MBABANE – A groundbreaking tuberculosis (TB) study conducted in Eswatini has revealed that many cases of drug-resistant TB may be going undetected by conventional diagnostic methods, potentially exposing patients to ineffective treatment and allowing resistant strains to continue spreading.
The findings, published in the scientific journal Nature Communications, emerged from a collaborative study involving researchers from Eswatini, Germany, the United States and other international partners. The research highlights the effectiveness of advanced genomic testing in identifying hidden forms of drug-resistant tuberculosis that routine tests often fail to detect.
The study focused on the use of targeted next-generation sequencing (tNGS), a genomic technology capable of analysing the genetic makeup of tuberculosis bacteria directly from patient samples. Researchers say the method provides far more detailed information about drug resistance than standard diagnostic tests currently used in many healthcare settings.
According to the researchers, the technology uncovered a significant number of tuberculosis strains carrying a mutation known as rpoB I491F, which causes resistance to rifampicin, one of the most important drugs used in treating TB. The mutation has long been recognised as a “diagnostic escape” mutation because it frequently evades detection by commonly used diagnostic tools.
Professor Stefan Niemann, project coordinator and director of the Infections Programme Area at the Research Center Borstel, Leibniz Lung Center in Germany, said accurate resistance testing was critical to successful treatment.
“Accurate resistance testing is the foundation of any successful TB treatment,” Niemann said. “Our results show that many patients who were initially classified as having lower levels of resistance actually harboured multidrug-resistant strains that were not detected by conventional diagnostic methods.”
The study analysed 234 patient samples collected between June 2021 and December 2024 from individuals suspected of having drug-resistant tuberculosis or experiencing treatment failure.
Using targeted sequencing, researchers identified rifampicin resistance in 159 TB strains. Of these, 64 per cent carried the rpoB I491F mutation, suggesting that a substantial proportion of resistant infections may not be recognised through routine testing.
Researchers described the findings as particularly significant for Eswatini, which continues to face a high burden of multidrug-resistant tuberculosis (MDR-TB).
The study also uncovered alarming levels of resistance to bedaquiline, one of the most effective medicines currently used in the treatment of multidrug-resistant TB.
Genetic markers associated with bedaquiline resistance were detected in 55 per cent of all rifampicin-resistant strains analysed. Among strains carrying the rpoB I491F mutation, the prevalence of bedaquiline resistance markers rose to 85 per cent.
Debrah Vambe of the Baylor College of Medicine Children’s Foundation Eswatini, who served as the study’s first author and principal investigator in Eswatini, warned that the findings could have serious implications for patient care.
“These findings suggest that a substantial proportion of patients may be receiving treatment regimens that include drugs to which their infecting strain is already resistant,” Vambe said.
Researchers noted that treatment decisions were directly influenced by the genomic testing results. Among patients for whom detailed clinical information was available, sequencing findings led to treatment modifications in more than half of the cases.
Despite the complex resistance patterns identified, treatment outcomes remained encouraging. The study reported an 88 per cent treatment success rate among patients whose outcomes were available for analysis, demonstrating the potential benefits of tailoring treatment based on comprehensive resistance profiles.
Health experts involved in the research say the findings expose weaknesses in existing diagnostic approaches and could have broader implications for tuberculosis control programmes both in Eswatini and internationally.
Current TB classification systems rely heavily on routine diagnostic tests to determine resistance patterns. However, if key mutations such as rpoB I491F are missed, patients may be incorrectly classified and prescribed treatment regimens that are unlikely to be effective.
The researchers also cautioned that the high frequency of combined rifampicin and bedaquiline resistance could undermine the effectiveness of standardised treatment regimens currently recommended for multidrug-resistant TB in some settings.
As a result, the study calls for wider adoption of sequencing-based diagnostic technologies to improve detection of drug resistance and support more personalised treatment approaches.
The researchers argue that earlier and more accurate identification of resistance could help reduce treatment failure, prevent ongoing transmission of resistant strains and limit the emergence of even more complex forms of drug resistance.
The study was conducted through a partnership involving the Baylor College of Medicine Children’s Foundation Eswatini, the Global TB Programme at Baylor College of Medicine in the United States, Eswatini Health Laboratory Services, the National Tuberculosis Reference Laboratory, the Ministry of Health, the National TB Control Programme, the Research Center Borstel and the German Center for Infection Research, among other institutions.
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