On World Tuberculosis Day, marked annually on March 24, health experts are raising alarms about the growing resistance to Sirturo (bedaquiline), one of the few effective treatments for multi-drug resistant tuberculosis (MDR-TB). This development underscores the urgent need for new therapies and increased funding to combat what has reclaimed its position as the world's deadliest infectious disease.
Resistance to Sirturo, an adenosine triphosphate (ATP) synthase inhibitor approved just over a decade ago, has been reported in South Africa, Mozambique, Eswatini, and provinces of China including Zhejiang, as well as other low- and middle-income countries where TB prevalence is high.
"Almost any drug you use is going eventually to have resistance developed against it. Programmes that are using it are being urged to be very strict about how they use it to try and minimise the development of resistance," explains Paul Sommerfeld, executive trustee of TB Alert and member of the community advisory body of UNITE4TB.
The Global TB Crisis
Tuberculosis has reclaimed its position as the world's top infectious killer after being temporarily displaced by COVID-19. Each year, approximately 10 million people fall ill with TB, and despite being preventable and curable, 1.5 million people die from the disease annually. TB is also the leading cause of death among people with HIV and a major contributor to antimicrobial resistance.
Dr. Tereza Kasaeva, Director of WHO's Global Programme on TB and Lung Health, emphasized the economic case for action: "Investing in ending TB is not only a moral imperative but also an economic necessity—every dollar spent on prevention and treatment yields an estimated $43 in economic returns."
The treatment landscape for drug-resistant TB remained limited until Johnson & Johnson's Sirturo received accelerated approval from the FDA in 2012 and conditional approval from the EMA in 2014. The drug finally received full approval from both agencies in 2024, but resistance has already emerged, threatening its effectiveness.
Research Efforts and Funding Challenges
According to GlobalData's Pharmaceutical Intelligence Centre, there are 308 clinical trials investigating therapies for TB, pulmonary TB, and mycobacterium TB infections that are ongoing or planned. However, the research pipeline is considered thin relative to the scale of the problem.
The UNITE4TB programme, established in Europe, aims to set new standards for anti-TB regimen development. It launched the PARADIGM4TB and DECISION trials in late 2023, followed by the Phase II ENABLE study evaluating BioVersys and GlaxoSmithKline's alpibectir plus ethionamide combination.
"We hope that with those, we will be able to hold the problems of resistance at bay, and secondly, that we will bring the length of time of treatment down," Sommerfeld says. "Now, somebody with TB who is not resistant is being treated for six months, and that's a lot of pills in a long period of time. So, we are hopeful that fairly quickly, we will have regimens which will bring us down at least to a four-month time period, and preferably two or three months."
Funding Crisis Deepens
The already underfunded TB response faces further challenges with the United States withdrawing from the WHO and cutting USAID funding. The WHO reports severe disruptions in TB response across several high-burden countries, with African nations experiencing the greatest impact, followed by countries in South-East Asia and Western Pacific regions.
In 2023, only 26% of the $22 billion annually needed for TB prevention and care was available. TB research is in an even more dire situation, receiving just one-fifth of the $5 billion annual target in 2022, delaying advancements in diagnostics, treatments, and vaccines.
"There's a fear that with less US money available, quite a lot of research will be slowed down or will not be able to happen. We've never got to a stage of having as much funding as we think would be necessary. We've always been working kind of hand to mouth," Sommerfeld notes.
Sirturo's Impact and Future Directions
Sirturo represented a significant breakthrough when it was approved. The drug works through a unique mechanism of action that inhibits mycobacterial ATP synthase, an enzyme essential for energy generation in Mycobacterium tuberculosis.
Phase 2 studies demonstrated that Sirturo decreased the time to culture conversion and improved culture conversion rates compared to placebo. The median time to culture conversion was 83 days for the Sirturo group versus 125 days for the placebo group at week 24. By week 120, the proportion of patients defined as cured was 57.6% in the Sirturo arm compared to 31.8% in the placebo arm.
Professor Martin Grobusch, Head of the Centre for Tropical Medicine and Travel Medicine at the University of Amsterdam, had noted at the time of approval: "MDR-TB is associated with a high mortality rate and poses a significant public-health threat, as individuals infected with drug-resistant strains are often unable to receive adequate treatment and can potentially spread their infection."
Cautious Optimism
Despite the challenges, experts maintain some optimism about the future of TB treatment. New combination therapies and prevention strategies offer hope, though the threat of resistance remains a constant concern.
"In a way, we are at a period of optimism in terms of TB. We do have this new regimen and we have new ideas for how to prevent TB developing in a person, but we always face this problem of resistance, and we desperately need to keep going with as much research as possible on alternative regimens," Sommerfeld concludes.
The theme for this year's World TB Day—"Yes! We Can End TB: Commit, Invest, Deliver"—reflects both the urgency and the possibility of progress. However, achieving the End TB 2030 target will require substantially increased investment in research and treatment programs, as well as coordinated global action to address the growing threat of drug resistance.
