South Africa: Sub-Clinical TB - Fascinating SA Research Helps Push Frontiers of TB Science

(File photo).
11 December 2020

As much as 80% of adults in the Western Cape may at some point have been infected with the tuberculosis (TB) bacterium. While estimates are uncertain, rates are believed to be high in the rest of the country as well, with likely millions of people having been infected with TB. Most people's bodies, however, manage to suppress the infection and they do not actually fall ill. People who have been infected but who do not fall ill are traditionally classified as having latent TB infection.

Only between three and 10% of those infected with latent TB will fall ill with TB over a lifetime, according to Professor Thomas Scriba, of the South African Tuberculosis Vaccine Initiative (SATVI). Once someone falls ill with TB, it is referred to as active TB.

Unfortunately, we have a poor understanding of precisely which three to 10% of people with latent TB will develop active disease. We know that people living with HIV are at a substantially increased risk of active TB, but beyond that we are mostly in the dark.

In recent years, however, a more nuanced understanding of TB has emerged, whereby the infection is not seen as simply latent or active, but as existing on a spectrum. Some researchers have proposed that two additional states should be included between latent and active, incipient TB and sub-clinical TB.

A paper published in the journal Clinical Microbiological Reviews proposed the following definitions for the two new categories:

"Incipient TB infection is an infection with viable tuberculosis bacteria that is likely to progress to active disease in the absence of further intervention but has not yet induced clinical symptoms, radiographic abnormalities, or microbiologic evidence consistent with active TB disease."

"Subclinical TB disease is disease due to viable tuberculosis bacteria that does not cause clinical TB-related symptoms but causes other abnormalities that can be detected using existing radiologic or microbiologic assays."

One thing that follows from this more nuanced understanding is that, if we could develop simple and affordable tests for incipient and sub-clinical TB, we could identify which three to 10% of people are likely to fall ill, and try to prevent that from happening by providing people with TB preventive therapy. This would not only benefit the health of the individuals involved, it will also prevent onward transmission since people receiving preventive therapy might never become infectious, or be infectious for shorter periods.

While such simple and affordable tests for incipient and sub-clinical TB do not yet exist, research conducted in South Africa has however taken us a significant step closer.

The CORTIS study

Scriba and others have been investigating whether a specific set of biomarkers (obtained through a blood sample analysed in a lab) could differentiate between people who will develop active TB and those who will not. Findings from their latest study, led by Professor Mark Hatherill, director of the clinical research team at SATVI, and titled Correlate of Risk Targeted Intervention Study (Cortis), were presented at the annual Union World Conference on Lung Health in October. A paper with the study findings is expected to be published in a medical journal soon.

In addition to testing how well the set of biomarkers can predict whether people will fall ill with TB, the study also looked at the impact of providing TB prevention therapy to people with biomarkers suggesting that they might develop active TB - in other words, whether the loop can be closed in that people at risk can be identified and then given treatment to prevent illness. There were 2 923 study participants.

In a somewhat disappointing finding, it turns out that in this study at least, the loop was not closed. Rates of active TB were roughly similar in those with suggestive biomarkers who were given TB prevention therapy (the 3HP prevention regimen was used) and those who had suggestive biomarkers, but were not given preventive therapy.

The findings were much more encouraging regarding the ability of the set of biomarkers to predict who will fall ill with TB. The test was particularly accurate at predicting who will fall ill within six months of getting the test - it was much less accurate at predicting illness that would occur 15 months after the test.

Using the set of biomarkers resulted in the identification of sub-clinical TB in more than one percent of the study population - 80% of whom had no symptoms (in other words, sub-clinical TB).

"We were able to identify more than one percent of supposedly healthy TB cases we could not otherwise diagnose because these people hadn't been sick enough to access testing. This might seem like a small number, but in a population like ours this translates to a significant number of people we can target with preventative therapy," says Scriba.

According to Professor Keertan Dheda, based at the University of Cape Town, "in infectious diseases terms, this is a very high percentage of people, and highlights the extraordinary high burden of TB in our communities".

He describes the form of TB identified in the one percent of study participants as incipient TB. "This is a 'sleeping' form of TB but over the short term (a year or two) it can progress to active TB and to a bug-level that can be detected by conventional tests," says Dheda. "Up to now this type of TB was invisible. We now have a biomarker that can detect this type of TB. This is a major breakthrough because it allows us to study this form of TB, develop better detection tools for it, and design appropriate treatments. The authors must be highly commended for discovering and validating this biomarker. Although it did not work as well as expected, and there are many possible reasons for this, at least it gives us a firm base from which to build on."

Breaking the cycle

The laboratory-based blood test used in the Cortis study "looks promising but it is not ready to be rolled out", says Scriba. He said that potential future development would focus on developing a point-of-care test, which delivers results rapidly without the need of a laboratory - that is affordable for low and middle-income countries.

Scriba says these results do however go some way to finding a predictor of disease.

He points out that, according to the World Health Organization, there are between 3 and 4 million people who have TB each year but who are not diagnosed or treated. "These people continue to transmit the disease, causing an ongoing cycle where more people get infected - broadening the pool of people from which a subset will go on to get sick," he said.

He said the Cortis results are important because it identifies a group where the "ongoing cycle" can be broken. "Ultimately we need better diagnostic tools to find even more people who are going to get sick, earlier in their disease progression before they become infectious and pass the disease on to others - then we will have a key way of intervening in the cycle of ongoing transmission."

Dheda makes a similar point, stressing what he calls the "often-forgotten fact that almost two of every five persons with TB globally remain undiagnosed or undetected".

"This amounts to almost 3 million cases globally (based on the Global 2020 TB Report) over 150 000 cases in South Africa alone," he says. "TB will never be controlled until this problem is addressed because a significant proportion of these cases, though they may not have much in the way of symptoms, can still transmit the disease."

Who to give preventive therapy

"The issue we have with TB is that in a population like ours in South Africa, there are too many people infected with the TB bacterium to offer preventative therapy to everyone. When you look at the adult population, a very large number of people are infected with the TB bacterium - research in the Western Cape estimates that this is the case for 80% of adults," says Scriba.

He says that people living in Europe, by contrast, where only a small percentage of people have latent TB, would benefit from receiving a preventative course of antibiotics for three to six months.

As a result of the rationing of resources and due to some mostly minor side effects, TB preventive therapy is currently reserved in South Africa for people living with HIV and young children who have been exposed to TB. The World Health Organization earlier this year recommended that not just kids under five, but all household contacts of people with active TB may be offered preventive therapy.

With the work being done by Scriba, Hatherill and others , there is now a real prospect that in a few years' time we might have a simple and affordable test that can tell us which additional individuals require preventive therapy. Such a test would be an important advance in the fight against TB.

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