Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to preventM. tuberculosisinfection in HIV-exposed uninfected children

Abstract

IntroductionHIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk ofMycobacterium 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 analysisWe 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 disseminationAn 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.Trial registration numberNCT02613169; Pre-results.

QuantiFERON-TB Gold Plus Performance in Children: A Narrative Review

“…It may have particular value in screening young BCG-vaccinated children for Mtb infection, by overcoming TST specificity limitations. Although studies are ongoing, 44 , 45 further prospective studies with larger cohorts are required to clarify the most appropriate methods for pediatric Mtb infection screening in both low- and high-incidence countries. In particular, longitudinal studies are needed to determine performance of QFT-Plus to predict future TB disease progression.…”

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV

“…Details of trial design and procedures have been previously published including the study power calculations (ClinicalTrials.gov NCT02613169). 12 , 13 Eligible infants 6–10 weeks of age, born to mothers living with HIV, with birth weight >2·5 kilograms, and >37 weeks gestation, were enrolled from prevention of maternal-to-child transmission of HIV (PMTCT) clinics. Infants were provided prophylactic antiretrovirals through PMTCT clinics.…”

Non-IFNγ Whole Blood Cytokine Responses to Mycobacterium tuberculosis Antigens in HIV-exposed Infants

“…We enrolled HIV-infected mothers and their infants in a nonblinded randomized nonblinded trial (ClinicalTrials.gov NCT02613169) of IPT to prevent Mtb infection in Kisumu, Kenya (N = 300, 2016-2019). 17,18 Eligible infants were 6-10 weeks old, birth weight >2.5 kg, and ≥ 37 weeks of gestation. We excluded infants at enrollment with known TB exposure (including maternal TB diagnosed in the past year) or enrollment in other TB prevention studies.…”

“…Further study information has been previously published. 17,18 Infants were randomized 1:1 to 12 months of INH (10 mg/kg dose) with pyridoxine or no INH. Primary endpoint was Mtb infection 12 months after randomization (approximately 14 months old) assessed by QuantiFERON-TB Gold Plus (QFT-Plus) and/or TST.…”

“…7,17 The Infant TB Infection Prevention Study (iTIPS) was a randomized nonblinded trial in western Kenya, an area of high HIV and TB burden. 17,18 HEU infants were randomized to receive IPT or no IPT for the first year of life with cumulative incidence of Mtb infection measured at 12 months postrandomization using TST and Quantiferon-Gold Plus (QFT-Plus). IPT was not associated with a significant difference in risk of Mtb infection (hazard ratio = 0.53, P = 0.11), though there was a trend toward lower risk of positive TST among HEU infants randomized to IPT (hazard ratio = 0.46, P = 0.07).…”