Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.

Author(s)
Garcia-Prats, Anthony J
Garcia-Cremades, Maria
Cox, Vivian
Kredo, Tamara
Dunbar, Rory
Schaaf, H Simon
Seddon, James A
Furin, Jennifer
Achar, Jay
Radke, Kendra
Sachs, Tina
Abubakirov, Amanzhan
Ahmed, Saman
Akkerman, Onno W
Al Ani, Nadia Abdulkareem
Amanullah, Farhana
Ahmad, Nafees
Anderson, Laura F
Asfaw, Meseret
Bango, Funeka
Bauer, Torsten
Becerra, Mercedes
Boeree, Martin
Brinkmann, Folke
Brown, Rosemary
Brust, James
Campbell, Jonathon R
Carvalho, Anna Cristina
Carvalho, Isabel
Cegielski, J Peter
Centis, Rosella
Chan, Edward D
Chauhan, Sandeep
Chiang, Silvia S
Chan, Pei-Chun
D'Ambrosio, Lia
Dalcolmo, Margareth
Daneilyan, Narine
de Vries, Gerard
Draper, Heather R
Fairlie, Lee
Francis, Joshua
Franke, Molly
Gegia, Medea
Restrepo, Camilo Gomez
Guenther, Annette
Gureva, Tatyana
Haecker, Brit
Harausz, Elizabeth
Hewison, Catherine
Hicks, Robert M
Huerga, Helena
Hughes, Jennifer
Isaakidis, Petros
Kadri, Syed M
Khan, Mazhar Ali
Kotrikadze, Tinatin
Kuksa, Liga
Lachenal, Nathalie
Lange, Christoph
Lecca, Leonid
Lopez-Varela, Elisa
Lucena, Sheila
Mariandyshev, Andrei
Mattoo, Sanjay
Mendez-Echevarria, Ana
Migliori, Giovanni Battista
Mitnick, Carole
Mohr-Holland, Erika
Mulanda, Winston
Murzabakova, Totugul
Myrzalieve, Bakyt
Ndjeka, Norbert
Niemann, Stefan
Ozere, Iveta
Padayatchi, Nesri
Parmar, Malik
Parpieva, Nargiza
Manzur-Ul-Alam, Mohammad
Rybak, Natasha
Sachdeva, Kuldeep Singh
Salmon, Kelly
Santiago-Garcia, Begoña
Schaub, Dagmar
Shah, Ira
Shah, Sarita
Shah, Vaibhav
Sharma, Sangeeta
Shim, Tae Shun
Shin, Sonya
Sinha, Animesh
Skrahina, Alena
Solanki, Hardik
Solans, Belen P
Soriano-Arandes, Antoni
Toktogonova, Atyrkul
van der Werf, Tjip
Velásquez, Gustavo E
Williams, Bhanu
Yim, Jae-Joon
Savic, Rada
Hesseling, Anneke
Publication Date
2025-02-01
Abstract
There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230).1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success.Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens.Unitaid.
Affiliation
University of Wisconsin-Madison, School of Medicine and Public Health, Department of Pediatrics, Madison, WI, USA; Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa. Electronic address: garciaprats@wisc.edu.
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA; Complutense University of Madrid, Department of Pharmaceutics and Food Technology, School of Pharmacy, Madrid, Spain; Institute of Industrial Pharmacy, Complutense University of Madrid, Madrid, Spain.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa; University of Cape Town, Center for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, Cape Town, South Africa.
South African Medical Research Council, Health Systems Research Unit, Cape Town, South Africa.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa; Imperial College London, Department of Infectious Diseases, London, UK.
Harvard Medical School, Department of Global Health and Social Medicine, Boston, MA, USA.
Karolinska Institute, Department of Global Public Health, Stockholm, Sweden; Stellenbosch University, DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Tygerberg, South Africa.
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
National Scientific Center of Phthisiopulmonology of the Ministry of Health of the Republic of Kazakhstan, Almaty, Kazakhstan.
Interactive Research & Development, Karachi, Pakistan.
University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, Netherlands; University of Groningen, University Medical Center Groningen, TB Center Beatrixoord, Groningen, Netherlands.
Iraq National TB Programme, Drug-resistant Tuberculosis Unit, Baghdad, Iraq.
Tufts Medical Center, Department of Pediatrics, Boston, MA, USA.
University of Balochistan, Department of Pharmacy Practice, Quetta, Pakistan.
World Health Organization, Global Malaria Programme, Geneva, Switzerland.
Partners in Health, Maseru, Lesotho.
South African Medical Research Council, Health Systems Research Unit, Cape Town, South Africa.
Helios Klinik Emil von Behring, Respiratory Diseases Clinic Heckeshorn, Berlin, Germany.
Harvard Medical School, Department of Global Health and Social Medicine, Boston, MA, USA.
Radboud University Medical Center, Department of Lung Disease, Nijmegen, Netherlands.
University Hospital Schleswig-Holstein, Campus Lübeck, Pediatric Pneumology, Lübeck, Germany; Airway Research Center North, Deutsches Zentrum für Lungenforschung, Großhansdorf, Germany.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Albert Einstein College of Medicine, Department of Medicine, Bronx, NY, USA.
McGill University, Departments of Medicine & Global and Public Health, Montreal, QC, Canada.
Oswaldo Cruz Institute, Fiocruz, Laboratory of Innovations in Therapies, Education and Bioproducts, Rio de Janeiro, Brazil.
Vila Nova de Gaia Hospital Centre, Pediatric Department, Vila Nova de Gaia, Portugal.
Emory University Rollins School of Public Health, Department of Epidemiology, and Emory Tuberculosis Center, Atlanta, GA, USA.
Istituti Clinici Scientifici Maugeri, IRCCS, Servizio di Epidemiologia Clinica delle Malattie dell'apparato Respiratorio, Tradate, Italy.
National Jewish Hospital, Denver, CO, USA.
World Health Organization, National Tuberculosis Elimination Programme, Technical Support Network, Central TB Division, New Delhi, India.
Alpert Medical School of Brown University, Pediatrics, Providence, RI, USA; Rhode Island Hospital, Center for International Health Research, Providence, RI, USA.
Taiwan Centers for Disease Control, The Division of Chronic Infectious Diseases, Taipei City, Taiwan.
Public Health Consulting Group, Lugano, Switzerland.
Fiocruz, Reference Center Hélio Fraga, Rio De Janeiro, Brazil.
Medecins Sans Frontieres, Medical Department, Paris, France.
National Institute for Public Health and the Environment, Centre for Infectious Disease Control, Bilthoven, Netherlands.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa; Respiratory Medicine & International Health, University of Lübeck, Lübeck, Germany.
Menzies School of Health Research, Charles Darwin University, Global and Tropical Health Division, Darwin, Australia; Royal Darwin Hospital, Department of Paediatrics, Darwin, Australia.
Harvard Medical School, Department of Global Health and Social Medicine, Boston, MA, USA; Harvard T H Chan School of Public Health, Epidemiology, Boston, MA, USA.
World Health Organisation, Global TB Programme, Geneva, Switzerland.
Medecins Sans Frontieres, Medical Coordination, Tashkent, Uzbekistan.
Helios Klinik Emil von Behring, Klinik fuer Kinder- und Jugenmedizin, Berlin, Germany.
Northern State Medical University, Department of Phthisiopulmonology, Arkhangelsk, Russia.
German Central Committee against Tuberculosis, Berlin, Germany.
Upstate Medical University, Department of Infectious Disease, Syracuse, NY, USA.
Medecins Sans Frontieres, Medical Department, Paris, France.
Mills-Peninsula Medical Center, Department of Radiology, Burlingame, CA, USA.
Epicentre, Field Epidemiology, Paris, France.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Medecins Sans Frontieres, Southern Africa Medical Unit, Cape Town, South Africa; University of Ioannina School of Medicine, Clinical and Molecular Epidemiology Unit Department of Hygiene and Epidemiology, Ioannina, Greece.
Department of Health, Epidemiology and Public Health, Kashmir, India.
Programmatic Management of Drug Resistant TB Unit, Lady Reading Hospital, Peshawar, Pakistan; Peshawar Medical College, Riphah International University, Islamabad, Pakistan.
Medecins Sans Frontieres France, Medical Coordination, Tbilisi, Georgia.
Riga East University Hospital, Tuberculosis and Lung Disease Clinic, Riga, Latvia.
Medecins Sans Frontieres, Medical Department, Geneva, Switzerland.
Respiratory Medicine & International Health, University of Lübeck, Lübeck, Germany; Department of Clinical Infectious Diseases, Research Center Borstel, Leibniz Lung Centre, Borstel, Germany; German Center of Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Socios En Salud, Lima, Peru.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa; ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
Hospital Municipal Raphael de Paula Souza, Department of Pneumology, Rio de Janeiro, Brazil.
Northern State Medical University, Department of Phthisiopulmonology, Arkhangelsk, Russia; Northern Arctic Federal University, Scientific Department, Arkhangelsk, Russia.
Government of India, Ministry of Health and Family Welfare, Central TB Division, National TB Elimination Program, New Dehli, India.
Hospital Universitario La Paz, Pediatric Infectious Diseases Unit, Madrid, Spain.
Istituti Clinici Scientifici Maugeri, IRCCS, Servizio di Epidemiologia Clinica delle Malattie dell'apparato Respiratorio, Tradate, Italy.
Harvard Medical School, Department of Global Health and Social Medicine, Boston, MA, USA.
Medecins Sans Frontieres, Epidemiology Department, Khayelitsha, South Africa.
Medecins Sans Frontieres - Holland, Medical Department, Kulob, Tajikistan.
KNCV, Bishkek, Kyrgyz Republic.
KNVC, Technical Department, The Hague, Netherlands; Kyrgyz State Medical Academy, TB Department, Bishkek, Kyrgyzstan.
National Department of Health, South Africa, National Tuberculosis Programme, Pretoria, South Africa; Department of Medicine, University of Cape Town, Cape Town, South Africa.
German Center of Infection Research, Partner Site Hamburg-Lübeck-Borstel-Riems, Germany; Research Center Borstel, Molecular and Experimental Mycobacteriology, Borstel, Germany.
Riga East Clinical University Hospital, State Centre of Tuberculosis and Lung Diseases, Upeslejas, Latvia; Riga Stradiņš University, Infectology, Riga, Lativa.
University of KwaZulu Natal, CAPRISA, Durban, South Africa.
World Health Organization, Country Office for India, Communicable Diseases, Tuberculosis, New Dehli, India.
Republican Specialized Scientific-Practical Medical Center of Phthisiology and Pulmonology, Ministry of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan.
Interactive Research & Development, Dhaka, Bangladesh.
The Warren Alpert Medical School of Brown University, Division of Infectious Diseases, Providence, RI, USA.
Molbio Diagnostics, Strategy Department, Goa, India.
Centre Hospitalier Universitaire Saint-Pierre, Pediatric Department, Brussels, Belgium.
Hospital General Universitario Gregorio Marañón, Instituto de Investigacion Sanitaria Gregorio Marañón, Pediatric Infectious Diseases Department, Madrid, Spain; CIBERINFEC ISCIII Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain.
Department of Clinical Infectious Diseases, Research Center Borstel, Leibniz Lung Centre, Borstel, Germany.
B J Wadia Hospital for Children, Pediatric TB Clinic, Department of Pediatric Infectious Diseases, Mumbai, India.
Emory Rollins School of Public Health, Department of Epidemiology, Atlanta, GA, USA.
World Health Organization, Information Support and Surveillance, Delhi, India.
National Institute of Tuberculosis and Respiratory Diseases, Department of Pediatrics, New Delhi, India.
University of Ulsan College of Medicine, Asan Medical Center, Department of Pulmonary and Critical Care Medicine, Seoul, South Korea.
Harvard Medical School, Department of Global Health and Social Medicine, Boston, MA, USA; Brigham and Women's Hospital, Division of Global Health Equity, Boston, MA, USA.
Medecins Sans Frontieres, Manson Unit, London, UK.
The Republican Scientific and Practical Center for Pulmonology and TB, Clinical Department, Minsk, Belarus.
World Health Organization, Department of Communicable Diseases, New Dehli, India.
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA; University of California, San Francisco, UCSF Center for Tuberculosis, San Francisco, CA, USA.
Hospital Universitari Vall d'Hebron, Pediatric Infectious Diseases and Immunodeficiencies Unit, Barcelona, Spain; Val d'Hebron Research Institute, Infection and Immunity in Children, Barcelona, Spain.
National TB Center, Scientific Department, Bishkek, Kyrgyzstan.
University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, Netherlands.
University of California, San Francisco, UCSF Center for Tuberculosis, San Francisco, CA, USA; University of California, San Francisco, Division of HIV, Infectious Diseases, and Global Medicine, San Francisco, CA, USA.
Northwick Park Hospital, Department of Paediatrics, London, UK.
Seoul National University College of Medicine, Department of Internal Medicine, Seoul, Republic of Korea.
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, CA, USA; University of California, San Francisco, UCSF Center for Tuberculosis, San Francisco, CA, USA.
Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Citation
Lancet Child Adolesc Health . 2025 Feb;9(2):100-111. doi: 10.1016/S2352-4642(24)00330-4.
ISSN
2352-4650
Pubmed ID
https://pubmed.ncbi.nlm.nih.gov/39855750/?otool=iaurydwlib
Link
MESH subject
Humans
Adolescent
Child
Rifampin
Tuberculosis, Multidrug-Resistant
Treatment Outcome
Antitubercular Agents
Child, Preschool
Infant
Female
Male
Title
Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.
Type of document
Journal Article
Entity Type
Publication

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