Preventive Levofloxacin Found to Reduce Drug-Resistant TB in Household Contacts

19 December 2024

Two studies published on 18 December 2024 in the New England Journal of Medicine show that 6 months of preventive treatment with levofloxacin in children and adults with household exposure to multidrug-resistant tuberculosis (MDR-TB) resulted in statistically non-significant reductions in TB incidence compared with placebo.

But an additional analysis of individual data from the two trials, which were conducted in Vietnam and South Africa, found that preventive levofloxacin led to a much larger relative reduction in cumulative incidence of TB than was initially observed.

Data from the two phase 3 randomized controlled trials have already been used by the World Health Organization (WHO) to update its recommendations for TB preventive treatment (TPT).

Preventing MDR-TB

MDR-TB develops in an estimated 400,000 people globally each year, according to the WHO, including approximately 30,000 children. While new, shorter treatment regimens have been introduced in recent years, MDR-TB treatment is longer and more expensive than drug-susceptible TB treatment, and treatment outcomes are worse.

Because TB is an airborne disease, people who share a household or have close contact with an infectious TB patient are considered a high risk for infection. TPT for both drug-susceptible and MDR-TB is therefore a cornerstone of the WHO efforts to reduce global TB incidence. But while the WHO has recommended preventive treatment for selected high-risk household contacts of MDR-TB patients since 2017, the original recommendation was based on low-quality evidence and didn’t specify use of any particular drug.

The two trials were designed to investigate whether levofloxacin, which is a component of some MDR-TB treatment regimens and has shown promise for reducing TB incidence among close contacts of people who have MDR-TB, is a safe and effective preventive treatment for household contacts in countries with high MDR-TB incidence.

In the TB-CHAMP trial, conducted at five sites in South Africa from September 2017 through January 2023, 922 children with household exposure to an adult with bacteriologically confirmed pulmonary MDR-TB were enrolled and randomly assigned 1:1 to receive a once-daily oral dose of levofloxacin or placebo for 6 months. The vast majority of participants (91%) were under 5 years of age. The primary end point was incident TB, including death from TB, at 48 weeks after randomization.

In the V-QUIN MDR trial, conducted at 10 sites in Vietnam from January 2016 through January 2022, a total of 2,041 children and adults with household exposure to a bacteriologically confirmed MDR-TB patient were enrolled and randomized 1:1 to the same treatment. The median age of participants was 40 years. The primary end point was bacteriologically confirmed TB within 30 months.

In TB-CHAMP, by week 48, TB had developed in 5 children (1.1%) in the levofloxacin arm and 12 (2.6%) in the placebo arm (hazard ratio, 0.44; 95% confidence interval [CI], 0.15 to 1.25). In V-QUIN MDR, confirmed TB occurred in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% CI, 0.19 to 1.62). Incidence of serious adverse events was low in both trials.

For both trials, the lower incidence of TB in the levofloxacin arms was considered not statistically significant. Investigators attributed the results in part to the number of TB cases in the placebo groups being much lower than they had anticipated, based on results from previous observational studies. As a result, they concluded that estimates of the treatment effect in both trials were imprecise.

Better results found in meta-analysis

But in a meta-analysis published on 18 December 2024 in NEJM Evidence, investigators from both teams conducted a combined analysis of the two trials, using individual participant data to assess TB incidence at 54 weeks.

They found that 8 levofloxacin-group participants developed TB, compared with 21 placebo-group participants, for a relative difference in cumulative incidence of 0.41 (95% CI, 0.18 to 0.92). They also found that musculoskeletal events of any grade occurred more frequently in the levofloxacin group (risk ratio, 6.36; 95% CI, 4.30 to 9.42).

“These results suggest that MDR-TB preventive treatment with levofloxacin was associated with a 60% relative reduction in TB incidence among adults and children but was associated with increased low-grade adverse events (particularly musculoskeletal),” they wrote. “Further evaluation of the risk–benefit balance, tolerability, and cost-effectiveness of MDR-TB preventive treatment in different populations is needed.”

In September, the WHO updated its recommendations for TPT in close contacts of MDR-TB patients, based on a review of data from TB-CHAMP and V-QUIN MDR and other observational studies by the WHO’s guideline development group (GDG). The group now strongly recommends 6 months of daily levofloxacin in contacts exposed to MDR or rifampicin-resistant TB.

“The strong recommendation reflects the GDG opinion that the benefits of levofloxacin outweigh the potential harm in most people who are eligible to receive it,” the WHO said. “Health programmes and clinicians should strictly ensure eligibility for its use, maximize the likelihood of treatment completion as expected and ensure that contacts are followed up regardless of whether TPT was completed.”

By Chris Dall, MA

Source: CIDRAP