TB treatment successful in children with MDR-TB

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The results of a large, international systematic review show that tuberculosis treatment is successful in children with multidrug-resistant tuberculosis (MDR-TB).

An IoL report says the study was used to inform the World Health Organisation guidelines on treatment of MDR-TB in children. It involved a collaborative group of international researchers, included a systematic review and patient data meta-analysis on the clinical characteristics and treatment outcomes of 975 children from 18 countries.

The results show that 78% (764 of 975) of these children had successful treatment outcomes when treated with second-line MDR-TB drugs.

Professor Anneke Hesseling from the Desmond Tutu TB Centre, faculty of medicine and health sciences, Stellenbosch University said an estimated 32,000 children develop multidrug-resistant tuberculosis each year. She said that treatment for MDR-TB is of a longer duration and requires drugs that are more toxic. “These regimens are frequently hard to tolerate, particularly in children, due to the length of treatment, drug toxicity and the lack of child-friendly formulations,” said Hesseling.

“To date, little has been known about the optimal treatment for these children. This review therefore gives vitally important information as to potential outcomes and some very good news for the TB field,” she said.

Dr Tamara Kredo, co-author and senior specialist at Cochrane South Africa, an intramural research unit of the South African Medical Research Council, said there are too few examples where researchers share their data for the public good. “This is impressively what this global team of researchers did – this helped to ensure that we could capture all published and unpublished evidence for treating children with MDR-TB. The search yielded 2772 reports and, ultimately, 33 studies were eligible for inclusion,” she said.

The review also showed the urgent need for HIV treatment in children with HIV and TB co-infection. TB treatment was less successful in children who were HIV positive but not receiving antiretroviral therapy (ART). “Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment during MDR-TB therapy,” said Hesseling, “Compared to 82% in children infected with HIV who received ART during MDR-TB therapy. This highlights the urgent need for ART in these children, which should be a priority in our setting, where rates of HIV/TB coinfection are so high,” she said.

Malnutrition was shown as another factor that affected treatment outcome and highlighted the need for aggressive solutions. Second-line injectable agents and high-dose isoniazid were associated with treatment success. However, a high proportion of children with non-severe disease who received no second-line injectable agents still did well.

“This means children with non-severe disease may be able to be spared from these more toxic medications,” said Hesseling.

“Further work is still needed on individual drug effects on treatment outcome,” said Kredo in the report.

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 (IPD) 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 three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed 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 infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 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% confidence interval [CI] 8%–19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%–48%, p = 0.006). 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 (adjusted odds ratio [aOR] 2.9, 95% CI 1.0–8.3, p = 0.041 and aOR 5.9, 95% CI 1.7–20.5, p = 0.007, respectively). 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 multidrug 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 children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

Authors
Elizabeth P Harausz, Anthony J Garcia-Prats, Stephanie Law, H Simon Schaaf, Tamara Kredo, James A Seddon, Dick Menzies, Anna Turkova, Jay Achar, Farhana Amanullah, Pennan Barry, Mercedes Becerra, Edward D Chan, Pei Chun Chan, Domnica Ioana Chiotan, Aldo Crossa, Peter C Drobac, Lee Fairlie, Dennis Falzon, Jennifer Flood, Medea Gegia, Robert M Hicks, Petros Isaakidis, SM Kadri, Beate Kampmann, Shabir A Madhi, Else Marais, Andrei Mariandyshev, Ana Méndez-Echevarría, Brittany Kathryn Moore, Parpieva Nargiza, Iveta Ozere, Nesri Padayatchi, Saleem- ur-Rehman, Natasha Rybak, Begoña Santiago-Garcia, N Sarita Shah, Sangeeta Sharma, Tae Sun Shim, Alena Skrahina, Antoni Soriano-Arandes, Martin van den Boom, Marieke J van der Werf, Tjip S van der Werf, Bhanu Williams, Elena Yablokova, Jae-Joon Yim, Jennifer Furin, Anneke C Hesseling

IoL report
PLOS Medicine abstract


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