safety and monitoring board. Researchers anticipate that the board chose to recommend that the study be stopped because the event rate was similar for the two study arms unsupervised isoniazid therapy for 12 months vs. two months of unsupervised treatment with daily rifampin plus pyrazinamide O’Brien tells TB Monitor. The results of the study will be presented in a late-breaker session at an antiretroviral conference in Chicago in February.
"The feeling has been that if the results of the CPCRA study are positive on rifampin and pyrazinamide that we would have enough information to make a sort of cautious recommendation on this new shorter regimen," he adds.
The efficacy of that two-drug combination for short-course preventive therapy is supported by two other studies yet to be published. The first study, conducted by Johns Hopkins University, treated patients in Haiti with twice weekly doses of the two drugs. The results are expected to be published soon in The Lancet, O’Brien says. A similar study was conducted in Zambia by the London School of Health and Tropical Medicine and was presented as an abstract at the meeting of the International Union Against Tuberculosis and Lung Disease in October.
One other noteworthy study of short-course preventive therapy was recently published in the New England Journal of Medicine, showing that pyrazinamide, in combination with isoniazid and rifampin taken for three months, reduced the risk of tuberculosis in HIV-positive patients.1 The triple-drug combination, however, had an unacceptable level of toxicity, or side effects, O’Brien notes.
The recommendation for combination therapy for preventing TB would not be applicable to low-income countries where even the use of isoniazid prophylaxis is still not widely accepted, O’Brien adds. In addition to considering treatment options, the meeting also will evaluate the more broad public health issue of who should receive preventive therapy
Hepatitis monitoring a sticky issue
One other issue to be addressed has a long and contentious history in TB research the need for monitoring patients for isoniazid-induced hepatitis. In rare cases, isoniazid prophylaxis causes hepatoxicity that can be fatal, especially in people older than 35 years. The estimated rates of fatal isoniazid-induced hepatitis have ranged from as high as 14 per 100,000 people to as low as one per 100,000 people. More recent studies have put the risk between four and seven cases per 100,000 people significant enough that in 1983 the American Thoracic Society and the CDC changed its guidelines to recommend that baseline and periodic liver function tests be obtained for people older than 35 or at high risk (drinking alcohol, injecting drugs, or having chronic liver disease), and that treatment be discontinued if aminotransferase levels exceeded three to five times above ormal.
An unresolved issue in the TB community has been the value of monitoring serum liver enzymes. The dearth of definitive data on its efficacy has resulted in inconsistent practices among TB practitioners, says John Jereb, MD, medical epidemiologist in the CDC’s division of TB elimination.
"This is an old issue that has been studied at many angles, and it has always been a dilemma as to what is the best public health solution," he tells TB Monitor. "There are conflicting demands when you include feasibility, affordability, and effectiveness into the equation."
Some at risk for liver dysfunction
As many as 10% to 20% of patients receiving isoniazid develop mild liver function abnormalities; however, they usually resolve themselves. The CDC guidelines also note that post-puberty blacks and Hispanic women are at greater risk for hepatitis or drug interactions and should be considered for regular monitoring, including testing liver function. From case studies of patients who have died from isoniazid-induced hepatitis, the scenario is fairly consistent, Jereb says. Typically, the patients continued to take their medication even though they became ill with the symptoms of hepatitis, he says, adding that the drug was continued after symptoms for a median of seven to 10 days.
Just how many practitioners follow the CDC guidelines is not known. Clearly, the risks are so small and the cost and feasibility of regular monitoring is high enough that some high-risk patients are not being monitored. Bruce Davidson, MD, a TB controller in Philadelphia and vice president of the National TB Controllers Association in Atlanta, told ACET members that even though directly observed therapy provides an opportunity for liver test monitoring, many patients are reluctant to have their blood drawn. "I think many programs carry patients in violation of the set of recommendations and are doing it with some sense of trepidation because . . . they could be found to be negligent," he said.
On the other hand, there are private providers who will not prescribe isoniazid preventive therapy without liver function monitoring, regardless of a patient’s risk profile, Jereb notes.
Whether the CDC should recommend more monitoring or whether it should change the criteria for those who should receive monitoring is difficult to answer with the current knowledge on how liver function testing has reduced the risk of isoniazid-induced hepatitis, Jereb says. A 1993 study that has been used to justify widespread use of liver function testing concluded that the rate of fatal isoniazid-induced hepatitis in the United States was lower than previously estimated and was negligible in those patients who were routinely monitored for liver toxicity.2-3 A study published in 1996, however, found that of the 62 cases of isoniazid-related fatal hepatitis reported between 1970 and 1992, 26 (42%) were monitored monthly in accordance with current recommendations indicating that even with regular monitoring, not all cases could be avoided.
"What is the real value of monitoring serum liver enzyme values?" Jereb asked at the ACET meeting. "We have to believe first of all that we can prevent cases by measuring enzymes. There isn’t a study yet that will prove that you can prevent anything by measuring serum enzymes, but from anecdotal evidence, we believe that we could probably prevent cases."
References
1. Whalen C, Johnson J, Okwera A, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with HIV. New Engl J Med 1997; 337:801-808.
2. Salpeter S. Fatal isoniazid-induced hepatitis: Its risk during chemoprophylaxis. West J Med 1993; 159:560-564.
3. Millard P, Wilcosky T, Reade-Christopher S, et al. Isoniazid-related fatal hepatitis. West J Med 1996; 164:486-491.
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