Tuberculosis (TB) is once again the world’s deadliest infectious disease, causing an estimated 1.25 million deaths in 2023. Despite longstanding knowledge that TB is both preventable and curable, progress has stalled. Here, Gerry Hughes discusses the latest research, consensus and progress in fighting TB with insights from sessions at ESCMID Global 2025.
With an estimated 10.8 million people falling ill with tuberculosis (TB) globally in 2023, the burden of disease remains staggeringly high – and, alarmingly, it is rising, with the World Health Organization (WHO) warning of this ‘unnecessary’ public health crisis.
In his keynote address at the recent ESCMID Global congress, Professor Guy Thwaites, professor of infectious diseases at the University of Oxford, offered a sober appraisal of the current landscape. ‘Tuberculosis is a disease of poverty,’ he said, calling out the structural and political forces that continue to drive global disparities in TB control.
Quoting data from the WHO Global TB Report 2024, he underlined how TB incidence rates, after a brief dip, have plateaued and begun to climb once more.
The targets set by the WHO in its 2015 End TB Strategy – particularly the goal of a 50% reduction in incidence – remain far from reach. Just an 8.3% reduction has been achieved over those nine years. ‘We still remain in the wrong place with TB,’ Professor Thwaites said.
Vaccines, diagnostics and the latency problem
An important contributor to this inertia is because the medical community is ‘still using old tools’ in the fight against TB, according to Professor Thwaites. He took aim at the diagnostic and preventive tools that have defined TB control for decades: the Bacillus Calmette-Guérin vaccine, Ziehl-Neelsen staining, microscopy and the tuberculin skin test.
While new technologies have emerged, they remain largely inaccessible to those who need them most. The GeneXpert platform, for example, offers improved diagnostics but is expensive and underutilised in many high-burden settings.
Professor Thwaites went on to challenge the conventional latent versus active TB paradigm. He described a recent pre-print study, where clinical imaging of 250 asymptomatic household contacts of rifampicin-resistant TB identified subclinical lesions in nearly 12% of individuals. These lesions strongly predicted progression to culture-positive disease, but this progression occurred slowly, taking up to four years for microbiological detection.
‘We are learning that subclinical TB can persist undetected for years,’ he said, which blurs the line between infection and disease. A recent paper aptly titled ‘Latent Tuberculosis: Two Centuries of Confusion’ discusses this conundrum for healthcare professionals.
Indeed, an international consensus now proposes four states of early TB – two subclinical and two clinical – based on symptomology. The International Consensus for Early TB framework, known as ICE-TB, distinguishes disease from infection by the presence of macroscopic pathology and confirms that the presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Understanding these disease dynamics, Professor Thwaites argued, will be critical to reimagining both diagnosis and prevention.
Encouragingly, TB vaccine development has somewhat accelerated. For example, a new candidate M72/AS01E, now in phase 3 trials across South Africa, Kenya, Zambia, Malawi and Indonesia, has recruited 90% of its 20,000 participants. Designed to prevent progression in those with latent TB, the vaccine could save an estimated 8.5 million lives, prevent 76 million new cases over 25 years and save $41.5bn in revenue if proven effective.
Tackling drug resistant TB and therapeutic innovation
While drug-susceptible TB can be treated with a six-month course of antibiotics, multidrug-resistant TB (MDR-TB) presents far greater challenges. For many, therapy remains lengthy, toxic and poorly tolerated.
Professor Thwaites discussed progress with research on newer, shorter regimens in his ESCMID Global session. Trials have demonstrated non-inferiority of a four-month regimen using rifapentine and moxifloxacin in adults when compared to standard treatment and non-inferiority of a four-month versus six-month standard regimen in children. ‘But even four months is too long,’ he argues, pointing to recent studies evaluating ‘ultra-short’ regimens.
One such phase 2/3 multicentre clinical trial assessed an eight-week bedaquiline-linezolid combination, demonstrating non-inferiority to the standard six-month regimen, with no apparent safety concerns.
Another promising avenue is the use of bedaquiline as short-course preventive therapy. With a half-life of around 160 days, bedaquiline is being explored as a single-month preventive regimen in the ongoing BREACH-TB trial. This trial focuses on people who are at high risk of having TB, such as those living with HIV and those who have had close contact with someone with drug resistant TB. It will also include populations who are conventionally excluded from such trials such as lactating adults.
While Professor Thwaites noted that further research is required for these ultra-short regimens, he said that such research may also lead to discovery of biomarkers which could predict relapse arising from these shorter regimens.
However, emerging resistance to bedaquiline threatens to undermine these advances. A study from India, published earlier this year, found 36% of 117 previously treated TB patients had bedaquiline-resistant strains, with unfavourable outcomes exceeding 80%. ‘We are developing new drugs,’ says Professor Thwaites, ‘but access remains unequal, and resistance is rapidly gaining ground.’
TB meningitis (TBM) presents a particularly devastating form of the disease, with high mortality and complex treatment needs being highlighted by several ESCMID Global speakers.
Professor Thwaites discussed the role of adjunctive anti-inflammatory therapies, including dexamethasone, noting that while a recent trial in HIV-positive adults with TBM showed no survival benefit, further investigation is warranted.
He advocated for larger studies and exploration of alternative anti-inflammatory agents such as infliximab and anakinra.
HARVEST-TB: no easy answers for TB meningitis
The clinical imperative to improve outcomes in TBM was the focus of a major late-breaker presentation at ESCMID Global, where Professor Reinout van Crevel unveiled findings from the HARVEST-TB trial.
Professor van Crevel, professor of infectious diseases at Radboud University Medical Centre, presented the first results of the HARVEST-TB trial – a phase 3, double-blind, randomised controlled trial evaluating high-dose oral rifampicin (35 mg/kg) for TBM.
This study was driven by the fact that rifampicin does not achieve satisfactory central nervous system concentrations. High dose rifampicin is currently being investigated in several TBM trials.
Furthermore, a previous phase 2 study demonstrated that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Conducted in Uganda, Indonesia, and South Africa, the trial enrolled 529 patients with confirmed TBM. Participants received either high-dose or standard-dose rifampicin alongside standard TB therapy and corticosteroids.
Disappointingly, results showed no measurable benefit. The hazard ratio was 1.17 (95% CI 0.89–1.54; p = 0.25), and subgroup analysis revealed no survival advantage in those with HIV, bacteriological confirmation or severe disease. Adverse event rates were similar between groups.
Professor van Crevel addressed ESCMID Global audience questions about the discrepancy between this result and earlier phase 2 findings using intravenous rifampicin. He attributed the difference not to formulation, but to study power: ‘This underlines the importance of doing adequately powered studies to detect clinical endpoints,’ he said.
On whether intravenous formulations should be revisited, his reply was ‘I don’t think so’, although he acknowledged the need to measure blood levels of both rifampicin and dexamethasone to explore possible drug interactions.
Radical rethinking of TB control
The ESCMID Global presentations by Professors Thwaites and van Crevel delivered a compelling message: TB control in 2025 demands radical rethinking. From vaccine deployment and subclinical disease classification to high-dose regimens and drug resistance, innovation is crucial. But so too is equitable access, rigorous research and the political will to act.
Professor Thwaites reiterated that exploiting and researching host-defence mechanisms is crucial: ‘We cannot just obsess over killing bacteria, we need to control the inflammatory response as well,’ he said.
Ending TB is not just a scientific challenge; it is a global moral imperative. The tools are within reach. The time to use them is now.
