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Study Warns Of Emergence, Spread Of Resistance To New Drug-resistant TB Treatments

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 last week 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 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 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.

TB Is Back After Eradication

TUBERCULOSIS (TB), a disease eradicated from the country in the late 1970s and early 1980s, has returned. 

But the Ministry of Health and Medical Services (MHMS) has still to announce what provinces the disease has reached their shores although it has announced the efforts to deal with it.

After the disease was eradicated, the MHMS closed down TB Wards in its hospitals in the country, including the Kirakira Hospital in the Makira-Ulawa Provincial Capital.

The hospital first reported TB cases in 2019/2020 and those affected were mostly children. 

Kirakira Hospital staff spoken to then expressed their worry about the disease's return as the hospital no longer has a TB Ward and the medicines to treat carriers. 

At the same time, hospital staff revealed an outbreak of scabies in Tawatana village of West Makira. 

A nearby clinic at Ubuna village has been reportedly giving out anti-scabies cream to Tawatana villagers and those from nearby villages of Ward 7, Arosi One, West Makira.

By George Atkin

 West Makira Journalist 

Tuberculosis Strains Resistant To New Drugs Are Transmitted Between Patients

Tuberculosis (TB) is the world's biggest infectious disease killer with multidrug-resistant TB (MDR-TB) posing a particular threat to global health. A study led by the Swiss Tropical and Public Health Institute (Swiss TPH) shows that resistance to the new MDR-TB treatment regimen recently recommended by the World Health Organization is already spreading between patients. The findings, published in the New England Journal of Medicine, highlight the urgent need for better surveillance and infection control to counteract the rise in antimicrobial resistance.

Multidrug-resistant TB is a major concern

More than 10 million people fall sick with tuberculosis (TB) every year. The disease remains the world's biggest infectious disease killers with an estimated 1.25 million annual deaths. The disease is still found in every country, but certain regions, such as India, Central Asia and Southern Africa, bear a particularly high burden. Multidrug-resistant TB (MDR-TB) continues to pose a major public health threat, adding to the growing concern of rising antimicrobial resistance.

The traditional treatment regimen for MDR-TB is lengthy, expensive, and comes with severe adverse event. In 2022, the World Health Organization (WHO) endorsed a new 6-month regimen -- the BPaL(M) -, based on evidence of its improved safety and efficacy from numerous clinical studies, including TB-PRACTECAL.

Monitoring the implementation of a new treatment regimen

"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," said Sébastien Gagneux, Head of the Department Medical Parasitology and Infection Biology at Swiss TPH and senior author of the study. "It was therefore crucial to study how the TB bacteria would react to the global roll-out of this new regimen."

A study led by Swiss TPH in collaboration with the National Centre for Tuberculosis and Lung Diseases in Tbilisi, Georgia, published yesterday in the New England Journal of Medicine now examined in detail whether resistance to the drugs in the new regimen has already emerged since its introduction, and whether this resistance is transmitting between patients.

Over a quarter of resistant strains result from transmission between patients

The researchers analysed the genomes of close to 90,000 M. Tuberculosis strains from Georgia and many other countries around the world. They identified a total of 514 strains that were resistant to TB drugs, including both the old and the new treatment regimens. These highly drug-resistant strains were found in 27 countries across four continents.

Alarmingly, 28% of these strains were transmitted directly from one patient to another. "We already had anecdotal evidence of resistance emerging to the new regimen, but we did not know to what extent transmission was responsible for the spread of these highly drug-resistant strains," said Galo A. Goig, postdoctoral collaborator at Swiss TPH and first author of the study.

"The good news is that the total number of these cases is still low. 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," added Goig.

Call for better surveillance and infection control

These findings have important implications for public health policy and interventions. "These new drugs have taken many years to develop, and to prevent drug resistance from emerging, it is essential to combine the deployment of these new regimens with robust diagnostics and surveillance systems," said Chloé Loiseau, postdoctoral collaborator at Swiss TPH and co-author of the paper.

The authors emphasize the need for improved diagnostic tools, better infection control and robust surveillance systems to curb the spread of these highly drug-resistant strains, and to safeguard the efficacy of the new treatment regimen.

Tackling antimicrobial resistance

While there are already new TB drugs in the pipeline, experts worry that M. Tuberculosis will continue to find ways to evade new drugs. "The example of these highly drug-resistant TB strains further illustrates that antimicrobial resistance is one of the most critical threats to global health today," said Gagneux. "We must stay ahead in this constant race between drug development and bacterial resistance, and take proactive steps to prevent a 'post-antibiotic era' for TB and other diseases."

About tuberculosis

Tuberculosis (TB) is an infectious disease caused by Mycobaterium tuberculosis. TB is spread from person to person through the air. Symptoms of the disease include coughing, chest pain, weight loss, fever and night sweats. Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to the two most effective first-line TB drugs. Only about 2 in 5 people with MDR-TB accessed treatment in 2022.

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