Tuberculosis (TB), an infectious and chronic disease caused by Mycobacterium tuberculosis, is one of the leading causes of death worldwide.1 Although considered an age-old, curable, and preventable disease, more than 10 million people are infected every year, and around 1.5 million dies. Children and adolescents are equally affected by the disease. In 2018, more than a million children were estimated to develop TB, and 250,000 died [1]. This represents 10% of the total burden of incident TB and 15% of associated total mortality [1,2].

One of the main challenges of managing the disease is that M. tuberculosis remains in the infected host in a latent state, causing latent TB infection (LTBI), a persistent immune response due to antigen stimulation without evident clinical manifestations of active TB [3,4]. It is estimated that up to a third of the world population is infected with M. tuberculosis, with most cases being asymptomatic and non-infectious. However, there are around 5–10% chances of reactivation of the bacteria and progression to active disease [5]. Moreover, patients with concomitant human immunodeficiency virus (HIV) infection are more prone to die due to the compromise of the immune system (i.e., preventing granuloma formation and bacillus containment at the primary infection site) and spread of the bacillus to various organs and systems [6]. This risk is even higher in children under five years old [3,5], who are more likely to progress to the most severe forms of the disease. This progression depends on the child's susceptibility, which is highest during the first years of life, probably from immunological immaturity [[7], [8], [9]]. Without Bacille Calmette-Guerin (BCG) vaccination, around 30% of infected infants (<1 year old) will progress to intrathoracic TB, and around 10–20% will develop disseminated disease. In children aged 1–2 years, the risk of progressing to intrathoracic TB or disseminated disease are 10–20% and 2–5%, respectively. These risks decline slowly until around ten years of age when the adult-type disease starts to emerge [10,11].

Transmission of pediatric TB is often associated with the inhalation of droplet nuclei expelled by infected in a household with active TB, but it can also be acquired congenitally [7]. Until February 2020, the World Health Organization recommended only the use of daily isoniazid (INH) (monotherapy) during 6–9 months for TB prevention. The updated guideline also includes the use of short-term regimens such as weekly rifapentine (RIP) plus INH, or daily INH plus rifampicin (RIF), both for three months [12].

Selection of the best therapeutic approach in each scenario considering drugs' clinical profile, patient's preferences, and access should be grounded in updated evidence. Currently, the comparative efficacy and safety of drug regimens for pediatric TB prevention come primarily from systematic reviews with pairwise meta-analysis [[13], [14], [15]]. Network meta-analysis, an extension of pairwise meta-analysis, can statistically combine in one single model both direct (i.e., available in the literature) and indirect evidence (i.e., estimated based on standard treatment comparators) across several treatments [16].

Thus, we aimed to compare the clinical profile (efficacy and safety) of all available drug regimens for LTBI in young children and adolescents (≤15 years old) through a broad and updated network meta-analysis.