Over the last decade, it has become clear that South Africa's progress against TB depends on diagnosing more people more quickly. In this Spotlight special briefing, Marcus Low asks how we can best go about it.
While tuberculosis (TB) rates in South Africa are declining, most experts agree they are not coming down quickly enough.
According to Thembisa, the leading model of HIV and TB in South Africa, just under 500 000 people aged 15 and older fell ill with TB in the country in 2005. By 2023, this number had dropped to around 330 000. Despite this decline, the World Health Organization (WHO) still classifies South Africa as a high TB burden country and with an estimated 427 cases of TB per 100 000 people, South Africa still ranks among the top countries in terms of TB incidence.
There are at least two interesting dynamics behind these trends - the close dance of HIV and TB and the problem of late diagnosis.
Start with the link between HIV and TB. People living with HIV who have compromised immune systems are dramatically more likely to fall ill with TB. As HIV numbers shot up through the 1990s and early 2000s, TB numbers inevitably followed in their wake. The tide turned as the number of annual HIV infections peaked and as more people started taking antiretroviral therapy - though it technically started earlier, the country's antiretroviral treatment programme only really blossomed from around 2008 after former President Thabo Mbeki left office. The decline in TB numbers over the last decade is driven largely by this dynamic of antiretroviral treatment keeping people living with HIV healthy and thereby preventing TB.
Then there is the problem of late diagnosis. In short, someone starts falling ill with TB. Their symptoms are mild, they shrug it off and get on with life. But, over time the night sweats, the coughing, and the weight loss gets worse. Eventually they go to the clinic and, if they are lucky, their TB is finally diagnosed. The catch is that by the time the diagnosis is made, the person may have transmitted TB to as many as 15 others - estimates of this number vary and are highly context dependent. Either way, the implications of this are far-reaching. For one thing, even if we somehow manage to treat everyone diagnosed with TB successfully, we will still fail to prevent most cases of TB transmission that happen prior to diagnosis.
Thus, while HIV treatment is helping to bring South Africa's TB numbers down, the fact that we have so much TB transmission before people are diagnosed, means TB numbers are not coming down as quickly as they might. On the face of it, a solution might simply be to make it much easier for people in South Africa to get a TB test.
"Earlier identification of people in early stages of TB disease is really critical if we hope to control TB," explains Professor Thomas Scriba, a TB expert from the University of Cape Town. "Earlier diagnosis would be better for the individual and for public health. Better for the individual because antibiotic treatment is more likely to be successful when the bacterial load is still relatively low and there is less lung damage than seen in more advanced or severe TB. Better for public health because treatment would stop transmission of the TB bacterium at an earlier stage of disease when the patient may be less infectious. This would also reduce the period of infectiousness of the patient, thus protecting those in contact with the patient."
Our evolving understanding of TB
TB is a very old disease. At times called phthisis, consumption, and 'the white death', Hippocrates wrote of it as far back as 460 BCE and signs of TB have been detected in Egyptian mummies. The bacterium was isolated for the first time by Robert Koch in 1882 and the first antibiotics effective against the bug were developed in the 1940s. Today, TB can be cured, typically using a combination of four different antibiotics for four or six months.
Over the last decade or so, our understanding of TB disease has become much more nuanced. We used to classify people into two disease states - latently infected or ill with active TB. Latent TB simply means that a person has TB bacteria in their body, but that their immune system has it under control and they are not showing any symptoms. Active TB, as the name suggests, refers to TB bacteria getting the upper hand over a person's immune system and causing illness.
As we now know, these old classifications doesn't quite capture what is going on. Most notably, there is an in-between stage of sub-clinical TB - a state where a person does not yet show symptoms, but where the TB bacteria has risen from its slumber and is preparing the ground for symptomatic illness. In this sub-clinical phase, illness has technically started in the lung and a person can be infectious, despite not yet having symptoms like the trade-mark TB cough.
The implications of sub-clinical TB are far-reaching. On the positive side, it holds out the promise that, with the right test, we can potentially diagnose and treat TB even before someone falls ill and serious damage is done to the lungs. On the negative side, much as with asymptomatic transmission of SARS-CoV-2, sub-clinical TB means that people who have no TB symptoms can transmit TB. This fact goes some way to explaining why reducing new TB infections is so hard, especially in the places where we still wait for people to report to clinics once they get TB symptoms.
World TB Day is marked in the same week that SA celebrates Human Rights Day. A human rights based approach to #TB mirrors a public health approach, argue @ingridsuidA, Sasha Stevenson, Janet Giddy, @reniercoetzee & Petula Pienaar #WorldTBDay #EndTB https://t.co/jfReP07E7k pic.twitter.com/cHNHFFfNk6
-- Spotlight (@SpotlightNSP) March 22, 2024
Meanwhile, as our understanding of TB has evolved over the last decade or so, there has also been a revolution in TB testing. For most of the last hundred years, TB tests involved looking at the bug under a microscope or growing it in the lab - a process that could take weeks. Just over a decade ago, however, new rapid molecular tests became available that provide a result in a few hours (though transporting samples to labs can delay things). These new molecular tests were rapidly rolled out in South Africa's public healthcare system from 2011 and today most TB tests are done in this way.
In addition to shiny new molecular tests, we have also in the last five years seen a resurgence in the use of much older technology in the form of X-rays. This resurgence is largely due to X-ray machines becoming both much safer to use and more portable - so much so that a truck with one of these machines in the back can now drop by a high TB burden area for a day of community testing. The case for X-rays has further been sweetened by the development of machine learning models that are as good at determining whether an X-ray image is indicative of TB as most human experts. The one snag with X-rays are that, while they are great at helping us spot the tell-tale lung damage associated with TB, they cannot yet tell us whether the image is indicative of a current case of TB or residual damage from TB that has already been cured. For this reason, X-rays are used for TB screening and must be followed up by a molecular test to confirm the diagnosis.
The good news is that even more new tests are on the horizon. Since some people, especially children, struggle to cough up sputum, researchers and developers are increasingly focusing on saliva, stool, and blood-based tests. One urine-based test is already in wide use to detect TB in people with HIV who are sick - the tests accuracy is poor in other groups.
Research, much of which has been conducted in South Africa, has shown that by looking at certain blood markers, it is possible to predict with a high degree of accuracy whether someone will develop TB symptoms in the next six months. "There is a lot of ongoing research to advance blood biomarkers for early TB," says Scriba, "unfortunately they are not yet ready for prime time". Scriba led some of the studies looking into blood markers for TB.
The revolution has started
While South Africa's Department of Health comes in for much criticism, it has often been ahead of the curve when it comes to tackling TB. A decade ago, South Africa was one of the first countries to switch over to molecular TB tests and more recently it led the world in switching to safer, shorter-duration medicines to treat drug-resistant forms of TB. It is now also pushing the envelope in trying to diagnose people before they show-up at clinics with TB symptoms.
The cornerstone of the new approach is something called targeted universal testing - TUT for short. The revolutionary idea behind TUT is simple, identify who is at highest risk of falling ill with TB and offer them a molecular TB test whether or not they have symptoms. Though not a foolproof approach, we know that people living with HIV in whose bodies the virus is not suppressed, people who have recently had TB, and people who have recently had close contact with someone with TB are all at an elevated risk. Focusing on these groups of people and targeting districts with high TB rates makes sense. A case might even be made for widening these criteria - recent research suggest working-age men are particularly worth targeting even if they are not living with HIV. There are trade-offs though, there is a risk that by casting the net too wide we may end up doing a lot of unnecessary testing.
In early 2021, results from a landmark study confirming that TUT increases TB detection was presented at a major scientific conference. Since then, several TUT pilot projects have been run in the country and early reports suggest that they are indeed increasing TB detection - although to our knowledge a thorough scientific assessment of South Africa's TUT pilots have not yet been made public. In one TUT study, it was found that over half of around 30 000 people who tested positive for TB did not have TB symptoms.
JUST PUBLISHED | "We were the first ones to do it": Innovative SA study takes TB testing to people's homes
New technology has made it possible to test people for TB in their homes. This could be a big deal for South Africa, where much TB goes undiagnosed, reports @Jeranji.... pic.twitter.com/OenDdfWSQn
-- Spotlight (@SpotlightNSP) July 17, 2024
The top TB official in the National Department of Health, Dr Norbert Ndjeka, has been vocal in his support of TUT. Earlier this year, he told Spotlight that TUT is national policy and that it has been rolled out across the country since 2022. (See Ndjeka's full response here.)
Figures shared by the department suggest that we are heading in the right direction. Around 2.1 million people were tested for pulmonary TB in 2019. This dropped below 2 million in 2020 and 2021 (due to the COVID-19 pandemic), but then increased to 2.4 million in 2022 and 2.7 million in 2023. These increases suggest that TUT is at least partially being implemented. Over the same period, the actual number of new TB cases are thought to have been stable or declining.
There have also been several pilot projects in the last two years looking at the use of mobile X-ray technology to help screen for TB in South Africa. Here too, the early reporting is promising, but no thorough scientific assessment of the pilots have yet been made public to our knowledge - although early signs are positive.
None of this is free. TUT involves conducting hundreds of thousands of additional TB tests while X-ray screening requires the purchase and maintenance of X-ray machines, software, and the people to operate them. The need to spend in these 'new' areas comes in a context where health budgets have been shrinking in real terms for several years.
Ndjeka explains that TB programmes are primarily funded by the state. The Global Fund for HIV, TB and Malaria - a multinational donor - is helping to pay for TB testing in some districts, but Ndjeka says the state will step in should the Global Fund pull out. With X-rays, the situation seems more tenuous. Currently, most of the machines are paid for by donors such as the Global Fund and USAID, but Ndjeka says provinces are starting to procure their own.
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Can we see it through?
That a TB revolution has started and that several good moves have already been made is of course only part of the picture. Against a backdrop of political uncertainty, a dwindling public purse, poor management in some provincial health departments, and chronic healthcare worker shortages, the outcome is very much still in doubt. The scale of the problem also remains sobering. The WHO estimates that TB claimed 56 000 lives in the country last year.
A good next step would be if South Africa's political leaders start talking about TB testing as they did about HIV testing a decade ago. Ndjeka and his colleagues' efforts are well and good, but President Cyril Ramaphosa and Minister of Health Dr Aaron Motsoaledi are the ones who should be on TV encouraging people to get tested and having their pictures taken outside mobile X-ray trucks. They should also use their political clout to convince big business to arrange testing for their employees and to drive engagement with HIV-style testing drives.
Getting many more people to buy into a TB testing drive will also require that government lays its cards on the table for all to see. Scientifically sound assessments of pilot projects should be made public as soon as possible and all provinces should have publicly available TB data dashboards such as that in the Western Cape. The recent history here is somewhat worrying - preliminary findings from South Africa's first TB prevalence survey conducted in 2018 and 2019 were only published in 2021.
If the accumulating evidence confirms that mobile X-ray screening and targeted universal testing is as effective, as they appear to be, it will be important to ensure that the money is there to implement and to keep implementing. The partial reliance on international donors means such programmes are at risk of collapsing should these donors pull out. If the aforementioned political will is there to deal with TB, such a collapse will not be allowed to happen, even in the context of shrinking budgets.
Finally, that cutting edge research on new TB tests is being done at South African universities is a precious green shoot that should be protected and nurtured. As with the increased local production of pharmaceuticals and potentially vaccines, there is not only an economic opportunity here, but the promise of the country taking charge of its own destiny when it comes to TB and reducing its dependence on foreign well-doers. Of course, spending more public money on TB research is a tough sell when belts are already tight, but South Africa has an existing edge in this area and the potential returns are manifold.
