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Shorter regimens of 2-drug therapy may be as effective as 9-month INH monotherapy for latent TB infection (LTBI)

Question

  • In U.S. children with LTBI, can a shorter course of therapy – compared with standard 9 months of INH – results in equivalent or reduced rate of conversion to active TB?

Clinical Bottom Lines

1. Adequate clinical trials are not available to change the current standard treatment for LTBI.
2. A 3- or 4-month regimen of two-drug therapy (INH and rifampin) results in better compliance than 9-month INH monotherapy, but it is not clear whether long-term outcomes are non-inferior.
3. The shorter regimens have plausible mechanisms for effectiveness, and there are other studies that support effectiveness in adults and tolerance in children – quality studies of effectiveness in children would be preferred.


Summary of Key Evidence

1. Groups of children under 15 years of age with LTBI (+TST, –CXR, no symptoms) with similar demographic characteristics were randomized and given different regimens: Group A (9 months INH) vs. Group B (4 months INH + rifampin).
2. There were more patients with poor compliance in the longer regimen (Group A: 13.8%) than in the shorter one (Group B: 7.6%) by a significant margin (p=0.029).
3. There were more new radiographic findings of suggestive of active TB in Group A (24.0% vs. 11.8%, p=0.001) after 4 months of therapy. No data are presented regarding outcomes later in the treatment and during follow-up periods. This limitation minimizes the validity of this study to my patient.
4. The 4 month vs. 3 month regimens of INH/rifampin, examined in a second period of the study, had no significant differences in compliance or measured effectiveness.

Additional Comments

  • This study1 used a secondary endpoint (new radiographic findings) as the measurable clinical outcome. This would have been acceptable, but the timing (4 months after initiation of treatment) was not adequate to determine non-inferiority of the shorter regimen in long-term follow-up of LTBI, which is what is clinically important. It also does not account for the final 5 months of INH monotherapy, since there are no additional follow-up data reported.
    • The relatively high rate of CXR conversion in the different arms of the study may have multiple contributing factors: drug resistance rates in Greece, higher overall pre-test probability in this population given the higher risk of TB infection in this population, and a “Hawthorne Effect” of the radiologists potentially over-calling the CXR findings because they knew they were in a study.
    • In the UK, a 3-month regimen of INH/rifampin is considered an appropriate alternative to standard 6-month INH monotherapy for LTBI2. This is based on other studies3-4 showing effectiveness in adults and overall tolerance of the drugs in children, as well as ease of administration (there are combination tablets), cost effectiveness, and improved compliance. AAP, CDC, and ATS guidelines still recommend 9 months of INH for LTBI in children5-6

Citation

  1. 1. Spyridis NP et al. The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study. Clin Infect Dis. 2007 Sep 15;45(6):715-22.
    2. Joint Tuberculosis Committee of the British Thoracic Society. Control and prevention of tuberculosis in the United Kingdom: code of practice 2000. Thorax. 2000 Nov;55(11):887-901.
    3. Ormerod LP. Rifampicin and isoniazid prophylactic chemotherapy for tuberculosis. Arch Dis Child. 1998 Feb;78(2):169-71.
    4. Ena J, Valls V. Short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis. Clin Infect Dis. 2005 Mar 1;40(5):670-6.
    5. Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics. 2004;114(4pt3):1175-1201.
    6. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep. 2000 Jun 9;49(RR-6):1-51.

CAT Author: Eric Dziuban, MD

CAT Appraisers: Beth Tarini, MD, MS

Date appraised: November 12, 2008

Last updated June 15, 2009
Department of Pediatrics and Communicable Diseases
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