TORONTO - Canadian researchers are about to embark on a quest for an answer that could make treating latent tuberculosis a lot easier and, it's hoped, more frequently successful.
Led by McGill University's Dr. Dick Menzies, they are on the verge of launching an international clinical trial to see if latent TB can be treated as effectively with a drug regime that takes less than half the time and that may pose a lower risk of serious side-effects than the current standard of care.
"The study is very much needed," says Dr. Michael Gardam, director of the tuberculosis clinic at Toronto Western Hospital, who was involved in pilot study but is not taking part in the clinical trial.
The clinical trial, which is being funded by the Canadian Institutes of Health Research, will be announced Tuesday in Montreal.
Nearly 6,000 people with latent (inactive) tuberculosis will be enrolled in five cities across Canada as well as in the West African countries of Benin and Guinee, in Brazil, South Korea, Australia and Saudi Arabia.
Half will receive the current regimen used to try to cure latent TB infection, once-a-day treatment with the drug isoniazid (called INH for short) for nine months. The other half will receive the drug rifampin (also known as rifampicin) for four months.
Both groups will be followed for 28 months from recruitment to see how many go on to develop active TB -- which should tell if rifampin is as efficacious as isoniazid. Menzies says it will take about seven years to arrive at the answer of the nearly $5-million study.
Finding a quicker treatment for latent TB would help considerably in managing the disease. It's a well-known fact in medicine that the longer the course of treatment, the harder it is to get what's known as compliance -- patients actually taking their treatment all the way to the end of the prescribed therapy.
With treatment of latent TB, compliance is poor. Researchers think a shorter course of therapy with rifampin holds promise that more people will take their drugs all the way through.
Some doctors, like Gardam, already use rifampin for some cases of latent TB. But they do so without scientific evidence showing what percentage of cases should be cured by this shorter course of therapy.
"Four months of rifampin is, I would say, an increasingly popular option. But everyone is limited by the same problem, which is that we're unsure how well it works," says Menzies.
There is an added attraction to rifampin, beyond the shorter duration of the treatment course.
Though isoniazid is considered a highly effective drug for TB strains that are susceptible to it, the drug can be toxic to the liver. The problem can be reversed if caught in time. But occasionally people being treated for latent TB suffer from liver failure and end up needing a transplant.
Only a small percentage of people who have latent TB -- somewhere between five to 10 per cent -- will go on to develop active disease. Given that fact, and the fact that people who have latent TB don't feel sick, telling people they should take a drug that might destroy their liver can be a "a hard sell," Gardam says.
Menzies agrees: "Very hard to sell to patients -- and even to doctors. A lot of doctors won't give this stuff."
Rifampin too can be toxic to the liver, but less frequently, Menzies says. A pilot version of this study found less than one per cent of patients on the drug developed liver problems compared to 3.8 per cent of people taking isoniazid.
The director of the World Health Organization's Stop TB department welcomes news of the clinical trial, saying it should answer an important scientific question.
But Dr. Mario Raviglione says if it turns out the treatment is as effective, people treating latent TB will have to screen patients carefully to make sure they have latent and not active TB -- a distinction not easy to make in some parts of the world with limited laboratory facilities.
Giving a dose meant to clear latent infection to a person with active TB could fuel the development of rifampin-resistant strains of tuberculosis. That would be considered a disaster. Rifampin is a critical weapon against TB and there are few new drugs in the development pipeline.
"The last thing we need is rifampin resistance," Raviglione says.
"If we lose rifampin ... we are in trouble. We are losing possibly the most powerful drug that we have today. So it's something that has to be taken with a bit of caution."
In fact, he suggests even if the trial shows four months of rifampin does work as well as isoniazid, there will likely be opposition in some quarters to its widespread use for latent TB treatment.
There are other issues with the drug. Gardam says rifampin interacts with a large number of other medications, including beta blockers, opiod pain killers and birth control pills -- which don't work for women taking rifampin.
"It's never going to be for everybody," he says. "But I think it would be a very viable option for a fair percentage of people."
