TB prophylaxis: Too long in kids or too short in adults?
Experts debate basis for differing lengths of therapy
When Lee Reichman goes on grand rounds at teaching hospitals, invariably he will be asked why adults generally are given six months of preventive isoniazid therapy while children are given nine. His answer has nothing to do with clinical factors.
"I will say, when asked, that the only reason it is nine months for kids is because that was the only way the American Academy of Pediatrics would endorse the statement," says the former president of the American Lung Association and director of the New Jersey National Tuberculosis Center in Newark.
When the academy wrote its recommendations in the "pediatric redbook" in the early 1990s, nine months of therapy for children was seen as a reasonable compromise from the limited study data looking at the clinical and cost-effective impact of varying durations of TTB prophylaxis in the general population, says Jeffrey Stark, MD, a pediatrician and associate professor of clinical pediatrics at Baylor University College of Medicine in Houston.
Originally, when treatment for TB disease in adults and children was 12 months, preventive treatment also was 12 months. Then, as studies showed that treatment of disease could be reduced to nine or even six months, in adults at least, the academy was faced with a conflict, he says.
"People were saying, Can you really treat infection longer than disease?’" Stark recalls. "Of course you can, but will doctors and families accept it? So the academy said, Let’s cut it back to nine months.’"
One of the paradoxes of TB treatment is that a patient with TB infection needs more treatment time than one with active disease, says George Comstock, MD, retired professor of medicine at Johns Hopkins University.
"I think it’s purely because in active disease your bugs are metabolizing like mad, and the drug gets at them," he says. "The reason you need a fair amount of time with prophylaxis is you have bugs that are not multiplying, and so you have to make sure you hit enough of them multiplying so you have protection."
Because treatment of disease in adults has been cut back to six months, the debate over length of prophylaxis has arisen once again. This time, however, Stark and his colleagues have argued that the nine-month recommendation should stand.
"There just aren’t much data about six months in children," Stark tells TB Monitor. "My rule of thumb is to shoot for nine months. If I get a good solid six months into a child, then I will accept that, but I still believe nine months is optimal."
While the Centers for Disease Control and Prevention has no immediate intentions of changing its recommendations for pediatric preventive therapy, some clinicians may decide that nine months is unreasonable and that six months is adequate, says Bess Miller, MD, assistant director of the division of TB elimination.
Miller mentions several trials in Eastern Europe in the 1980s looking at differences in six months and 12 months of treatment in adults only. "People on 12 months did best, but people who were on six months did very well," she says, adding that "it is difficult to keep people on therapy for nine to 12 months."
Weighing costs and benefits
Like Stark, Reichman agrees that nine months is an optimal duration for preventive therapy for children. However, he points to a CDC cost-benefit analysis undertaken a decade ago showing that six months of treatment, while less effective clinically, was more effective cost-wise when considering such factors as the risk of hepatitis and the expense of monitoring liver enzymes.
With hepatitis and its complications accounting for a large part of the cost for extended treatment, the question, put forth by Gisela Schecter, MD, MPH, former TB controller of San Francisco, comes down to this: Once you achieve six months of therapy, is the incremental increase in protection you gain from treating for nine months instead of six months worth the incremental increase in hepatitis seen in adults?
"Her answer is probably not,’ Stark says. My answer, for children, is that it probably is because the risk for hepatitis is so low in kids, and they have a lot of years left to live."
Comstock thinks nine months is warranted for children and for adults.
"If you go by the data, it is nine months," he says. "If you want to cut down the protection, go ahead."
More than 10 years ago, Comstock published a study of preventive therapy in adults and children in Alaska. The results showed that patients receiving more than nine months of therapy experienced no more protection than those patients treated with nine months only. However, nine months’ protection was "appreciably better than at six," he says.
Indeed, Comstock argues that isoniazid preventive therapy for adults should be increased to nine months from the current practice of six months. "I think we badly need to go back to nine months," he says. "I would have written that editorial years ago if I weren’t retired."
Yet the move for preventive treatment is to shorten, rather than lengthen, therapy by using alternative regimens, says Miller. CDC researchers are looking at rifampin alone or in combination with pyrazinamide or other long-acting TB drugs.
The CDC also is studying the use of six months of preventive therapy given twice-weekly under observation and comparing it to the traditional nine months of therapy. Trading off some protection may be more beneficial if patients are more likely to complete their therapy, she adds.
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