In a randomized clinical trial, the effectiveness of 12 weekly directly observed doses of rifapentine and isoniazid was compared to the effectiveness of standard treatment (self-administration of daily isoniazid for nine months). Patients aged 2 to 17 years with latent tuberculosis at 29 sites in Brazil, Canada, Hong Kong, Spain, and the United States were enrolled from 2001 to 2010, with follow-up until 2013.

Nine hundred five children out of the 1058 total who enrolled were eligible for analyzing effectiveness. Of the 471 receiving the combination therapy, 415 (88.1%) completed treatment, while only 351 of 434 (80.9%) on isoniazid alone completed treatment (p = 0.003). Between the two treatment groups, discontinuation due to adverse events was similar and less than 1%. No one in the combination-therapy group developed tuberculosis, whereas three children (0.74%) developed the disease in the isoniazid-only group (p = 0.098).

Results from this clinical trial demonstrated that the combination therapy had a similar (non-inferior) effect in preventing latent tuberculosis infection compared to isoniazid-only therapy. However, the completion rate for the combination-therapy group was higher than the isoniazid-only group.

COMMENTARY

Tuberculosis continues to be a major problem worldwide, and children are at particular risk. Prevention of illness in TB-exposed and infected children is especially important since children are at relatively increased risk of severe disease, are more likely to progress from latent infection to illness, and have more potential years of life at risk of TB illness. Fortunately, children also tolerate preventive TB treatment better than adults do. However, adherence to long treatment regimens is problematic for asymptomatic children, and simplified yet effective treatment courses would be helpful.

Recent investigation has suggested that shorter, simpler courses of preventive TB medications are safe and effective in healthy yet infected adults.1 Aware of favorable pharmacokinetic data for the use of rifapentine in children, the investigative team undertook the current pediatric study and found similar results. This offers a helpful new option for the treatment of TB-exposed and TB-infected children.

However, there is already vast variation in the treatment of latent tuberculosis infection in children. For instance, national guidelines include either three months of rifampin and isoniazid or six months of isoniazid in the United Kingdom and South Africa, nine months of isoniazid in the United States, and six months of isoniazid per the World Health Organization.2 Having more uniform, consistent recommendations might help improve compliance and adherence among patients between various sites.

Also, the current study was not only a comparison of various medication regimens. The short-course combined therapy subjects had directly observed therapy, and the longer isoniazid group had self-administered medication. Some of the variation in outcome might have been due to observation and contact with medical providers rather than simply due to medication differences. And, even the control single medication group had more careful follow-up than might be provided in regular clinical situations. A key to effectiveness of tuberculosis therapy is adherence, so “real world” treatments will have to be implemented carefully to ensure adequate delivery of medication.

As pointed out in an editorial accompanying Villarino’s paper, young children are of particular concern for latent TB infection treatment, and the current paper did not include very many pre-schoolers.3 Future studies of younger children will be useful as various treatment regimens and dosing schemes are evaluated.

Even while further research continues, the rigorous study by Villarino is very helpful. Clinicians now have a shorter, simpler regimen to consider in treating latent tuberculosis infection in children aged 2 to 17 years.

REFERENCES

  1. Sterling TR, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155-2166.
  2. Turkova A, et al. Management of paediatric tuberculosis in leading UK centres: Unveiling consensus and discrepancies. Int J Tuberc Lung Dis 2014;18:1047-1056.
  3. Marais BJ. Twelve-dose drug regimen now also an option for preventing tuberculosis in children and adolescents. JAMA Pediatrics 2015:169:208-210.