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. 2014 Oct 15;59(8):1049-63.
doi: 10.1093/cid/ciu572. Epub 2014 Jul 23.

Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis

J Peter Cegielski  1 , Tracy Dalton  1 , Martin Yagui  2 , Wanpen Wattanaamornkiet  3 , Grigory V Volchenkov  4 , Laura E Via  5 , Martie Van Der Walt  6 , Thelma Tupasi  7 , Sarah E Smith  1 , Ronel Odendaal  6 , Vaira Leimane  8 , Charlotte Kvasnovsky  1 , Tatiana Kuznetsova  4 , Ekaterina Kurbatova  1 , Tiina Kummik  9 , Liga Kuksa  8 , Kai Kliiman  9 , Elena V Kiryanova  10 , HeeJin Kim  11 , Chang-ki Kim  11 , Boris Y Kazennyy  10 , Ruwen Jou  12 , Wei-Lun Huang  12 , Julia Ershova  1 , Vladislav V Erokhin  13 , Lois Diem  1 , Carmen Contreras  14 , Sang Nae Cho  15 , Larisa N Chernousova  13 , Michael P Chen  1 , Janice Campos Caoili  7 , Jaime Bayona  14 , Somsak Akksilp  3 ; Global Preserving Effective TB Treatment Study (PETTS) Investigators
Collaborators, Affiliations

Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis

J Peter Cegielski et al. Clin Infect Dis. .

Abstract

Background: Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance.

Methods: To assess the GLC's impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC.

Results: In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16-.47) for XDR tuberculosis, 0.28 (.17-.45) for FQ, and 0.15 (.06-.39) to 0.60 (.34-1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07-.62) for acquired XDR tuberculosis and 0.23 (.09-.59) for acquired FQ resistance.

Conclusions: Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.

Keywords: Green Light Committee; extensively drug-resistant tuberculosis; multidrug-resistant tuberculosis; tuberculosis.

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Figures

Figure 1.
Figure 1.
Derivation of the study population. Abbreviations: CDC, US Centers for Disease Control and Prevention; DST, drug susceptibility testing; SLD, second-line drug.
Figure 2.
Figure 2.
Risk of acquired drug resistance in Green Light Committee (GLC)–approved and non-GLC programs, stratified by baseline resistance to second-line drugs, in 9 countries, 2005–2010. Abbreviations: CI, confidence interval; GLC, Green Light Committee.
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References

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