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Treatment of latent tuberculosis has never been a simple affair.

Nine months of a drug known as isoniazid, taken daily, is the standard of care and can help clear the infection. But it also causes liver damage in a fairly significant percentage of cases.

Now, researchers say, a pair of studies that were conducted across multiple countries have shown that four months of therapy with another drug, rifampin, is as effective as the standard of care. Furthermore, the shorter course of treatment meant patients were more likely to follow the regimen to the end.


“This is something I deal with every week in my clinic. We’re giving out these medications all the time,” said Dr. Michael Gardam, an infectious diseases professor at the University of Toronto who runs a tuberculosis clinic in the city. “And being able to actually now say … it seems to be about as good. It’s very helpful.”

The research was published Wednesday in the New England Journal of Medicine. It was led by Dr. Dick Menzies, a respirologist and professor of medicine at Montreal’s McGill University, who has been studying rifampin since 2001.


One study compared effectiveness of the drugs in adults, and also collected comparative data on safety and patient adherence to the regimen. The second study, which looked at safety in children, also gathered data on effectiveness and adherence.

The adult study was done in nine countries: Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea; the pediatric study was conducted in the first seven countries on that list.

Menzies said for years doctors knew rifampin — which is also used to treat active tuberculosis — was safer to use when trying to clear latent disease.

In another study, he and co-authors found that roughly 1,000 patients a year are put on isoniazid, also known as INH, in Quebec. Over a decade, one or two of them a year would go on to have a liver transplant. The data were taken from administrative records, so Menzies cannot be certain the drug alone caused the liver failure. But that rate is much higher than what you would see in the general population.

“When you think maybe 250,000 people get treatment for latent TB in the U.S. every year, then that’s 250 liver transplants a year,” Menzies said.

Some side effects from the treatment of a dangerous disease are generally accepted. Chemotherapy is toxic, but with some cancers it enhances survival.

In the case of latent TB, however, the calculations involved in deciding whether to pursue a treatment with potential side effects are different. People with latent TB aren’t sick, and many will never be sick. They have the potential to develop active disease.

“You think about the heartbreak … giving somebody a medication to prevent a disease they don’t yet have that causes serious liver damage,” said Gardam, who was not involved in this research. “You never want to be in that setting.”

Still, clinicians have never had solid evidence to show that rifampin was as effective as INH. And there was no impetus for pharmaceutical companies to conduct the research.

“You couldn’t get a drug company to fund it, because it’s made by generics everywhere in the world. So that window was long past,” Menzies said.

With more than $5.5 million in funding from the Canadian Institutes of Health Research — and some additional money through the Australian and Brazilian governments to cover costs in those countries — Menzies and colleagues set out to try to generate the data, enrolling over 6,000 patients in the adult study and over 800 in the pediatric study.

As it turns out, they would have needed a larger study to conclude whether rifampin is more effective than INH. But the researchers were able to show that it was non-inferior — it performed as well.

The studies also showed relatively high compliance rates for both the patients getting INH and those getting rifampin — higher than one would probably see in a non-study setting. But more people in the rifampin group finished their full round of treatment.

That could help address one of the other big issues with treatment of latent TB: Patients often don’t want to take daily pills for months, so may refuse to be treated or may stop taking the medication too soon.

Menzies said the study showed virtually everything the scientists hoped it would.

“It was safer. It was completed better. And the incidence of active TB was the same or even slightly lower. We honestly couldn’t ask for better,” he told STAT.

“It’s very gratifying that it does work well. Very.”

Still, rifampin won’t be for everyone with latent TB. The drug interacts with a number of other medications, including oral contraceptives. Some of these interactions can be managed — for instance, women can be urged to supplement their oral birth control with condoms while taking rifampin, Menzies said. But in other cases the drug might not be the right choice.

And it will be important for doctors to be sure the patient being treated truly has latent TB, not active disease. Treatment of active TB with a single drug risks the development of a drug-resistant strain. Tuberculosis that is resistant to rifampin is difficult to treat, Gardam said.

Menzies said he hoped groups like the Centers for Disease Control and Prevention and medical specialty groups will now rewrite treatment recommendations to encourage doctors to start using rifampin rather than INH for latent TB in cases where it is possible to do so.

“If you read the recommendations from CDC, from American Thoracic Society, Canadian recommendations, whatever, INH is still the standard,” he said. “I think that it’s really time to move away from that, completely, and put INH to be a reserve regimen.”

  • These studies could not have been done in the United States. Any kind of comparison study would have been shut down by industry lawyers, and the researchers, threatened with legal action. The Pharma industry has virtually shut down any comparison studies, they are bad for business, and cut into profitability. Here in the US, this kind of scientific study is no longer done, and never funded by Pharma or other interests. They really pathetic thing, is that no one noticed. Now they are trying to spread this distorted science overseas. There is a reason our administration is attacking global health organizations! This kind of science can interfere with industry profits.

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