Two recent simultaneous trials – one conducted in South Africa among children, the other involving Vietnamese adults – found that levofloxacin reduced the risk of multidrug-resistant tuberculosis (MDR-TB) in adults and adolescents by an impressive 45%.
The findings showed that the oral antibiotic levofloxacin taken once-daily for six months substantially reduced the risk of developing drug-resistant tuberculosis (TB), and almost halved adults’ and children’s risk of developing MDR-TB, reports MedicalXpress.
“Multidrug-resistant TB is a major global public health problem, affecting more than 400 000 people each year. It is associated with significantly poorer outcomes than drug-susceptible TB,” said Professor Gregory Fox, director of the NHMRC Centre for Research Excellence in Tuberculosis who led the VQUIN trial at the University of Sydney’s Woolcock Institute of Medical Research in collaboration with the Vietnam Tuberculosis Programme.
“We now have a way of stopping people with early TB infection from becoming sick and spreading their infection to other people.”
The trial enrolled 2 041 family members of people with drug-resistant TB. These relatives had early infection, which had not yet developed into the active form of drug-resistant TB. The study was conducted across 10 provinces in Vietnam, a country with a high rate of drug-resistant TB.
The trial found that levofloxacin reduced the risk of MDR-TB in adults and adolescents by 45%.
The trial findings were combined with the second trial, TB-CHAMP, in South Africa and which involved the same treatment in children.
Together, the two studies demonstrated that levofloxacin could stop the risk of MDR-TB among family and other household members, curtailing the global impact of this dangerous pathogen. The combined analysis was published on the same day in the companion journal NEJM Evidence.
Evidence to date has been limited on MDR-TB preventive treatment since no randomised controlled trials had ever been conducted.
“The VQUIN trial is a major step forward in the fight against drug-resistant TB. This evidence changes the way we care for people at risk of drug-resistant TB in Australia and globally. The benefits to the families and communities at risk of MDR TB are substantial,” said Fox, who is also research leader at the Woolcock Institute of Medical Research.
“MDR-TB is one of the most challenging diseases to cure, and children have always been the most neglected patients,” said Professor Ben Marais, a chief investigator from VQUIN TB-CHAMP from the University of Sydney.
In the trial, 2 041 adults and children living with a person with MDR-TB in the household were given six months of levofloxacin and monitored for 30 months. The study found that there were 45% fewer cases of TB in the group given levofloxacin compared with the placebo group. A lower number of cases of TB occurred in the placebo group than expected.
Overall, levofloxacin was found to be safe and well-tolerated in adults and children.
In September 2024, the World Health Organisation issued new guidelines for MDR-TB preventive therapy. The guidelines were based on the findings of the VQUIN trial.
The trial also completed work on other important considerations such as acceptability of the drug regimen, feasibility, health economics, pharmacokinetics and antimicrobial resistance.
The teams from the VQUIN trial in Australia and TB CHAMP trial in South Africa collaborated before the trials were unblinded. They combined their data on efficacy and safety in traditional and novel Bayesian approaches.
Jointly, they showed that across both trials, levofloxacin reduced the risk of developing TB by 60%. Novel Bayesian analysis showed similar results for each trial, individually.
Study details
A Meta-Analysis of Levofloxacin for Contacts of Multidrug-Resistant Tuberculosis
Trinh Duong, Simon Schaaf, Frances Garden, Ben Marais, Thu Anh Nguyen, Ian White et al for the TB-CHAMP and VQUIN MDR-TB trial teams.
Published in NEJM Evidence on 18 December 2024
Abstract
Background
Data from randomised trials evaluating the effectiveness of tuberculosis (TB) preventive treatment for contacts of multidrug-resistant (MDR)-TB are lacking. Two recently published randomised trials that did not achieve statistical significance provide the opportunity for a meta-analysis.
Methods
We conducted combined analyses of two phase 3 trials of levofloxacin MDR-TB preventive treatment — Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis (VQUIN) trial and the Levofloxacin preventive treatment in children exposed to MDR-TB (TB-CHAMP) trial. Following MDR-TB household exposure, VQUIN enrolled mainly adults in Vietnam; TB-CHAMP enrolled mainly young children in South Africa. Random assignment in both trials was 1:1 at the household level to daily levofloxacin or placebo for 6 months. The primary outcome was incident TB by 54 weeks. We estimated the treatment effect overall using individual participant data meta-analysis.
Results
The VQUIN trial (n=2041) randomly assigned 1023 participants to levofloxacin and 1018 participants to placebo; TB-CHAMP (n=922) assigned 453 participants to levofloxacin and 469 participants to placebo. Median age was 40 years (interquartile range 28 to 52 years) in VQUIN and 2.8 years (interquartile range 1.3 to 4.2 years) in TB-CHAMP. Overall, 8 levofloxacin-group participants developed TB by 54 weeks versus 21 placebo-group participants; the relative difference in cumulative incidence was 0.41 (95% confidence interval [CI] 0.18 to 0.92; P=0.03). No association was observed between levofloxacin and grade 3 or above adverse events (risk ratio 1.07, 95% CI 0.70 to 1.65). Musculoskeletal events of any grade occurred more frequently in the levofloxacin group (risk ratio 6.36, 95% CI 4.30 to 9.42), but not among children under 10 years of age. Overall, four levofloxacin-group participants and three placebo-group participants had grade 3 events.
Conclusions
In this meta-analysis of two randomised trials, levofloxacin was associated with a 60% relative reduction in TB incidence among adult and child household MDR-TB contacts, but with an increased risk of musculoskeletal adverse events. (Funded by the Australian National Health and Medical Research Council, UNITAID, and others.)
See more from MedicalBrief archives:
Common drug slashes risk of MDR-TB – SA-led study
DNA technology may impede MDR-TB progress – SA Health Department