Tuberculosis (TB) is the world’s leading infectious disease killer; in 2024, 10.7 million people fell ill with TB and 1.23 million died. Prevention is crucial, and while promising vaccine candidates are in the pipeline, preventive therapy is the best course for people at risk of moving from infection to active disease. Current TB preventive therapy (TPT) regimens require taking antibiotics for one to six or more months, but not all are eligible for the existing one-month treatment option. For people with TB infection, it is challenging to sustain a long therapy course, especially because those without active disease do not have symptoms. It also challenges families and treatment programs to have to give different regimens depending on people’s health conditions — for example, pregnancy, HIV or exposure to drug-susceptible or drug-resistant TB. SMART4TB’s Bedaquiline Roll-out Evidence in Contacts and People Living with HIV to Prevent TB (BREACH-TB) trial is attempting to tackle some of these challenges with a simplified universal TPT of one month of bedaquiline.

The trial’s first site is in Tanzania, led by Dr. James Ngocho, a clinical research scientist at Kilimanjaro Clinical Research Institute and a senior lecturer at Kilimanjaro Christian Medical College University. Dr. Ngocho is inspired by the potential of a shorter treatment plan that has the potential to retain more people on treatment and lower costs for healthcare systems. “If this trial is successful, one-month preventive therapy for all would be sustainable for our communities, physicians and systems. We know from experience that as time goes on, we lose people who do not want to take medication when they are not experiencing an active infection. We would have a much easier time keeping them on treatment for one month.”

U.S.-based trial co-investigator, Dr. Eric Nuermberger, a professor of medicine at Johns Hopkins University School of Medicine, believes prevention is key to managing TB worldwide and a one-month regimen will help people who have been exposed to drug-resistant TB or who must manage complex drug-drug interactions, as the only existing one-month TPT regimen can interact with drugs, including some antiretrovirals used to treat HIV. “It has become clear over the last decade or two, the easier that we can make regimens for people to both tolerate and complete, the more effective they can be. Because this regimen is based on just one drug for one month, and has fewer drug-drug interactions, it reduces pill burden and is easier to take with other medications.”

Both Dr. Ngocho and Dr. Nuermberger were drawn to working on TB by the potential to make a real-world impact on a disease that they had seen historically and contemporaneously ravage societies. “I started my career working with people living with HIV, and TB was a common co-infection, so I wanted to learn more about it and help improve the lives of people living with HIV. I have seen children, families and relatives struggle with TB, and I know that if we can stop it from moving through a household, it will make a big difference,” said Dr. Ngocho.

If the trial is successful, it paves the way for a long-acting injectable, a form of treatment that Dr. Nuermberger describes as an efficient “one and done” solution. However, that will work for some, but not all, people who need preventive treatment. “We know from experience that it is important to have options. Oral treatment will always play a role, so having this potential in our arsenal to help end TB is vital.”

BREACH-TB plans to open sites in Mongolia, Peru and Uganda later this year.

 

 

 

In the capital city of Maputo, Mozambique, sits a low-slung yellow building encasing some of the most vital, national-standard scientific research to serve the public health concerns of a country with well over 30 million people. The Centro de Investigação e Treino em Saúde da Polana Caniço (CISPOC), part of the Instituto Nacional de Saúde de Mozambique (INS), has a rich history with public health and biomedical research. In addition to clinical and operational research on tuberculosis (TB), HIV and emerging infections, the center is a vital training ground for students and health professionals. In 2015, INS ran its first TB clinical trial and by 2025, they were running five adult and pediatric TB clinical trials.

Dr. Celso Khosa, a researcher at INS and the general director of CISPOC, believes the last decade-plus of innovation in TB in Mozambique shows the kind of evolution that is possible when you are strategic and work with strong collaborators. Starting with trials of both diagnostics and implementation science in adults, researchers built up the capacity to start working with children, a population with unique challenges when it comes to TB and particularly important in Mozambique. As partners in both U.S. Government-funded SMART4TB trials, Assessing Diagnostics at Point-of-Care (ADAPT) for Kids and Shortened Regimen for Drug-susceptible TB in children (SMILE)-TB, the INS team is leading the way in transformative research on pediatric TB diagnostics and treatment.

When children arrive at a healthcare clinic with symptoms like a cough and fever, clinicians and their patients are immediately thrust into a series of challenges. In addition to the fundamental difficulty of getting a sputum sample from a child, doctors must find dedicated space for the child to produce the potentially infectious sample and often need suction and aspiration devices, especially for younger children. The likelihood of a clinic having the space, healthcare workers having the necessary training and consistent power for the devices makes traditional TB diagnostics a difficult hurdle.

Ever since ADAPT for Kids, a study examining new point-of-care TB diagnostic tests for children like tongue swabs, urine samples and AI-based technologies, launched at INS the clinic has seen a marked improvement in diagnosis and the national health system has benefitted from these advances. “It’s exciting to talk to parents and caregivers about the new tests, it’s more comfortable for them and their child and it eases the fears of clinicians as well,” said Dr. Denise Banze, a researcher at INS and co-principal investigator on the ADAPT for Kids study. “You see a lot of TB in Mozambique and our goal is to make it a less scary prospect in children’s lives, both by getting them test results quickly and offering them treatment options that are manageable.” This is where the SMILE-TB study comes in, evaluating if a treatment shortening two-month regimen of a series of antibiotics—isoniazid, rifapentine, pyrazinamide and moxifloxacin—is as effective as the current standard of four-to-six months of isoniazid, rifampicin and pyrazinamide with or without ethambutol.

Dr. Banze estimates that 80% of enrollees in the SMILE study will come from a positive diagnosis made possible by the ADAPT for Kids trial, ensuring a seamless treatment path for children and their parents and caregivers. The potential for shorter treatment is vital for helping children complete treatment and ensure they can live healthy, productive lives. “We know how hard it is to take antibiotics for even seven days, now imagine asking a child to take it for months on end, it is a big challenge,” said Dr. Khosa.

In addition to managing the trials, clinicians and staff at INS have dealt with many unexpected challenges that have changed the frequency of patients coming for care, including flooding, civil unrest and healthcare worker strikes. Through it all, the team has maintained its commitment to providing children with the highest level of consistent care and has shown resilience by keeping their doors open. “We feel very confident doing TB diagnostics for children and have earned the trust of health facilities around the country so even in these challenging times, we still get calls from providers who would like us to look at a child,” said Dr. Banze.

Study coordinator Dr. Márcia Mutisse recalls a mother bringing in her sick 12-year-old daughter, desperate for answers as the girl was losing weight, coughing, and having trouble breathing. Despite the difficulty of reaching the clinic because of the lack of public transportation, the mother returned the next day to receive the results. The study team arrived early to ensure they could meet the family and support them through the process, which led to a diagnosis of multi-drug-resistant TB. Although the diagnosis was difficult, the mother and daughter persevered, and the child began to show improvement within a week after starting treatment. Reflecting on the patient and parent, Dr. Mutisse noted, “This experience showed me that what we are doing can help children and their families not only in the future but right now. Parents need people like us to design new strategies and to be there for them, no matter the circumstances.”

The evidence that Mozambique is generating will help influence global diagnostic guidelines and treatment recommendations, an important opportunity for local knowledge to inform broader policies and practices.

As for the day-to-day of running the trials, Dr. Khosa credits the local community members who advise them on their studies and help inform potential participants about the trial and its benefits for their success so far. “They are amazing, leaders in their community and in our work. Together, we are all working to help children have better, healthier lives.”

Childhood tuberculosis (TB), while impacting nearly a million children across the globe, isn’t as well diagnosed and is likely under or overtreated compared with TB in adulthood. The Shortened Regimen for Drug-Susceptible TB in Children (SMILE-TB) trial, led by the SMART4TB Consortium, and funded by the U.S. government, is focused on addressing this critical population, evaluating a shorter treatment regimen for children with pulmonary and lymph node tuberculosis. When children are diagnosed and treated quickly and effectively, it can have an enormous impact on their future and their caregivers. SMILE-TB is currently enrolling participants in Uganda, Indonesia, and Zambia, where local researchers are seizing this opportunity to improve treatment and care.

Dr. Chishala Chabala is a pediatrician and lecturer at the University of Zambia and the principal investigator of the SMILE-TB trial in Zambia.

How did you come to the field of TB and specifically, pediatric TB?
I’ve worked on TB for 20 years, starting out as a provincial TB coordinator in Southern Zambia and seeing the impact of TB in clinics, particularly people with HIV and TB. As a pediatrician, it was glaring how neglected TB in children was. We saw so many changes in treatment for adults based on trials, but such little attention was given to children, so that motivated me.

What is the potential for the SMILE-TB trial to impact children living with TB, their caregivers, and families? It’s potentially a game-changer; the standard treatment was six months, then it was reduced to four months based on the results of the SHINE trial (Shorter Treatment for Minimal Tuberculosis in Children) and now, in SMILE-TB, we’re looking at two months, encompassing  pulmonary and lymph node TB.

The current treatment requires going to a facility for the duration of the treatment, which is a big cost, both for the family and the health service. Parents sometimes have to take off work for several days and the longer you are taking medication, the more potential for side effects and adverse events. We also know that when a child presents with TB, more often than not there is another person in the house who has TB so caring for the child and adult makes it difficult. With shorter treatment, you know that you are saving costs for the family, and you are reducing side effects for the child.

What is unique about the TB epidemiology in Zambia?
Zambia is a high-burden TB country, we have high rates of HIV infection and high rates of TB in children who are malnourished. This trial gives us an opportunity to look at children with added health complexities, including taking a lot of medication (in the case of HIV and TB) and managing their nutrition. What we learn in Zambia will be applicable to similar settings in sub-Saharan Africa.

Why is research like this important to pursue right now?
Typically, these types of trials are done in adults, and we have to extrapolate from those results what to do with children. With SMILE-TB, we are providing answers that adult treatment trials can’t answer. As healthcare spending goes down, we can show that when we invest in children, when we invest in research, we can make a big impact.

Dr. Bwendo Nduna is the Senior Medical Superintendent Arthur Davison Children’s Hospital and an investigator of the SMILE-TB trial in Ndola, Zambia.

How did you come to the field of TB and specifically, pediatric TB?
I had an interest in neonatology and infectious diseases as a medical student and a strong interest in research because as I was doing my specialization, most of our learning was through evidence-based practices. You start to learn how children are managed throughout the world, and you are learning how to provide the best standard of care. When you look at TB diagnosis in children, it’s difficult to make. Even an experienced clinician will toil around and have difficulty and that worried me. The first battle is that you must convince the parent that the child has TB, and then when you start the treatment, it’s so long.

When I started out, it was common to start a child on first line antibiotic treatment, switch to second line antibiotics when there was a poor response, by the time you get to the third line you start to worry that it’s TB. That would mean six months of “imprisonment” on medication. Parents would then be worried about how long they will be in the hospital, how many injections they will get, and things like that.

When the various healthcare workers I’ve trained to manage pediatric TB see me at the grocery store, they think of TB, and I take it as a sign of how passionate I am about this work.

What is the significance of the SMILE-TB study in Ndola? What is the study’s potential for children living with TB, caregivers, and their families?
I’m so excited, whenever you think of pill burdens, it’s huge. A child who has HIV is already taking so many pills, and then you give them a diagnosis of TB and now they are swallowing even more pills for a long duration. I want to make life easier for these children and get them the shortest, most effective therapy.

I always say, we have to improve the quality of this child’s life, the dignity of the patient. It’s a game changer, and it opens other avenues for research and collaboration. A child being unwell is not a natural thing. You see the catastrophic costs of patients who have TB, and this trial has the potential to lessen all of that. It’s such a welcome thing.

Crucial treatment-shortening trial with potential to dramatically improve care for one of the most dangerous forms of TB begins enrollment in Mongolia

The U.S. government-funded Supporting, Mobilizing, and Accelerating Research for Tuberculosis Elimination (SMART4TB) consortium is excited to announce that The Program for Rifampicin-Resistant Disease with Stratified Medicine for TB (PRISM-TB) trial, led by investigators from University of California, San Francisco, has launched at the National Center for Communicable Diseases in Ulaanbaatar, Mongolia with 10 participants enrolled. PRISM-TB (ClinicalTrials.gov NCT06441006) is one of three randomized, controlled trials aiming to optimize TB therapeutics and provide life-saving benefits for the millions suffering from the leading infectious disease killer in the world.

PRISM-TB is a two-stage trial that evaluates a stratified medicine approach to shortening drug-resistant TB treatment with bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM) to three or four months from a standard of six months. “PRISM-TB is an exciting opportunity to move away from a one-size-fits-all approach and evaluate a more personalized approach that we hope keeps people on treatment and helps them return to their lives faster,” said Bazarragchaa Tsogt, principal investigator for the trial at the National Center for Communicable Diseases.

It is estimated that 390,000 people develop drug-resistant TB each year; this form of TB does not respond to first-line treatments and consequently, is difficult and expensive to treat. Current standard treatments for drug-resistant TB are six to nine months; shorter treatment has the potential to make it easier for more people to complete treatment, to reduce the length of potentially difficult side effects, to ease burden on TB programs and to allow people return to healthy, productive lives faster. PRISM-TB will enroll 200 participants, including adults, adolescents, pregnant and lactating women and people living with HIV, and randomize them into standard treatment, four months of BPaLM, or a stratified arm of three or six months of BPaLM, depending on individual risk factors. The treatment stratification uses an algorithm based on factors demonstrated to be associated with TB outcomes like age, sex, HIV status, bacterial load in sputum and presence of cavitary lung disease to determine if a participant receives shorter or longer treatment.

“PRISM-TB will not only generate crucial data that we hope can inform guidelines and improve treatment in the U.S. and around the world, but we are employing a first-ever risk-benefit analysis with a desirability of outcome ranking at the end of Stage One to select the optimal treatment for Stage Two,” said Dr Gustavo Velásquez, PRISM-TB principal investigator and assistant professor of medicine in the Division of HIV, Infectious Diseases, and Global Medicine and the Center for Tuberculosis at University of California, San Francisco. “We believe these unique trial elements in addition to including priority populations such as adolescents and pregnant women will both optimize treatment and improve access.”

PRISM-TB trial drug donations include bedaquiline by Johnson & Johnson and pretomanid by Viatris/Mylan Pharmaceutical Private Limited. In addition to Mongolia, the PRISM-TB trial plans to open in clinical sites in Peru and Uganda soon. SMART4TB anticipates preliminary analysis in 2027.