ATS: Short Treatment Promising for Latent TB

By Michael Smith
TORONTO, 22 may 2008 -- A short course of rifampin (Rifadin, Rimactane) to treat latent tuberculosis is cheaper and safer than the standard nine months of isoniazid (Nydrazid) although comparative efficacy is still up in the air, researchers said here. In a multinational randomized phase II trial, four months of once-daily rifampin cost about $1,060 for each patient who completed the course, compared with about $1,540 for patients who finished the daily isoniazid, according to Anne Aspler, M.Sc., of McGill University in Montreal.If the efficacy of the two regimens were the same, preventing one case of active TB would cost $10,549 less using rifampin than isoniazid, Aspler said at the American Thoracic Society meeting.
Treatment during the latent period "is a very effective way of preventing TB," Aspler said. Her poster presentation was one of two highlighting results from the trial.
The actual efficacy of the shorter regimen in preventing latent TB from becoming active won't be known for several years, but one estimate suggests it's about 70%, according to Dick Menzies, M.D., who led the study and presented another poster on it.
That's compared with about 90% efficacy for patients who complete the nine months of isoniazid, he said.
At that rate, Aspler said, preventing one case of active TB would cost $3,799 less using the rifampin instead of the isoniazid.
But the efficacy numbers may be misleading, since only 64% of those given isoniazid actually finished treatment in the current study, compared with 81% of those on rifampin. The difference was significant at P<0.0001.
In practice -- outside clinical trial conditions -- the percentage completing isoniazid treatment is closer to 50%, Dr. Menzies said.
"Part of the game with the shorter regimen," he said, "is just that more people complete it."
Adverse events, including hepatitis, were the largest drivers of the high dropout rate in the isoniazid group, Dr. Menzies said.
The study enrolled 847 patients with latent TB and randomized them to the two regimens in a phase II examination of safety. A data safety monitoring committee stopped the trial late last year when it became apparent that the rifampin regimen was substantially safer than isoniazid.
Grade three and four serious adverse events had occurred in 4.1% of isoniazid patients, compared with only 1.8% of those on rifampin, Dr. Menzies said, which was a significant difference (P=0.02).
Grade three and four hepatitis was seen in 4.1% of isoniazid patients and 0.8% of those on rifampin, a difference that was significant at P=0.002, he reported.
Dr. Menzies said there's no way of telling how well the rifampin regimen worked in preventing active TB except by waiting. He said the researchers are continuing to follow their patients.
The study was conducted in North America and two outside centers (in Brazil and Saudi Arabia), Aspler said. In areas more hard-hit by TB, the study could not be ethically justified because it would divert scarce resources away from treating active TB.
But if the efficacy of the shorter course is high enough, it may be a useful tool to prevent active TB in places where the disease is endemic, she said.
"This is a preliminary observation that needs to be followed over time," said
Ganesh Raghu, M.D., of the University of Washington Medical Center in Seattle, who was not involved in the study.
But he said it's not surprising that the side effect profiles of the two regimens differed so markedly. "The shorter the duration, the less exposure and fewer complications -- that's a good philosophy," he said.
But a key question is whether the shorter regimen actually prevents latent TB form turning active and that will take more time to sort out, he said. If it does, the next question is how well it will work in endemic areas, Dr. Raghu added.
As efficacy of the rifampin regimen is assessed, it's also important to monitor development of resistant TB when this drug is used alone, especially in individuals with INH-resistant TB.
The study was sponsored by the Canadian Institutes of Health Research. The researchers reported no conflicts.
Primary source: American Journal of Respiratory and Critical Care MedicineSource reference:Aspler A, et al "Costs and cost-effectiveness of a randomized trial of 4 months rifampin versus 9 months of isoniazid for treatment of latent tuberculosis infection (LTBI)" Am J Respir Crit Care Med 2008; 177: A790. Additional source: American Journal of Respiratory and Critical Care MedicineSource reference: Dion MJ, et al "A randomized trial comparing adverse events with 4RIF and 9INH in the treatment of latent TB infection" Am J Respir Crit Care Med 2008; 177: A789.