Sir, We read with great interest the manuscript ‘Effects of isoniazid resistance on TB treatment outcomes under programmatic conditions in a high-TB and -HIV setting: a prospective multicentre study’, by Nagu et al.,1 recently published in the Journal of Antimicrobial Chemotherapy. This Tanzanian study showed that initial resistance to isoniazid is associated with unfavourable programmatic treatment outcomes in patients on first-line TB treatment. Twenty-three (2.7%) out of 863 new TB cases with an available drug susceptibility testing (DST) result were diagnosed with isoniazid-resistant/rifampicin-susceptible TB. Of 23 patients with isoniazid-resistant/rifampicin-susceptible TB, 3 died, 1 failed treatment and 1 was lost to follow-up. The authors concluded ‘early laboratory detection of isoniazid resistance is important for commencing appropriate TB therapy’.1 As a way of considering the policy implications, in terms of a benefit–cost assessment of systematic DST prior to starting first-line TB treatment in new cases, we calculated the number that need to be tested to diagnose one patient with isoniazid-resistant/rifampicin-susceptible TB and the number of patients with isoniazid-resistant/rifampicin-susceptible TB that need to be treated with a strengthened regimen to avert one unfavourable outcome, assuming that a strengthened regimen would be equally effective for isoniazid-resistant/rifampicin-susceptible TB and isoniazid-susceptible/rifampicin-susceptible TB. Moreover, we discuss limitations that hamper the interpretation of mortality amongst patients with isoniazid-resistant/rifampicin-susceptible TB. In the study by Nagu et al.,1 data were not available for many cases investigated, which illustrates well the challenges TB programmes are confronted with. Of 1735 new TB cases, about half (n = 872, 50.3%) had either no result for culture or no result of DST and 23 had isoniazid-resistant/rifampicin-susceptible TB.1 The proportion of unsuccessfully treated patients with isoniazid-resistant/rifampicin-susceptible TB and isoniazid-susceptible/rifampicin-susceptible TB was 21.7% and 7.0%, respectively, a difference of 14.7%.1 Thus, the number that need to be treated with another regimen appropriate for isoniazid-resistant/rifampicin-susceptible TB to avoid one unfavourable outcome is 7 (100/14.7). In Tanzania, with ∼62 000 new TB cases per year,2 and a low isoniazid resistance prevalence of 2.7%, the number that need to be tested to find one case of isoniazid-resistant/rifampicin-susceptible TB is 38 (863/23). Or 268 new TB cases should be tested to avoid one unfavourable outcome. Or, in other words, if DST is performed successfully in all 62 000 patients, 231 unfavourable outcomes can be avoided (0.4%), if patients with isoniazid-resistant/rifampicin-susceptible TB are subsequently treated with a strengthened regimen. The gain seems to us limited in view of the technological and logistical hurdles to overcome. However, this rough estimate of benefit and cost may be quite uncertain, due to some important limitations of the study. Presented numbers are small, especially in the group with isoniazid-resistant TB. Thus, findings might have been affected by chance. Moreover, bacteriologically defined treatment outcomes (i.e. cure versus failure) may be the best measure of the effectiveness of TB treatment regimens in achieving relapse-free cure, especially because all were smear-positive at the start. In the study by Nagu et al.,1 the proportion of bacteriological unfavourable outcomes in patients with isoniazid-susceptible/rifampicin-susceptible TB and isoniazid-resistant/rifampicin-susceptible TB was 1.1% and 4.3%, respectively, with only one isoniazid-resistant against nine isoniazid-susceptible failures. Moreover, relapses were not reported. While mortality, the main unfavourable outcome (13% of patients with isoniazid-resistant/rifampicin-susceptible TB, but only three cases), may not have been due to ineffective TB treatment with rifampicin still active, it may have been due to other causes, such as HIV infection. An alternative cause would be undetected resistance to rifampicin, which is not as rare as often assumed.3 Only five patients (0.6% of 863 cases with a DST result) had rifampicin resistance (either isoniazid-susceptible/rifampicin-resistant TB or isoniazid-resistant/rifampicin-resistant TB),1 considerably lower than the 1.3% rifampicin-resistant TB prevalence among new cases reported as the national average, which was probably still an underestimate considering the 50% sensitivity for rifampicin resistance among new cases found by rechecking.4 Therefore, accurate diagnosis of rifampicin-resistant TB is a priority to prevent MDR-TB cases from being treated with a first-line regimen. Moreover, it is not yet clear how to operationalize the early laboratory detection of isoniazid resistance into a programme for commencing appropriate TB therapy. The effectiveness in terms of improving programmatic and bacteriological treatment outcomes will depend on a number of factors, including: (i) the availability of DST methods in the programme; (ii) the turnaround time of DST; (iii) the effect of delayed treatment initiation on dropouts and patient outcomes; (iv) the effectiveness of an alternative treatment for patients with isoniazid-resistant/rifampicin-susceptible TB; and (v) the limitations of DST methods, which are far from 100% accurate. Moreover, programmes will have to divert resources to prioritize the implementation of this target. Nevertheless, the WHO has a target of implementing DST in all newly diagnosed cases by 2025.5 Programmes will soon have to systematically screen all newly diagnosed TB cases for resistance to rifampicin.2 A similar recommendation is expected for isoniazid, together with a strengthened regimen for isoniazid-resistant TB. In most resource-poor countries this will be very hard to implement correctly, i.e. without excessively delaying the start of TB treatment. Moreover, accurate exclusion of rifampicin-resistant TB by rapid molecular testing—and not slower culture-based DST—will be the first and more efficient step towards improving treatment outcomes with the standard first-line regimen. Transparency declarations None to declare. Author contributions T. D. and A. V. D. wrote the first draft. All authors contributed to the subsequent draft and approved the final version. References 1 Nagu TJ, Aboud S, Matee MI et al. Effects of isoniazid resistance on TB treatment outcomes under programmatic conditions in a high-TB and -HIV setting: a prospective multicentre study. J Antimicrob Chemother 2017; 72: 876– 81. Google Scholar PubMed 2 WHO. Global Tuberculosis Report 2016 . Geneva, Switzerland: WHO Press, 2016. http://apps.who.int/medicinedocs/en/d/Js23098en/. 3 Van Deun A, Aung KJM, Bola V et al. Rifampin drug resistance tests for tuberculosis: challenging the gold standard. J Clin Microbiol 2013; 51: 2633– 40. Google Scholar CrossRef Search ADS PubMed 4 Chonde TM, Basra D, Mfinanga SGM et al. National anti-tuberculosis drug resistance study in Tanzania. Int J Tuberc Lung Dis 2010; 14: 967– 72. Google Scholar PubMed 5 WHO. Implementing The End TB Strategy: The Essentials . Geneva, Switzerland: WHO Press, 2015. http://www.who.int/tb/publications/2015/end_tb_essential.pdf? ua=1. © The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Dec 25, 2017
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