Individual patient meta-analysis of multidrug-resistant tuberculosis treatment regimens and outcomes in children

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Title: Individual patient meta-analysis of multidrug-resistant tuberculosis treatment regimens and outcomes in children
Authors: Harausz, E
Garcia-Prats, A
Law, S
Schaaf, H
Kredo, T
Seddon, JA
Menzies, R
Turkova, A
Achar, J
Amanullah, F
Barry, P
Becerra, M
Chan, E
Chiotan, D
Crossa, A
Drobac, P
Fairlie, L
Falzon, D
Flood, J
Gegia, M
Hicks, R
Isaakidis, P
Kadri, S
Kampmann, B
Madhi, S
Marais, E
Mariandyshev, A
Mednez-Echevarria, A
Moore, B
Ozere, I
Padayatchi, N
Rybak, N
Santiago-Garcia, B
Shah, S
Sharma, S
Shim, T
Skrahina, A
Soriano-Arandes, A
Van den Boom, M
Van der Werf, M
Williams, B
Yablokova, E
Yim, J
Furin, J
Hesseling, A
Item Type: Journal Article
Abstract: Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and Findings To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of 3 children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and where treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with individual patient data provided for 28 of these. All data were from published or unpublished observational cohorts. We analysed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were HIV-infected. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be HIV-infected, to be malnourished, and to have severe TB on chest radiograph (p<0.0001 for all characteristics) . Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy; 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% CI 8-19%, p<0.0001). Treatment was successful in only 56% of bacteriologically confirmed HIV-infected children who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in HIV-infected children who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5-48%, p=0.0063). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (aOR 2.9, 95% CI 1.0-8.3). These findings for high dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multi-drug regimens; only observational cohort studies were available for inclusion; and treatment decisions were based on the clinician’s perception of illness with resulting potential for bias. Conclusions: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in HIV-infected children who did not receive ART during their MDR-TB treatment highlights the need for ART in HIV-infected children with MDR-TB. Our findings of individual drug effects on treatment outcome should be further evaluated.
Date of Acceptance: 17-May-2018
URI: http://hdl.handle.net/10044/1/60226
ISSN: 1549-1277
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Medicine
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Keywords: 11 Medical And Health Sciences
General & Internal Medicine
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Department of Medicine
Faculty of Medicine



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