United under the Zero-TB Initiative

Peru and Pakistan may be on different continents, but their TB programs are united under the umbrella of the Zero TB Initiative, an international coalition of community-based health organizations, local and federal governments, the Stop TB Partnership, and NGOs aiming to drastically reduce TB rates across the world. From Karachi to Chennai, Mexicali to Lima, Shenzhen to Ho Chi Minh City, they are working to create TB-free zones in targeted regions – and ultimately everywhere.

The goal is to use the search-treat-prevent strategy that was so successful in the past, refined for local contexts and optimized through the exchange of experiences among regions. The faster and easier it is to accurately test for both TB disease and so-called “latent” TB infection in low-resource areas, the sooner the disease can be eradicated.

“There’s knowledge and tools in each of those components that haven’t been used to their maximum yield in specific places all at once,” says Mercedes Becerra, an epidemiologist and professor of global health and social medicine at Harvard Medical School. “Places that have done that have managed to drop TB rates much faster than the global average of just over 1% per year.”

“Tuberculosis is the quintessential disease of poverty,” says Salmaan Keshavjee, director of the Harvard Medical School Center for Global Health Delivery, which is a founding partner of the Zero TB Initiative. “When you look at the stats, you have to pause and say, ’Four thousand people die every single day from a disease that’s been treatable for 70 years? That is outrageous!’”

The husband and wife team are also TB specialists with Advance Access & Delivery and Partners In Health, organizations that support TB programs around the world. They see eliminating TB as a way to right global inequities with deep historical roots. “There’s this kind of acceptance that there’s one type of strategy or set of tools that we use in the US and Europe that’s just not available to the rest of the world,” Becerra says. “But it does not have to be this way.”

Righting historical inequities

Becerra and Keshavjee both began to focus on TB while graduate students at Harvard University, where they met. Before shifting to public health, Becerra had studied history and Keshavjee medical anthropology.

“TB serves as a really good marker of historical health inequities and processes that continue to make it difficult for some people to be healthy and have access to healthcare,” Becerra says. The gaps in TB case rates between former colonies and former colonial empires are so vast, they’re difficult to put on the same graph, she says. “These historical processes have left health systems weaker, unable to provide the services that those populations need – not just for TB but across many diseases.”

In the 1990s, both of them went to work with Partners In Health, one of the world’s preeminent public health NGOs that supports community health. Becerra went to Peru, where she focused on family transmission of TB and multi-drug-resistant TB (MDR-TB).

“If you’re sick with TB, you spread it to the people you love,” Becerra says. “And even if you get treatment, the people around you may not appear sick, but will end up with the disease later if they go undiagnosed. Grandparents who have TB and don’t get treatment can infect a small child. And that child may only get sick 10 or 20 or 30 years later. It’s a terrible cycle that can be broken if you can get people on preventive treatment.”

Meanwhile, Keshavjee went to Tomsk, Russia, where a large outbreak of TB was happening in a prison; the death rate was close to 400 per 100,000. Those who did survive, and were eventually released, went on to infect their families. Many had MDR-TB. “The prisons were an epidemiologic pump,” he says. “So with our Russian partners, we supported both prison- and community-based treatment programs for TB.”

TB case rates dropped by 40% in five years. “That was the kernel for the Zero TB Initiative, because it taught us a lot,” he says. “And it continues to this day.”

That success laid the seeds for the Zero TB Initiative. “The idea was to create a coalition of communities that were committed to creating islands of TB elimination using the comprehensive search-treat-prevent approach,” says Keshavjee.

An “island of elimination” is a place where the search, treat, and prevent strategy is implemented with the goal of driving down rates of TB. “At first it may not be the whole population, but it’s going to be an island within it,” Keshavjee says.

Testing is essential

Testing has played an essential role in the development of these kinds of programs. Timing is key. For TB disease, a chest x-ray returns immediate results. For those determined to be at risk of TB, a rapid molecular test can confirm disease within a few hours. This is a far cry from the days of exclusive reliance on smear microscopy, a sputum test that is still in use in some places for TB diagnosis, but which misses almost half of sick adults and three-quarters of sick children.

For those who need testing for “latent” TB infection, IGRA tests can be used, and results take about a day. The alternative, a skin test in which tuberculin is injected under the skin of the lower arm, has to be checked by a health professional after two or three days to see whether the site has swelled or hardened.

Skin tests are falling out of favor because they can result in false negatives and require at least two patient visits. And a positive result may indicate exposure to other mycobacteria, a lot of which exists in the environment and is unrelated to TB.

Daniela Puma, a nurse and the coordinator of Socios En Salud’s mobile TB unit, says that follow-up visits to check skin test results can be challenging. “We are located in an area of northern Lima where most people work all day. They have one day off, maybe. So they have to take full advantage of that day of consultation to have their complete evaluation and get a diagnosis. If we can do everything on one single day, it’s better for everyone.”

That’s why molecular testing, like the QuantiFERON-TB Gold Plus IGRA test, offers an important alternative with advantages over skin tests wherever health systems have been able to use it to diagnose TB infection. The WHO recommends IGRA tests in its TB guidelines. Done with a simple blood draw, the QuantiFERON IGRA test has a sensitivity of >94% and a specificity of 97%.

“The benefit of the IGRA test is that it’s much more specific for tuberculosis, so you end up having to treat fewer people,” Keshavjee says. “You don’t want to expose people to medicines that they don’t need, and you want to make sure that local health delivery capacity is directed at groups at high risk for TB.”

The Zero TB Initiative’s search-treat-prevent approach has begun to show success in multiple locations. In Karachi, it has reduced TB cases in a dense urban area of two million people by 25–30%. In northern Lima, early results are also promising.

These “islands of elimination” in progress have inspired community health partners across the globe to launch their own search-treat-prevent programs.

The future of testing

The use of as much targeted testing as possible, as early as possible, is critical to the future of TB elimination. That’s why the Zero TB Initiative co-founder, Advance Access & Delivery, is also evaluating the QIAreach Quantiferon-TB system in Mexicali, Mexico, with local partners. The assay provides ultrasensitive digital detection of latent TB infection using a rugged, portable, battery-operated detection device.

“It’s going to be a leap forward,” Keshavjee predicts. “It will allow you to have the device sitting in a clinic, or a doctor’s office, or a community health clinic, and you’ll be able to just put the blood in and within hours know the results. I think it’s going to be a game changer.”

COVID-19, however, has set back the fight against TB. It’s estimated that 30% of TB cases are missed every year. That number is believed to be much higher now. “When people aren’t found, and continue to go untreated, they spread the disease to their families and their communities. The sick go undiagnosed, and the exposed and infected don’t receive preventive therapy,” Keshavjee says. “So I think, in many ways, the pandemic has been a catastrophe for the communities struggling against TB. We are going to see the effects for many years.”

On the upside, Keshavjee believes that the community health activities advanced by the Zero TB Initiative can also be used to screen, treat and prevent a range of diseases, including cancer, COPD, asthma, diabetes, hepatitis – and COVID-19. “What we’re building is a healthcare delivery platform,” he says. “We’re extending the reach of clinics and laboratories into the communities where people live and work, so it’s actually an incredible tool for health-system strengthening.”