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To the Editor,
We read with interest the recent commentary by Batt and Khan in the CMAJ about our recent publications of trials comparing 4 months Rifampin (4R) with 9 months isoniazid (9H) in adults 1 and children2. In those two trials, and an earlier trial among adults3, we have shown that 4R is consistently significantly superior to 9H for completion and safety in adults and is very safe and well tolerated in children. In both populations, efficacy of 4R was non-inferior to that of 9H 1,2. In summary, 4R is shorter, safer, better completed and as effective as 9H. Seems like an easy choice for patients and providers.
However, Batt and Khan raise concerns regarding the potential risk of creating Rifampin resistance if 4R is given to patients with undetected active TB. We agree that creation of resistance by inadvertent mono-therapy of active TB is a very important potential risk, but we believe it is important to adequately review the available evidence regarding this risk. There have been 2 relevant systematic reviews: The first, cited by the author , reviewed 6 studies of rifamycin-containing regimens and found no evidence of increased risk of acquired rifampin resistance 4. The second reviewed 13 studies, including 6 among HIV-infected persons, and found no evidence of increased risk of acquired resistance to INH in randomized trials or cohort studies using INH to treat latent TB 5. This evidence suggests that risk of acquired drug resistance from latent TB therapy is very low.
The authors recommend that clinicians in settings without access to sputum induction should refer their patients to centers where this is performed. What is the evidence that sputum induction is necessary? To answer this, we reviewed carefully the methods used to exclude active TB before initiating LTBI treatment in all the published studies included in the 2 systematic reviews 4,5. Our reasoning was that since there was no evidence of acquired resistance, then the methods to exclude active TB in these studies were adequate to safeguard against creating resistance. Of the 17 studies, all but two described the procedures used to exclude active TB before starting latent TB therapy; none of these 15 studies described use of sputum induction to exclude active TB prior to starting latent TB therapy. The evidence from all these studies suggests that symptom assessment, physical examination, chest radiography and spontaneous sputum collection is adequate to prevent the emergence of drug resistance. We suggest that Batt and Khan should provide supportive evidence for their opinion that sputum induction is essential; this is inaccessible in many settings, creating a barrier to safe preventive therapy for many populations.
The authors also suggest that creation of INH resistance was preferable. However, there is published evidence that treatment outcomes in patients with INH resistant strains are significantly worse, including frequent progression to multi-drug resistant TB 6. They cite the difficulties of treatment of Rifampin resistant TB (RR-TB) with lengthy regimens including many months of injections, and ignore recommendations made in 2018 by WHO for an all-oral regimen as first-line treatment of RR TB 7 which uses much more effective drugs8.
Finally, the authors suggested that the study population does not reflect the typical Canadian clinical experience. In the 4R trials we have conducted, a total of 1748 participants were enrolled at Canadian sites. This is, we believe, the largest number of participants in any randomized trial of latent TB therapy enrolled in Canada. If these results are not results are not relevant to Canadian practice, what would be?
In summary, while we acknowledge that the concerns regarding Rifampin resistance are important, we believe there is a substantial body of evidence that symptom screening, physical examination, chest radiography and spontaneous sputum examination will be adequate to safeguard against this risk. We believe that 4R offers very important benefits for patients in Canadian settings - as it is a better tolerated, more acceptable and much safer regimen for latent TB therapy than the current standard of 9 months INH.
Dick Menzies, Victoria Cook, Richard Long, and Rovina Ruslami.
References:
1. Menzies D, Adjobimey M, Ruslami R, et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med 2018;379:440-53.
2. Diallo T, Adjobimey M, Ruslami R, et al. Safety and Side Effects of Rifampin versus Isoniazid in Children. N Engl J Med 2018;379:454-63.
3. Menzies D, Long R, Trajman A, et al. Adverse events with 4 months rifampin or 9 months isoniazid as therapy for latent TB infection: results of a randomized trial. Annals of Internal Medicine 2008;149:689-97.
4. den Boon S, Matteelli A, Getahun H. Rifampicin resistance after treatment for latent tuberculous infection: a systematic review and meta-analysis. Int J Tuberc Lung Dis 2016;20:1065-71.
5. Balcells M, Thomas S, Godfrey-Faussett P, Grant A. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51.
6. Gegia M, Winters N, Benedetti A, van Soolingen D, Menzies D. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis. Lancet Infect Dis 2017;17:223-34.
7. World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva2019.
8. Collaborative Group for the Meta-Analysis of Individual Patient Data in MDRTBt, Ahmad N, Ahuja SD, et al. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. Lancet 2018;392:821-34.