A boundary-pushing global collaboration is betting on the power of science

This home visit in Peru was part of an international clinical trial that brought new combinations of the latest drugs to participants with drug-resistant tuberculosis. Image: Joanna Arcos/Partners In Health

This is a story about how science can fuel hope to drive away despair.

It’s about an ambitious project that, over the past decade, has brought new, patient-friendly treatments to some of the places hardest hit by the deadly global epidemic of drug-resistant tuberculosis.

It’s about how the project, called endTB, has improved tuberculosis care through a series of scientific studies while pushing the boundaries of what’s thought possible: in clinical trials, in epidemiology, and in the thinking about where you can do the science required to deliver world-class health care where it’s needed most.

Patients who have participated in these studies told doctors and researchers that when they received their TB diagnosis, they were afraid.

They spoke of having recently lost family members to the disease, of the terrible prospect of being isolated from their children for a two-year treatment plan that might not work, of being unable to care for their families, earn a living, or pursue their studies because of the rigors of the disease and of the readily available treatments.

And they spoke of how those fears turned to hope when they learned that there were new, alternative treatments available thanks to endTB, with fewer pills to take and no painful injections.

Even with a cure for TB available, the crisis continues

“TB is one of our oldest and deadliest infectious foes,” said Carole Mitnick, professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School, research director of endTB, and co-principal investigator of its two clinical trials.

Each year approximately 500,000 new cases occur worldwide of multidrug-resistant tuberculosis (MDR-TB) — a form of TB that is resistant to rifampicin (also known as rifampin), one of the most important frontline drugs for curing TB.

Although effective treatments for MDR-TB do exist, over the past five years, fewer than 31 percent of people diagnosed with the disease received any treatment. Fewer than 15 percent of those who fell sick were cured.

Carole Mitnick on the power of science to help vulnerable populations beat TB.

Even among the few who do get treatment, most do not have access to regimens developed in the past decade that shorten the overall length of treatment, avoid injections, and have fewer side effects than earlier regimens. Instead, they go through a grueling course of treatment over 18 to 24 months, with thousands of pills and painful daily shots with severe side effects.

Some of the medications in these shortened regimens aren’t appropriate for all patient populations, such as children and people who are pregnant or have certain other diseases. Some of the drugs in existing regimens are in short supply. Some just don’t work in some people with TB. As a result, many patients are left without a viable treatment option.

The team at endTB is working to change this.

The project represents a partnership of Médecins Sans Frontières, Partners In Health, and Interactive Research and Development, with help from researchers and clinicians at HMS and other academic medical centers and research hubs around the world.

As part of their work with endTB, Mitnick and other HMS researchers and clinicians have played crucial roles in creating and testing new treatment regimens, developing implementation plans, building local know-how to deliver the therapies in challenging settings, and collecting and analyzing data from their studies and clinical trials.

“Our work at endTB is part of a huge transformational moment, helping us fulfill the promise of the therapeutic breakthroughs of the 21st century,” said Mitnick. “Science is one of the most powerful tools we have to end human suffering.”

Picking up where pharma leaves off

Key to endTB’s program are two phase 3 randomized clinical trials — studies conducted in many populations in different countries, often the last step before a new treatment is approved. The first tests five new MDR-TB regimens.

The treatments under study take nine months to complete instead of two years. They are all administered orally with pills, no injections needed. And they use one or two of the three new drugs developed to treat TB in the past 60 years: bedaquiline, which, in 2012, became the first U.S. Food and Drug Administration-approved drug for TB since rifampicin was approved in 1971, and delamanid, approved by the European Union in 2014.

The third drug, pretomanid, received emergency authorization from the FDA for specific use within a regimen against highly drug-resistant TB in 2019, after the endTB clinical trial was underway, and is not included in the regimens used in these trials.

The trial launched in 2017, eventually enrolling 754 patients across seven countries: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa.

The endTB trial fills a crucial research gap. New drugs are usually tested by the pharmaceutical companies that developed them in an effort to receive approvals so the drugs can be brought to market. Once a drug is approved, there is little incentive to conduct complex treatment programs that use combinations of new drugs developed by different companies or repurposed drugs that may be available as generic versions and can be produced by many different companies.

There is also a common misconception that it’s not possible to deliver complex care in the kinds of settings and populations where MDR-TB is most common. The endTB program was designed to address these additional challenges, including how to:

• Maximize treatment success and access while minimizing side effects and cost.
• Implement complicated research in health systems struggling to meet the clinical needs of the people they serve.
• Generate enough data about the kinds of people who are sick with the disease to understand the nuances of how the treatment works in real-world situations.

Promising progress

After completing data collection in late 2023, the endTB team reported at the Union World Conference on Lung Health that three of the five new regimens were found to be safe and effective across a population that included important subgroups: children, pregnant women, and people who were also infected with other illnesses, such as HIV and hepatitis C, common in populations with high rates of TB.

Clinical trial offers multiple new shortened drug regimens to treat adults and children with multidrug-resistant tuberculosis. Video: endTB

The team also reported that a fourth regimen, which did not perform as well as the current standard of care, might still be a valuable alternative for those patients who can’t take two key drugs found in the World Health Organization-recommended regimens for MDR-TB and in the other endTB regimens. The endTB team recommends further research on this regimen in a population that cannot take these drugs to see if it might be the first all-oral, shorter regimen treatment alternative for people with serious side effects or drug interactions that prevent them from taking the standard regimens.

The researchers noted that the regimens tested in the endTB trial could provide a much-needed complement to the shortened regimens that the WHO currently recommends. All of the individual drugs used in the endTB trial are already approved and widely available, meaning they could quickly translate into new alternatives for care in countless people with MDR-TB if the WHO recommends the regimens.

The trial data haven’t been peer-reviewed or published, so some of the details of the recommendations may change before they are finalized. The researchers said that while they are looking forward to completing the review, they felt it was important to share their initial data analysis as quickly as possible because of the potential to save lives and reduce suffering.

The best evidence possible

Over the past decade, endTB has been an important part of a new wave of scientific collaborations transforming TB treatment and research, said Molly Franke, HMS associate professor of global health and social medicine.

Investing in research in the communities that have the highest burden of TB has great potential to improve health systems and train new researchers, Franke said. Many of endTB’s research sites had never hosted any kind of study before. The endTB researchers and colleagues at other groups are running more studies that maximize the amount that can be learned from observational studies, which are often more feasible — and sometimes more ethical — to conduct than trials.

Franke was a leader of one such study: a large-scale prospective observational study with endTB that laid the groundwork for the regimens tested in the endTB clinical trial.

The study, conducted from 2015 to 2019, enrolled 2,804 participants in 17 countries on four continents, making it the largest closely followed cohort of patients receiving bedaquiline or delamanid in the world.

One of the goals of endTB is to show that it’s possible to do high-quality research in places that are struggling to control TB, Franke said.

“If you want to beat TB, you need to take the fight — and the best scientific tools in our arsenal — to where the disease is strongest,” Franke said. “Where the science leads, the cure can follow.”

Franke and colleagues continue to mine the data collected in the observational study to find evidence that can be used to improve treatment and research methods. Recently, they have optimized the length of treatment regimens that use bedaquiline and improved the methods used to estimate relapse after TB treatment. By including rigorous protocols to examine and analyze the combined side effects of all the drugs in the various regimens employed in the endTB observational study, endTB was able to demonstrate definitively that regimens containing bedaquiline, delamanid, or both are safe and well-tolerated and that the older drugs in the regimens pose greater concerns for toxicity than the new drugs.

Not the end of the story

There are no eureka moments in this story, no solitary geniuses at work alone in the lab. Instead, there are generations of researchers, clinicians, students, patients, and families working tirelessly across years to tackle a tenacious, ever-evolving microbe.

The endTB community includes veterans of many campaigns against TB.

Among them is Michael Rich, HMS assistant professor of medicine at Brigham and Women’s Hospital, who serves as senior medical officer of PIVOT, an NGO that works to strengthen health systems in rural Madagascar, and is primary author of multiple WHO guidelines on managing MDR-TB.

Another is K.J. Seung, HMS assistant professor of medicine the Division of Global Health Equity at Brigham and Women’s. Seung has worked closely with government ministries, the WHO, and community health organizations to develop programs in communities around the world, including in North Korea, that are often fighting dual epidemics of HIV and TB.

The endTB team has also welcomed newcomers to TB research, including Harvard trainees and local health officials and caregivers, among them physicians and community health workers, post-doctoral fellows, master’s students, and other early-career researchers.

This new generation of researchers and care providers will help write the story of TB’s next chapter.

Already, endTB leaders and others are working toward making key TB drugs and diagnostics more affordable.

Work is also well underway on a new trial, endTB-Q, which seeks to improve treatment for a strain of tuberculosis known as pre-extensively resistant (pre-XDR) TB that is resistant to the most important standard medications.

“The work we’ve done at endTB is an important reminder that TB is curable, even when it’s drug-resistant, and that it is possible to deliver person-centered care all around the world,” Mitnick said. “Science, service, and compassion are powerful allies.”

Improvements in screening and diagnosis could help to eradicate this curable disease.

Growing up in Burundi, a country of 13 million people in East Africa, Mireille Kamariza was familiar with the devastating effects of tuberculosis (TB). “It’s a long and torturous disease,” she says. “You have relatives and loved ones that are sick, and you see them suffer through it. It’s not a quick death.”Part of Nature Outlook: Medical diagnostics

When she moved to the United States at 17, she was struck by how different the situation was there. “The question that I had when I arrived here was, how come this is not a problem here?” That question led Kamariza, now a chemical biologist at the University of California, Los Angeles, on a quest to find ways to eradicate the disease in areas where it is widespread. A key challenge is determining who is infected, so that they can be treated and the disease stopped from spreading. But current diagnostic methods are slow, often expensive, sometimes difficult to administer and not easily accessible in the low-income regions where TB is most prevalent.

TB researchers are pushing to develop faster, more accurate and more accessible tests. In 2014, the World Health Organization (WHO) set the goal of reducing the number of new cases worldwide by 80% between 2015 and 2030; it considers widespread screening and rapid diagnosis as crucial to achieving this. Replacing older testing methods with newer diagnostic and screening techniques could help individuals with the disease to be identified quicker and start treatment before their symptoms worsen — potentially before they can spread the disease. “It’s the people who have TB and don’t know they have it, they’re the ones who are spreading the disease,” says Jerry Cangelosi, an environmental-health scientist at the University of Washington School of Public Health in Seattle.

TB has been infecting people for at least 9,000 years, and it has often been the leading cause of infectious-disease deaths globally. It was eclipsed in the past few years by COVID-19, but, as the pandemic wanes, TB could retake the top spot. According to the WHO, an estimated 10.6 million people caught TB globally in 2022 and 1.3 million died¹.

The disease is caused by Mycobacterium tuberculosis, a microorganism that is spread through coughing, sneezing and spitting. It thrives in crowded conditions where there is poverty, poor nutrition and a lack of accessible health care. Fortunately, the disease is treatable with antibiotics, and the drugs used now are less toxic and taken for a shorter time than those used in the past — a few months, rather than a couple of years — even for drug-resistant strains. Around 4% of new cases are resistant to multiple drugs, and that rises to 19% among people who have previously received treatment.

But treatment and prevention require the identification of people who have and could spread the disease. “There’s a huge gap in the number of TB cases that we know are out there and what we’re actually diagnosing,” says Adithya Cattamanchi, a pulmonologist and epidemiologist at the University of California, Irvine. At least 3 million people of the WHO’s 10.6 million estimate are undiagnosed, he says.

Part of the problem, Cattamanchi says, is that the most prevalent test for TB is the sputum smear test, for which health-care workers collect a mix of saliva and mucus coughed up from the lungs; stain it with auramine, a dye that attaches to a large family of bacteria; and examine it under a microscope. The technique behind the test was developed in the 1880s by the German microbiologist and Nobel prizewinner Robert Koch. “It’s still, 150 years later, the test that we most commonly use,” Cattamanchi says.

But it has limitations. Some people have trouble coughing up sputum; people with HIV and children under five are less likely to produce much of the substance. Health-care workers collecting the sample could be exposed to the pathogen while the person is coughing. The thick sputum has to be thinned to be placed on a microscope slide. Finding the bacteria can take a day or two, and even then, it is unknown whether the strain is drug resistant. To work this out, physicians can culture the bacteria against various drugs — but that takes several weeks, which can delay administration of the right treatment. Often, physicians simply start people on the most common treatment and see whether they improve.

Molecular tests can be faster than microscopy and more accurate than cultures, because they can amplify DNA and identify resistant strains directly. But the uptake of such tests has been slow. Nucleic acid amplification tests (NAATs) have been available for almost three decades, but the earliest ones were labour intensive and required specialized skills to administer. More recent NAATs, such as the semi-automated polymerase chain reaction tests, can identify the bacteria and whether they are resistant to the first-choice antibiotic, rifampicin, in about three hours. These tests still have limitations, Cattamanchi says, because the equipment is expensive and needs to be kept in a facility that can reliably supply power and maintain an appropriate temperature — putting the machines out of reach of many local health-care facilities, where people usually seek care first. The WHO recommended a molecular test, branded Xpert, in 2010, but the cost of the individual test cartridges is prohibitive to the communities that need them. Danaher in Washington DC, the company that sells Xpert, announced last September that it was lowering the price from US$10 per cartridge to $8. But health advocates want that to go down to $5, which they say would make the test more accessible while still allowing the company to make a profit.

Bodily fluids

Kamariza is working on a cheaper diagnostic test, a fluorescent tag that binds to a product of living TB bacteria and makes them quickly identifiable under a microscope. Although fluorescent probes are common in biology, there are surprisingly few for TB, she says. In fact, auramine is the only other one.

Kamariza developed a dye molecule that binds to a sugar, trehalose, on the surface of the bacterial cell. Staining a sputum sample with the dye does not require much preparation, Kamariza says, and the bacteria light up in minutes. While still a PhD student at Harvard University in Cambridge, Massachusetts, she co-founded a company — OliLux Biosciences, based in Los Angeles — to commercialize the probe. Since then, she has learnt that although her dye was easy to spot with the high-end microscope in her laboratory, it was too dim for the cheaper equipment used in a typical clinic in Uganda, where the company is testing the assay. So she is developing a brighter dye that those microscopes can detect¹.

For now, Kamariza’s method still requires sputum and a microscope. That could change, however; she has collected some data (not yet published) suggesting that it will work on bacteria in blood samples as well. Although this is not the molecular approach that the WHO is pushing for, Kamariza feels that her test could be an intermediate step — many countries do not have the infrastructure to use molecular tests widely. She hopes that her test can speed up the identification of resistant strains during culturing as well. Getting results in a day or two will lead to people receiving the correct treatment more quickly, she says.

Other researchers are looking beyond sputum. Biochemist Tony Hu, who directs the Center for Cellular and Molecular Diagnostics at Tulane University’s School of Medicine in New Orleans, Louisiana, is developing several tests to detect products of TB bacteria in blood samples, which could be collected by a finger prick. In one test, he introduces a nanoparticle engineered to bind to a particular protein produced by the bacteria, called CFP-10. The nanoparticle amplifies the protein in the sample, making it more detectable by a mass spectrometer. Hu tested the method on blood samples from children under five, who can be difficult to diagnose because their TB symptoms can be attributable to other diseases. He found TB in 100% of children who also had HIV and had had TB confirmed by another method, and in 84% of children with HIV who had tested negative with other methods but were later diagnosed². People with HIV are more likely to have extrapulmonary TB, which leaves fewer bacteria in the lungs and makes it harder to diagnose.

Hu also uses nanoparticles to target the TB-associated proteins lipoarabinomannan (LAM) and lipoprotein LprG. Cells shed waste by releasing particles called extracellular vesicles, which, in people with TB, contain LAM and LprG. “The most important thing for us is the abundance,” Hu says. “One cell can secrete 10,000 vesicles every day.” And those vesicles persist in the blood for longer than the proteins alone would, making them available for detection.

Hu coats his nanoparticles with antibodies that bind to the vesicles, and then looks for them using a microscope³. He’s even designed and tested a small system that can replace the microscope. It includes a smartphone and an objective lens, and uses a mobile app — aided by a machine-learning algorithm that screens out background noise — to find the nanoparticles. The portable device showed results similar to those from a microscope. A third test that Hu has developed, which uses gene-editing technology to amplify TB DNA floating in the blood, is also simple. It uses a paper strip to hold the sample, a small amount of reagent and a smartphone-sized reader⁴.

Another easy-to-collect sample is urine, which also contains LAM. The first WHO-recommended version of a LAM urine test has low sensitivity, identifying only about 40% of people with TB if they are also infected with HIV, and 20% of people without HIV⁵. New generation urine tests are being developed that have a sensitivity of around 70%.

That’s not as high as physicians would like, but the tests are still useful for targeted populations, such as people with HIV, says Ruvandhi Nathavitharana, an infectious-disease specialist at Harvard Medical School in Boston, Massachusetts. “If you can do a urine-based bedside test and it’s positive, then a clinician can get that person on TB treatment straight away,” she says.

Algorithm-aided screening

Whereas urine collection requires some privacy, swabbing people’s tongues is so straightforward that a nurse could walk around a classroom testing students while they sat at their desks, says Cangelosi. That sort of community screening will be necessary to get TB under control, he says. And “if we want to envision going into workplaces or schools or communities and actively screening people, sputum collection is a non-starter”.

Even when it’s not easy for someone to produce sputum, TB bacteria come up from the lungs when people cough, and land on the back of the tongue, where they can persist for hours⁶. So far, tongue swabs have not proved as sensitive as other tests, but that could be because they’re being used in conjunction with testing platforms that have been optimized for sputum, Cangelosi says. That could change, however. The COVID-19 pandemic led many diagnostic companies to develop platforms for testing nasal swabs, and those could be adapted for tongue swabs.

Whether it involves tongue swabs or another approach, community screening is important to stem the spread of TB. Chest X-ray has a venerable history as a screening tool. “We used it way back when in the United States to really reduce the prevalence of TB,” Cattamanchi says. Today’s portable, digital X-ray machines don’t require the expensive film and process of past machines, and they can be placed in local health centres or driven around in a van. The main barrier to X-ray screening is a lack of skilled radiologists to interpret the scans.

To address that shortage, several research groups are using artificial intelligence (AI) to identify TB in lung images. Google, for instance, has been training an AI system using X-rays of people who are known to have TB, so that the tool can learn how the various types of lung damage caused by the disease look in an image and can spot them in new X-rays⁷. People flagged by the AI tool could then take a more established type of test, such as a NAAT, to confirm whether they have TB, says Daniel Tse, a health researcher at Google Research in Mountain View, California. Such screening, which Google’s test⁷ found was comparable with that performed by radiologists, could reach more people and mean that diagnostic tests are targeted more specifically, keeping costs down. For now, Tse says, images are processed by Google’s cloud servers, but for areas that have unreliable Internet access, the diagnostic algorithm might be stored on a smartphone or a dongle. Google has licensed the technology to Right to Care, a non-profit health-care organization in Centurion, South Africa.

AI could be applied to other information as well. Researchers at Stellenbosch University in South Africa, for instance, are working on algorithms that can identify TB from coughing sounds, recorded by a smartphone⁸. Others have explored doing something similar with lung sounds recorded by digital stethoscopes⁹. Tse says that several researchers are exploring whether an AI tool that combines multiple data sources might boost TB identification further.

Screening and diagnostic tests are continuing to improve, but to really fulfil their potential, they need the kind of funding and political will that was directed against the COVID-19 pandemic, says Nathavitharana. “The technologies are advancing, but honestly, it’s too slow,” she says. “We saw how much could be achieved for COVID in a very short time with the resources and targeted attention.” TB is both preventable and curable, and a major push could end its devastation, she argues. “No one should be dying of a disease like TB when we can do better.”