Study Warns of Emergence, Spread of Resistance to New Drug-Resistant TB Treatments
9 January 2025
A new study indicates resistance to shorter and less toxic drug regimens for multidrug-resistant tuberculosis (MDR-TB) is emerging and spreading between patients.
In a letter published in the New England Journal of Medicine, scientists with the Swiss Tropical and Public Health Institute (Swiss TPH) and Georgia’s National Center for Tuberculosis and Lung Diseases say analysis of Mycobacterium tuberculosis genomes from 27 countries identified more than 500 strains of MDR-TB with additional resistance to at least one of the compounds in the BPaL/M (bedaquiline, pretomanid, and linezolid with or without moxifloxacin) regimen.
More than a quarter of those strains appeared to have spread between patients.
Endorsed by the World Health Organization (WHO) in 2022, BPaL/M is a 6-month, all-oral drug regimen that is significantly shorter than the previous MDR-TB regimen, which lasted longer than 15 months and involved injectable drugs with severe and painful side effects. Randomized trial data has shown BPaL/M also has a much higher cure rate—90% or higher, compared with 50% and below for the previous regimen.
The authors of the letter said that while much of the global burden of MDR-TB is driven by patient-to-patient spread, they thought that acquiring additional resistance to BPaL/M compounds might reduce its competitive fitness and make it less transmissible. They conducted the study to investigate that theory.
“While this new regimen is a game changer for patients suffering from MDR-TB, we knew that it will be difficult to outsmart Mycobacterium tuberculosis, the bacteria causing TB,” senior study author Sébastien Gagneux, PhD, head of the Department Medical Parasitology and Infection Biology at Swiss TPH, said in a press release. “It was therefore crucial to study how the TB bacteria would react to the global roll-out of this new regimen.”
Genomic analysis reveals resistance mutations
The researchers began by analyzing the genomes of 6,926 M tuberculosis isolates collected over 13 years in Georgia, a country with a high MDR-TB burden. From those isolates, they identified 60 TB strains with mutations conferring resistance to isoniazid and rifampicin (the first- and second-line drugs for treating drug-susceptible TB), fluoroquinolones, and at least one of the BPaL/M drugs.
Further analysis of these strains—defined as “highly drug-resistant”—found that 16 of 58 (28%) were grouped in four genomic clusters in which all the strains had an identical mutational profile, indicating patient-to-patient transmission.
To see if transmission of these highly drug-resistant TB strains was occurring elsewhere, the researchers then analyzed 81,576 genomes from 26 countries. They identified 454 highly drug-resistant strains, and 117 of 420 (28%) were linked to direct transmission.
“The good news is that the total number of these cases is still low,” said study co-author Galo Goig, PhD, a postdoctoral researcher at Swiss TPH. “However, the fact that more than a quarter of these highly drug-resistant cases are due to patient-to-patient transmission, only two years after WHO endorsed the new regimen, is worrying.”
The team also found that nine strains carried resistance mutations to all of the BPaL/M drugs. These strains, found in four countries—Belarus, Georgia, India, and South Africa—were classified as “totally drug-resistant.”
The WHO estimates that 400,000 people globally developed MDR-TB in 2023. A recent survey of national TB program staff members projected that BPaL/M regimens will reach 78% of MDR-TB patients by 2026. The hope is that the shorter regimen will improve uptake and adherence.
But the study authors warn that their findings suggest that the longevity of the regimen could be at risk without improvements in diagnostic capacity, infection control, and surveillance.
By Chris Dall, MA
Source: CIDRAP
