Update on MDR-TB preventive therapy towards the global TB elimination.

Multidrug-resistant tuberculosis (MDR-TB), the deadliest form of TB, has been included in the 2024 WHO's priority list of antibiotic resistant bacterial pathogens due to its severe public health implications. Almost 2 billion people are infected by TB worldwide, but the burden of MDR-TB infection remains uncertain. Mathematics modelling estimates that MDR-TB affects nearly three in every 1,000 people globally, highlighting the urgent need to address tuberculosis preventive treatment (TPT) for contacts of MDR-TB cases. Before 2018, only close monitoring of contacts of people with MDR-TB was recommended, rather than TPT. However, considering the ethical and public health concern of leaving infected individuals untreated, WHO updated its guidelines initially in 2018, 2020 and 2022. Despite limited evidence at that time, WHO suggested considering quinolone-based TPT for selected high-risk cases. To close the evidence gap, two large scale, prospective, randomized controlled trials were conducted: VQUIN and TB-CHAMP. Both trials evaluated the efficacy of levofloxacin compared to placebo for MDR-TB following household exposure, in adults and children, respectively. A combined meta-analysis of the two trials showed a 60% reduction in TB incidence in the levofloxacin group, and the difference was statistically significant. Based on these results, in 2024 the WHO recommended the use of six-month of daily levofloxacin (6Lfx) as TPT for contacts exposed to MDR/RR-TB. This regimen is cost-effective, safe, demonstrates good efficacy and does not interact with HIV therapies. Despite this promising data, pre-XDR-TB (MDR-TB with documented resistance to quinolones) is an emerging concern. Two ongoing trials will address this challenge: the PHOENIx trial, evaluating the efficacy of delamanid compared to isoniazid for preventing M/XDR-TB after household exposure, and the BRANCH-TB trial, that will assess the efficacy and safety of a one-month of bedaquiline regimen compared to WHO-recommended TPT regimens. Preventing MDR/RR-TB remains a significant challenge towards global TB elimination. While the recent WHO recommendation for 6Lfx is a promising step, expanding TPT options for pre-XDR-TB and addressing drug intolerance are critical. Ongoing as well as new trials are essential to develop alternative treatment and achieve TB elimination.