New test predicts TB a year ahead – landmark SA discovery

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SATVIThe Lancet publishes a landmark study reporting the discovery of a blood test that can predict the likelihood of a person developing tuberculosis (TB) more than a year before the disease manifest. This is the fruition of a 10-year effort led by scientists at the SA Tuberculosis Vaccine Initiative of the University of Cape Town and the US Centre for Infectious Disease Research.

TB is a global public health crisis, with more than 3,000 people dying daily from it worldwide. Infection with the bacterium Mycobacterium tuberculosis is thought to affect a third of the global population, 90% of whom will never develop TB disease.

With the newly discovered biomarker test we will now be able to identify three quarters of those who will progress to TB disease, ensuring early detection and benefit from health care. The “correlate of risk” blood test measures expression of a few genes, or a gene expression signature. According to Professor Willem Hanekom, principal investigator of the study, “Importantly, the test can predict progression to TB more than 1 year before disease manifests, which provides a window of opportunity to use treatment to prevent the disease.”

The scientists studied gene expression patterns in blood samples selected from more than 6,000 teenagers from the town of Worcester in the Western Cape Province of South Africa, who were followed for more than 2 years to identify those who did or did not develop TB disease.

Confirmation that the gene expression signature could predict TB disease was completed using samples from another cohort of 4,500 adults from South Africa and The Gambia. These study participants were enrolled within a large international collaborative effort between researchers from South Africa, The Gambia, Ethiopia, Uganda, Kenya, Germany, The Netherlands, the UK and the US.

Professor Mark Hatherill, principal investigator of the new trial, said: “If the trial is successful, mass campaigns using a ‘screen & treat’ strategy have potential for major impact on the global epidemic, by stopping TB before it manifests and becomes infectious to others.”

Interviewed by International Innovation, Hatherill said: “If we can predict who would get tuberculosis, we would have an ideal opportunity to treat those people with preventive therapy. We are about to launch the Correlate of Risk Targeted Intervention Study (CORTIS), which I lead on behalf of a consortium of South African, US and UK researchers. CORTIS is a randomised, partially-blinded, clinical trial that will test whether Isoniazid and Rifapentine therapy can prevent pulmonary tuberculosis in high-risk (COR+) individuals. If CORTIS shows that the COR test enables selective treatment for those at high risk of tuberculosis, we would start developing a point-of-care tool that would have potential for major impact on the global tuberculosis epidemic.

Dr Thomas Scriba, associate professor at the University of Cape Town and deputy director of immunology at SATVI said: “Our research to date has focused only on individuals without HIV infection. However, given the large number of people living with HIV, we also want to develop the COR test in such a way that we can predict the risk of developing tuberculosis in HIV-infected people.”

 

MedicalBrief reported in February (https://www.medicalbrief.co.za/archives/simple-blood-test-could-transform-tb-diagnosis/) that researchers at the Stanford University School of Medicine had identified a gene expression “signature” that distinguishes patients with active tuberculosis from those with either latent tuberculosis or other diseases. The finding fills a need identified by the World Health Organisation (WHO), which in 2014 challenged researchers to develop better diagnostic tests for active TB.

WHO estimates that 9.6m people got sick with TB in 2014 and that 1.5m people died of the disease that year. Yet it remains difficult to diagnose. “One-third of the world’s population is currently infected with TB. Even if only 10% of them get active TB, that’s still 3% of the world’s population – 240m people,” said Professor Purvesh Khatri, assistant professor of medicine and senior author of the paper.

Traditional diagnostic methods, such as the skin prick test and interferon assays, can’t separate patients with active TB from those who are no longer sick or have merely been vaccinated against TB (and most countries vaccinate everyone against TB). These older diagnostics can miss a case of TB in patients with HIV.

A common way to test for TB is to look for the disease-causing bacterium in sputum samples coughed up by patients. But sometimes it’s hard for people to produce sputum on demand, said research associate Dr Tim Sweeney, first author of the paper. “If someone can’t produce adequate sputum, or if you have a kid who can’t follow directions,” it’s hard to diagnose them, he said. And the sputum test is almost useless for monitoring how someone is responding to treatment. As people start to get better, they can’t produce sputum for the test.

The new test developed in the Khatri lab works on an ordinary blood sample and removes the need to collect sputum. It can signal a TB infection even if the individual also has HIV. And it won’t give a positive response if someone only has latent TB or has had a TB vaccine. It also doesn’t matter which strain of TB has infected a person, or even if it has evolved resistance to antibiotic drugs. The test works in both adults and children.

WHO has called for a test that would give a positive result at least 66% of the time when a child has active TB. The Khatri test is 86% sensitive in children. And if the test comes up negative, it’s right 99% of the time. That is, of 100 patients who test negative with the Khatri test, 99 do not have active TB.

The requirements of the test are simple enough that it can potentially be done under relatively basic field conditions in rural and undeveloped areas of the world. Any hospital should be able to perform the test. Villages without electricity could likely use ordinary blood samples and a solar-powered PCR machine, which multiplies strands of DNA, to accurately test people for active TB.

When pathogens infect the cells of the body, the infection sets off a chain reaction that changes the expression of hundreds of human genes. Khatri’s team identified three human genes whose expression changes in a consistent pattern, revealing the presence of an active tuberculosis infection.

The team validated the new three-gene test in a separate set of 1,400 human samples from 11 different data sets, confirming the diagnostic power of the test. The new test not only accurately distinguishes patients who have active tuberculosis, it could also be used to monitor patients to see if they are getting better and how well they are responding to different treatments. Thus, it can be used not only for diagnosis and to inform treatment, but also to study the effectiveness of different treatments. The test’s hugely accurate negative response would be especially helpful in monitoring the effectiveness of treatments during clinical trials, said Khatri.

He has already begun collecting funding to develop the test for widespread use, both to diagnose TB in patients and to monitor recovery in clinical trials, allowing for more rapid development of better and cheaper treatments.

South African Tuberculosis Vaccine Initiative material
The Lancet abstract
Stanford University material
The Lancet Respiratory Medicine abstract


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