Tuberculosis: So much accomplished and so much more to be done

An ancient bacterial disease that has persisted for an estimated 70,000 years, tuberculosis remains a vexing health issue in modern times.¹ According to the World Health Organization (WHO) approximately one quarter of the world’s population has been infected, 10.7 million people fell ill in 2024, and 1.23 million people died making tuberculosis the leading cause of mortality among all infectious diseases.² Notably, India accounts for the largest burden of tuberculosis globally with 25% of all cases.³

In 2014, the WHO developed the End TB Strategy and many countries including India have taken bold strides to reduce tuberculosis incidence but much more needs to be done.⁴ Even today not all the cases of active disease that exist are recorded and we face diagnostic delays in those we do, therefore there is ongoing new transmission. We have new safer, shorter tuberculosis treatments and yet not all who need them are accessing them. We have therapies to prevent tuberculosis disease from occurring, but we are still not providing them to all who need them and we still do not have a new efficacious vaccine to prevent tuberculosis for all who need it. Furthermore, a major challenge is that the current funding for implementation of the End TB strategy worldwide is only around 27% of the USD 22 billion needed,^1,2 and recent reductions in global programme funding could lead to an estimated 36% jump in cases, and a 68% rise in deaths in high burden.⁵ So our work to end tuberculosis is far from over.⁶ But the progress we made in the field of tuberculosis during the last 15 years is encouraging and therefore now is not the time to take our foot off the pedal of progress. We have seen health systems strengthened, the development of new diagnostics, discovery of new classes of drugs and drug combinations for TB prevention and treatment, and the advancement of new vaccine candidates in the pipeline.

Once thought to present as two types of infection—latent or dormant disease, and active disease, we now know that there is a spectrum of tuberculosis that requires unique care approaches, including latent infection, incipient infection, asymptomatic disease, clinical disease and post-TB lung disease.⁷

In a nationwide tuberculosis prevalence survey and subnational survey in Tamil Nadu with hundreds of thousands of persons screened, approximately 40% of persons diagnosed with tuberculosis in the community had no symptoms.^8,9 This completely changes what we know about community spread and how we need to approach TB screening in high-burden areas like India.

Another new finding has to do with comorbidities. We have long known that those at the highest risk for acquiring disease after exposure to tuberculosis are young children,¹⁰ people living with HIV, adult household contacts, people who are severely malnourished, people who have substance use disorders, and patients with silicosis. But thanks to the Rations Trial, conducted in India we now know the clear benefit of nutritional supplementation; providing a monthly package of macro and micronutrients to household contacts of TB patients, the risk of developing tuberculosis was reduced by up to 48%.¹¹ So we need to ensure we do a better job of integrating tuberculosis screening and diagnosis into routine primary healthcare and offering preventive care services to reduce comorbidities such as undernutrition.

Furthermore, we can no longer just think our job is done when a patient has completed their tuberculosis treatment. Several studies have shown us that there are long lasting impacts of tuberculosis including impaired lung function, reduced quality of life and likely increased risk for cardiovascular disease.¹² But who is at highest risk of developing post-tuberculosis lung disease and why this happens needs further investigation.

We have seen great leaps in tuberculosis diagnostic development, including molecular diagnostics. Near point-of-care (POC) and POC tests are now available that offer faster diagnosis of both drug susceptible and drug-resistant TB strains, reducing time to treatment, reducing transmission and resulting in better treatment outcomes.¹³ Some examples includes POC chest X-rays that can be safely done with portable cameras, computer-aided technologies based on artificial intelligence that can provide rapid analysis of chest images in minutes and that are just as effective as human readers,¹⁴ non-sputum-based rapid diagnostics, such as using tongue swabs and a portable battery-operated platform which reduce the time to diagnosis from weeks to minutes, rapid molecular tests that can identify rifampin resistance, as well as other drug resistance.

These breakthrough diagnostic technologies can simplify sample collection, deliver results more rapidly, and accelerate treatment initiation at lower costs. But as we know, these breakthroughs alone are not enough. Governments and other stakeholders need to ensure these diagnostics are cost-effective, have sustainable financing, appropriate supply chains, and can readily be integrated into care systems with equitable access.

For treatment of patients with drug susceptible tuberculosis, medication regimens were 6 months or longer in duration. For treatment of patients with drug resistant tuberculosis, the regimen was a challenging with multiple (6 or more) medications some of which were injectable and treatment 18-24 months.¹⁵ The side effects were difficult to endure: gastrointestinal disturbance, numbness in the extremities, loss of hearing, change in skin pigmentation, thyroid abnormalities, and more.¹⁵ Thus, medication adherence was challenging, and development of further drug resistance and high rates of morbidity and mortality often resulted.

However, major advances in drug development and novel drug combinations have resulted in regimens that are far safer, better tolerated, and shorter: as short as one month for tuberculosis preventive therapy (e.g. 1 month isoniazid and rifapentine), 6 months for drug resistant tuberculosis (e.g. BPAL-M), and 4 months, and potentially less, for drug susceptible tuberculosis. In 2024, India rolled out the BPAL-M regimen and already more than 15,000 people have been placed on these new regimens and outcomes are reportedly much improved. There are also several newer drugs being assessed in Phase 1-3 trials, such as more potent diarylquinolines (e.g. TBAJ-587), newer oxazolidinones (e.g. delpazolid) and nitroimidazoles (e.g. quabodepistat).¹⁶ We are also employing more advanced analytics, integrating drug pharmacokinetics and drug characteristics to rationally develop new regimens to test in combination (e.g. PReDicTR Consortium).¹⁷

We have learned that children most often have paucibacillary disease and therefore can do just as well with taking tuberculosis treatment for 4 months as they would for 6 months.¹⁸ There is also new evidence for the prevention of multidrug-resistant tuberculosis (MDR-TB) where a 6-month course of fluroquinolones reduces tuberculosis risk by 50%.^19,20 There are ongoing trials assessing newer agents including delamanid and bedaquiline for the prevention of TB and most exciting is the development of long-acting formulations, with the design of a trial to assess one shot of bedaqualine for tuberculosis prevention.²¹ Research on long-acting tuberculosis treatment is at an early stage, but it’s not difficult to imagine what a game-changer one shot for TB prevention would be for ending the deadly cycle of transmission.²² Tuberculosis therapeutic research is robust, with 18 clinical trials assessing treatment-shortening regimens for drug-susceptible TB, and 9 trials for drug-resistant tuberculosis.¹³

In terms of vaccines, progress has been slower as BCG is still the only approved tuberculosis vaccine, it was developed more than 100 years ago, and it’s not effective in older children and adults. But there are now currently 17 vaccine candidates in various stages of trials.²³ These include subunit vaccines like M72/AS01E, recombinant BCG (rBCG) such as VPM1002, and live-attenuated vaccines like MTBVAC, alongside emerging mRNA and viral-vector platforms.

Tuberculosis research and programme innovation is in an exciting time with new diagnostics, therapeutics and new vaccines being studied. But we know that screening is sub optimal and we are missing at least a million asymptomatic and symptomatic cases, including young children, pregnant women, and people who have extrapulmonary TB. We need better diagnostics especially for those who have paucibacillary or extrapulmonary disease, but waiting for these new tools is not the answer, we already have a lot of new tools to fight tuberculosis, now we need to increase access and ensure affordability. We also need implementation science, cost effectiveness studies and, new policies and financing to improve the reach of new tools. Importantly we need community engagement and advocacy. Science has developed many tools and approaches but if they aren’t getting to the people who need them, then we have failed our communities and our mission to eliminate tuberculosis.