Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent M. tuberculosis infection in HIV-exposed uninfected children

• Type of Material: Article
• Authors: Sylvia M. LaCourse, University of Washington; Barbara A. Richardson, University of Washington; John Kinuthia, Kenyatta National Hospital; A. J. Warr, Baylor College of Medicine; Elizabeth Maleche-Obimbo, University of Nairobi; Daniel Matemo, Kenyatta National Hospital; Lisa Cranmer, Emory University; Jaclyn N. Escudero, University of Washington; Thomas R. Hawn, University of Washington; Grace C. John-Stewart, University of Washington
• Language: English
• Date: 2020-01-01
• Publisher: BMJ Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Author(s).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/bmjopen-2019-034308
• Title of Journal or Parent Work: BMJ Open
• Volume: 10
• Issue: 1
• Start Page: e034308
• End Page: e034308
• Grant/Funding Information: This work was supported by the Thrasher Research Fund, National Institute of Allergy and Infectious Diseases (NIAID), Fulbright programme awarded to the Northern Pacific Global Health Fellows Program by the Fogarty International Center of the National Institutes of Health (NIH/Fogarty), and National Center for Advancing Translational Sciences at National Institutes of Health (NIH) (Thrasher to GJ-S, NIH/NIAID K23AI120793 to SML, NIH/NIAID 2K24AI137310 to TRH, NIH/Fogarty R25TW009345 to AJW and NIH UL1TR000423 for REDCap).
• Keywords: Prophylaxis; Double-blind; Antiretroviral therapy; isoniazid; protocol; Release assays; tuberculosis; Medicine, General & Internal; General & Internal Medicine; prevention; Science & Technology; Childhood; Skin test; High prevalence; Cape-town; Life Sciences & Biomedicine; Follow-up; pediatric; Cytokine response
• Research Categories: Health Sciences, Immunology; Health Sciences, Public Health; Biology, Biostatistics; Health Sciences, Epidemiology

Abstract

Introduction: HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population. Methods and analysis: We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ∼10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry. Ethics and dissemination: An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants.