Levofloxacin for Preventing Multidrug-Resistant Tuberculosis
Gregory Fox, PhD discusses the V Quinn trial's results, exploring levofloxacin’s role in reducing TB incidence and the study's approach to combining data with the TB Champ trial.
Preventing drug-resistant tuberculosis (TB) in high-risk individuals, such as household contacts of patients with multidrug-resistant TB (MDR-TB), is a global health priority. The V Quinn trial evaluated the use of levofloxacin as a preventive treatment for TB in contact with individuals with rifampicin-resistant or MDR-TB in Vietnam.
Out of 3948 individuals screened, 2041 were randomized, and 1995 (97.7%) completed 30 months of follow-up. TB developed in 6 participants (.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio: .55; 95% CI, .19 to 1.62). This difference was not statistically significant.
Although grade 3 or 4 adverse events were similar between the two groups (risk difference: 1 percentage point), adverse events of any grade were more common in the levofloxacin group (31.9%) compared to the placebo group (13%) (risk difference: 18.9 percentage points). Importantly, no acquired fluoroquinolone resistance was observed.
In an interview with Gregory Fox, PhD, MIPH, FRACP, MBBS, BSc(Med), GAICD, researcher from the University of Sydney, discussed the V Quinn trial, explained the rationale for choosing levofloxacin over other fluoroquinolones,“Levofloxacin is a fluoroquinolone that is effective against tuberculosis, particularly MDR-TB, which does not respond to two of the most effective first-line therapies, isoniazid and rifampicin. For people exposed to MDR-TB, levofloxacin is a good option because it’s generally very well tolerated, widely available, and low-cost. Importantly, it has lower cardiac toxicity compared to moxifloxacin, another fluoroquinolone, so we chose levofloxacin to avoid the need for cardiac monitoring.”
In this double-blind, randomized controlled trial, participants were randomized to receive either six months of daily levofloxacin or a placebo. The primary endpoint was bacteriologically confirmed TB within 30 months, while secondary endpoints included adverse events, mortality, and drug resistance.
Fox described the importance of the trials methodology, “We allocated participants to either levofloxacin or an identical placebo. Neither the participant nor the treating doctor knew which group they were in before or during treatment. This design helps reduce bias and ensures that any differences between the groups are due to the actual difference in the presence of the drug, not due to expectations.”
Although the V Quinn trial alone did not yield a statistically significant result due to lower-than-expected TB cases, Fox and his team combined the data with that from the TB Champ trial to increase statistical power. Fox explained this approach,“Both the V Quinn trial and the TB Champ trial showed a reduction in TB incidence, but neither was able to provide a precise estimate of the effect because the number of TB cases was lower than expected. So, before we analyzed the data from either trial, we pre-specified a combined analysis plan where we would merge the results. This allowed us to do an individual patient meta-analysis, bringing both trials together and making it possible to obtain a statistically significant and more precise estimate of levofloxacin’s effectiveness.”
The combined analysis revealed a statistically significant reduction in TB incidence with levofloxacin, a result that was presented to the World Health Organization. Fox concluded, “Although neither of the trials individually showed a statistically significant difference, the combined analysis provided a clear and reliable estimate. This approach gave us confidence in levofloxacin’s effectiveness in preventing MDR-TB. By pre-specifying the outcomes and conducting a combined analysis, we were able to confidently present our findings to the WHO.”
Overall, Levofloxacin showed a lower incidence of TB compared to placebo, the difference was not statistically significant. The treatment was associated with more adverse events, but no fluoroquinolone resistance emerged.
These findings suggest that levofloxacin may not significantly reduce TB incidence in this high-risk population. The study underscores the need for further research into alternative prevention strategies for MDR-TB, particularly in settings where drug-resistant strains are prevalent.
Stay tuned for Part 2, where we discussed study limitations and key takeaways.
