Scientists from the University of Leicester have discovered that tuberculosis disrupts glucose metabolism in the body. The findings, which have now been published in PLoSPathogens complement the understanding that diabetes worsens the symptoms of tuberculosis. Importantly, they now say, undiagnosed tuberculosis could be pushing vulnerable patients towards metabolic disease such as diabetes.
Tuberculosis (TB) remains one of the most devastating infectious diseases worldwide, killing over 4,000 people every day. Prevention through the development of improved vaccines remains a priority for the World Health Organisation. Currently only one vaccine exists for TB and this is predominantly given to infants and young children to help protect them from severe forms of infection.
Scientists at the University are researching tuberculosis in the hope of creating improved vaccines and are specifically looking at ways in which undiagnosed and subclinical infection can impact health. This new discovery, they say, could pave the way to define the molecular pathways by which the immune response changes liver metabolism, thereby allowing for the creation of targeted interventions.
She said: “Our paper changes the focus from diabetes making TB worse to the possibility that late diagnosis of TB can contribute to disruption of glucose metabolism, insulin resistance and therefore can promote progress towards diabetes in those that are susceptible.
“As diabetes compromises drug treatment, our paper also supports the idea that metabolic screening should be involved in any drug or vaccine trials.”
The study first used laboratory models of pulmonary TB to examine the changes happening within the liver during the early stages of infection. It found that an immune response was triggered within the liver cells and glucose metabolism was altered.
First author Dr Mrinal Das then reanalysed published metabolic data from humans, where he found that liver glucose metabolism was also disrupted when people progressed to TB from latent infection.
Professor Cooper added: “Our future aim is to define the molecular pathways by which the immune response is changing liver metabolism, allowing us to potentially create targeted interventions.
“We will also be investigating how latent TB (which is infection with the bacterial agent of TB without significant symptoms) might be impacting metabolic health in humans.”
A therapy showing promise to help control tuberculosis (TB) does not interfere with combined antiretroviral therapy (cART), according to research by Texas Biomedical Research Institute (Texas Biomed) which was recently published in JCI Insight.
“This is an important hurdle that this host-directed therapy had to clear in order to help patients battling both HIV and TB,” said study leader Professor Smriti Mehra, PhD of Texas Biomed.
TB is responsible for more than 1.3 million deaths worldwide every year. Dr. Mehra and her team have been investigating a therapy currently used in cancer as a potential treatment for patients with drug-resistant TB and/or comorbid HIV. While many cases of TB can be controlled with months of antibiotics, the infection can return in people who are immunocompromised as a result of HIV. Now that cART is so effective at controlling HIV, a resurging TB infection can often be deadly to those individuals.
Dr Mehra is studying a host-directed therapy that blocks or inhibits an immune system protein naturally found in the body. The protein, called IDO (short for Indoleamine-2,3-dioxygenase), normally suppresses the immune system, preventing it from causing excessive inflammation and organ damage. Inhibiting IDO for short intervals of time has led to more successful cancer treatments. Dr. Mehra’s team has previously shown the same approach improves control of TB in conjunction with antibiotics.
This current study in nonhuman primates with both TB and simian immunodeficiency virus, the nonhuman primate version of HIV, showed the IDO inhibitor does not interfere with cART.
Researchers compare the impacts of cART by itself versus cART plus the IDO inhibitor in lung tissue of nonhuman primates with both TB and SIV. Left: Following just cART, significantly more IDO is detected in pink. Right: With the IDO inhibitor and cART, immune cells recruited to fight bacteria are observed inside the granuloma, a hallmark structure of TB. Specifically, CD4+ T cells are in green and CD68 proteins expressed by macrophages are in red.
“There was no increase in viral load in animals given cART and the IDO inhibitor, compared with animals only given cART, proving the inhibitor is safe to give to patients with HIV,” Dr. Mehra said.
Now that the researchers have shown the inhibitor works well in conjunction with TB antibiotics and with cART separately, they plan to study how it performs when given in conjunction with both antibiotics and cART together. This treatment regimen is standard for patients with both HIV and active TB. Dr. Mehra said that longer-term studies are also needed to confirm there are no unintended side effects.
The IDO inhibitor is already FDA-approved for use in patients with cancer, which shortens the path to potential approval for patients with TB/HIV when compared with developing a brand-new drug.
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
A compound found in African wormwood – a plant used medicinally for thousands of years to treat many types of illness – could be effective against tuberculosis, according to a new study available online in the Journal of Ethnopharmacology.
The team, co-led by Penn State researchers, found that the chemical compound, an O-methylflavone, can kill Mycobacterium tuberculosis, or Mtb, that causes tuberculosis in both its active state and its slower, hypoxic state, which the mycobacteria enters when it is stressed.
Bacteria in this state are much harder to destroy and make infections more difficult to clear, according to co-corresponding author Joshua Kellogg, assistant professor of veterinary and biomedical sciences in the College of Agricultural Sciences.
While the findings are preliminary, Kellogg said the work is a promising first step in finding new therapies against tuberculosis.
“Now that we’ve isolated this compound, we can move forward with examining and experimenting with its structure to see if we can improve its activity and make it even more effective against tuberculosis,” he said. “We’re also still studying the plant itself to see if we can identify additional molecules that might be able to kill this mycobacterium.”
Tuberculosis is one of the world’s leading killers among infectious diseases, according to the Centers for Disease Control and Prevention. There are about 10 million cases a year globally, with approximately 1.5 million of those being fatal.
While effective therapies exist for TB, the researchers said there are several factors that make the disease difficult to treat. A standard course of antibiotics lasts six months, and if a patient contracts a drug-resistant strain of the bacteria, it stretches to two years, making treatment costly and time consuming.
Additionally, the bacteria can take two forms in the body, including one that is significantly harder to kill.
“There’s a ‘normal’ microbial bacterial form, in which it’s replicating and growing, but when it gets stressed – when drugs or the immune system is attacking it – it goes into a pseudo-hibernation state, where it shuts down a lot of its cellular processes until it perceives that the threat has passed,” Kellogg said. “This makes it really hard to kill those hibernating cells, so we were really keen to look at potential new chemicals or molecules that are capable of attacking this hibernation state.”
Multiple species of the Artemisia plant have been used in traditional medicine for centuries, the researchers said, including African wormwood, which has been used to treat cough and fever. Recent studies in Africa have suggested that the plant also has clinical benefits in treating TB.
“When we look at the raw plant extract that has hundreds of molecules in it, it’s pretty good at killing TB,” Kellogg said. “Our question was: There seems to be something in the plant that’s really effective – what is it?”
For their study, the researchers took raw extract of the African wormwood plant and separated it into “fractions” – versions of the extract that have been separated into simpler chemical profiles. They then tested each of the fractions against Mtb, noting whether they were effective or ineffective against the bacteria. At the same time, they created a chemical profile of all of the tested fractions.
“We also used machine learning to model how the changes in chemistry correlated with the changes in activity that we saw,” Kellogg said. “This allowed us to narrow our focus to two fractions that were really active.”
From these, the researchers identified and tested a compound that effectively killed the bacteria in the pathogen’s active and inactive states, which the researchers said is significant and rare to see in TB treatments. Further testing in a human cell model showed that it had minimal toxicity.
Kellogg said the findings have the potential to open new avenues for developing new, improved therapeutics.
“While the potency of this compound is too low to use directly as an anti-Mtb treatment, it may still be able to serve as the foundation for designing more potent drugs,” he said. “Furthermore, there appear to be other, similar chemicals in African wormwood that may also have the same type of properties.”
The researchers said that in the future, more studies are needed to continue exploring the potential for using African wormwood for treating TB.
A Competition Commission probe recently resulted in a patent on an important tuberculosis medicine being dropped in South Africa. Twenty years ago, a similar Competition Commission case resulted in a settlement that helped drive down the prices of several antiretrovirals, thereby helping to set the stage for the country’s HIV treatment programme. Fatima Hassan and Leena Menghaney connect the dots between the two landmark cases and map out what has and has not changed over the last two decades.
In the late 1990s and early 2000s, South Africa faced a major uncontrolled AIDS epidemic, worsened by state sponsored AIDS denialism. South Africa was at the epicentre of a global epidemic, with hundreds of thousands of people getting sick and dying, needlessly, because lifesaving antiretroviral medicines were out of reach.
This was in the main because of the Mbeki government’s deadly science denialism denying public sector patients antiretrovirals and the high cost of some of these medicines, which at the turn of the century was available in the private sector but only for the very rich or medically insured. The private sector price for the combination of three antiretrovirals needed by most people living with HIV was exorbitant.
This was because of patent monopolies held at the time by multinational pharmaceutical companies, particularly GlaxoSmithKline (GSK) and Boehringer Ingelheim (BI). In essence, people in South Africa living with HIV had to beg to live – by seeking donations and charity or pressuring their respective medical schemes to provide coverage. Meanwhile, lifesaving antiretrovirals were generally available in the Global North and in some parts of the Global South where governments like those in Thailand and Brazil had taken action to reduce prices.
Looking for a way to challenge the high prices of key antiretrovirals, activists turned to South Africa’s newly revamped post-apartheid competition law. In September 2002, the Treatment Action Campaign, Hazel Tau, a woman living with HIV and several others lodged a complaint with the country’s Competition Commission. They alleged that the price that GSK and BI were charging for important antiretrovirals was excessive and anti-competitive, undermining not just Competition Law but also the right to health as enshrined in the country’s still fairly new Constitution.
The Competition Commission agreed to investigate. Several months later, they announced that there was a prima facie case of excessive pricing and that they would be referring the matter to the Competition Tribunal (the next phase of a complaint to the Competition authorities). Almost immediately after that announcement, TAC was approached by GSK and BI to “settle” the matter. This meant there would be no public hearings, and the companies would not have to defend their pricing decisions in the dock.
The terms of the settlement, negotiated by the TAC’s legal team, mirrored what TAC had publicly demanded at the beginning of the case. Most importantly, GSK and BI agreed to grant voluntary licenses to several generic manufacturers that would allow them to make and sell the antiretrovirals in question. It was this generic competition that would drive down the prices of antiretrovirals in the years that followed.
Even though the Competition Commission only has jurisdiction in South Africa, the licenses included many other African countries, which meant those countries could also benefit from the generic competition and lower prices. The settlement (including the terms of the voluntary licenses) was agreed to by the Competition Commission, made an order and publicly announced, leading to the conclusion of the complaint.
The case, which came to be known as the Hazel Tau case, would in the years to come be recognised as one of the foundations that made large HIV treatment programmes possible in South Africa and other African countries. Despite this victory, the ongoing effects of AIDS denialism meant that it would in reality be several years before the more affordable generic antiretrovirals would be made widely available in South Africa.
20 years later, the spotlight is on TB drugs
HIV has not been the only health crisis to affect SA. According to the World Health Organization (WHO), Tuberculosis (TB) is one of the leading infectious causes of death globally, and drug-resistant TB (DR-TB) remains a public health crisis. The WHO estimates that around 304 000 people fall ill with TB in South Africa per year, and it claims over 50 000 lives, which means it remains one of the country’s top killers. While TB rates are slowly declining, there is concern that rates of drug-resistant forms of TB (DR-TB) are increasing. DR-TB requires newer, more expensive treatments.
Shared geographic origin between TB strain and human host could amplify risk for infection
Tuberculosis bacteria. Credit: CDC
For some forms of tuberculosis, the chances that an exposed person will get infected depend on whether the individual and the bacteria share a hometown, according to a new study comparing how different strains move through mixed populations in cosmopolitan cities.
Results of the research, led by Harvard Medical School scientists and published in Nature Microbiology, provide the first hard evidence of long-standing observations that have led scientists to suspect that pathogen, place, and human host collide in a distinctive interplay that influences infection risk and fuels differences in susceptibility to infection.
The study strengthens the case for a long-standing hypothesis in the field that specific bacteria and their human hosts likely coevolved over hundreds or thousands of years, the researchers said.
The findings may also help inform new prevention and treatment approaches for tuberculosis.
In the current analysis, believed to be the first controlled comparison of TB strains’ infectivity in populations of mixed geographic origins, the researchers custom built a study cohort by combining case files from patients with TB in New York City, Amsterdam, and Hamburg. Doing so gave them enough data to power their models.
The analysis showed that close household contacts of people diagnosed with a strain of TB from a geographically restricted lineage had a 14 percent lower rate of infection and a 45 percent lower rate of developing active TB disease compared with those exposed to a strain belonging to a widespread lineage.
The study also showed that strains with narrow geographic ranges are much more likely to infect people with roots in the bacteria’s native geographic region than people from outside the region.
The researchers found that the odds of infection dropped by 38 percent when a contact is exposed to a restricted pathogen from a geographic region that doesn’t match the person’s background, compared with when a person is exposed to a geographically restricted microbe from a region that does match their home country. This was true for people who had lived in the region themselves and for people whose two parents could each trace their heritage to the region.
This pathogen-host affinity points to a shared evolution between humans and microbes with certain biological features rendering both more compatible and fueling the risk for infection, the researchers said.
“The size of the effect is surprisingly large,” said Maha Farhat, the Gilbert S. Omenn, MD ’65, PhD Associate Professor of Biomedical Informatics in the Blavatnik Institute at HMS. “That’s a good indicator that the impact on public health is substantial.”
Why differences matter
Thanks to the growing use of genetic sequencing, researchers have observed not all circulating strains are created equal. Some lineages are widespread and responsible for much of the TB around the world, while others are prevalent only in a few restricted areas. Given that the complex nature of TB transmission in high-incidence settings where people often have multiple exposures to different lineages, researchers have not been able to compare strains under similar conditions and have been left to speculate about possible explanations for the differences between strains.
Many factors increase the risk of contracting tuberculosis from a close contact. One of the best predictors of whether a person will infect their close contacts is bacterial load, measured by a test called sputum smear microscopy, which shows how many bacteria a person carries in their respiratory system.
But the new study showed that for geographically restricted strains, whether a person has ancestors who lived where the strain is common was an even bigger predictor of infection risk than bacterial load in the sputum. In the cases analyzed in the study, this risk of common ancestry even outweighed the risk stemming from having diabetes and other chronic diseases previously shown to render people more susceptible to infection.
The findings add to a growing body of evidence of the importance of paying attention to the wide variation between different lineages of tuberculosis and to the details of how different lineages of tuberculosis interact with different host populations.
Previous studies have shown that some genetic groups of TB are more prone to developing drug resistance and that TB vaccines appear to work better in some places than others. There is also evidence that some treatment regimens might be better suited to some strains of TB than others.
“These findings emphasize how important it is to understand what makes different strains of TB behave so differently from one another, and why some strains have such a close affinity for specific, related groups of people,” said Matthias Groeschel, research fellow in biomedical informatics in Farhat’s lab at HMS; resident physician at Charité, a university hospital in Berlin; and the study’s first author.
In addition to the analysis of clinical, genomic, and public health data, the researchers also tested the ability of different strains of TB to infect human macrophages, a type of immune cell that TB hijacks to cause infection and disease. The researchers grew cells from donors from different regions. Once again, cell lines from people with ancestry that matched the native habitat of a restricted strain of tuberculosis bacteria were more susceptible to the germs than cells from people from outside the area, mirroring the results of their epidemiologic study.
Until now, most experiments of the interaction between human immune cells and TB have not compared how TB interacts with cells of hosts from different populations or places, the researchers said.
While this experiment was not designed to capture insights about the mechanism underlying the affinity between human and TB populations sharing geographic backgrounds, it highlights the importance of using multiple strains of TB and cells from diverse populations to inform treatment and prevention. It also points to the need for more basic research to understand the genomic and structural differences in how bacterial and host cells interface, the researchers said.
“It’s so important to appreciate that the great diversity of human and tuberculosis genetics can significantly impact how people and microbes respond to one another and to things like drugs and vaccines,” Farhat said. “We have to incorporate that into the way we think about the disease.”
“We’re at the very beginning of appreciating the importance of that diversity,” Groeschel said. “There’s so much more to learn about how it might impact the efficacy of drugs, vaccines, and the course that disease takes in different strains.”
Advances in gene sequencing create a new puzzle
While the closely related but distinct genetic groups of tuberculosis were discovered with more traditional methods of genotyping, the widespread use of whole genome sequencing by public health departments around the world allowed doctors and researchers to better profile TB germs and track outbreaks and drug resistance genetically.
The realization that highly localised stains didn’t spread well to other regions led researchers to speculate that regionally constrained strains were less infectious than widespread strains. Since the constrained strains persisted within their limited ranges, some researchers speculated that localised populations of the bacteria may have coevolved with their human hosts, making different human populations more susceptible to different types of TB. This could also mean, researchers hypothesised, that different strains of TB would have different susceptibility to different treatments and vaccines. For example, structural differences in the shape of the bacteria might prevent some drugs from binding effectively with bacteria from different strains.
Until recently, these hypotheses were nearly impossible to test, given the differences between cultural and environmental conditions that might affect infection rates in different communities and other parts of the world. Furthermore, the fact that the constrained stains strayed from home so rarely made it challenging to gather enough data to measure differences across strains.
Multidisciplinary science cracks the case
To overcome these obstacles, the research team collaborated with public health departments and research teams from the U.S., the Netherlands, and Germany to assemble a massive database integrating tuberculosis case reports, pathogen genetic profiles, and public health records of infection rates among close contacts. The analysis also incorporated demographic details about the social networks of infected people to assess how the different genetic lineages of tuberculosis spread in other populations. In total, the study included 5256 TB cases and 28 889 close contacts.
“This study is a great example of why it’s so important for researchers to collaborate with many different kinds of partners,” said Groeschel. “We were able to merge public health data from three big cities and use the powerful computational biology tools that we have access to in academic medicine to answer a complicated question that has important implications for public health and evolutionary biology, vaccine development, and drug research.”
Most tuberculosis (TB) tests still require a trip to the clinic. Now, new technology has made it possible to test people at home. This could be a big deal for South Africa, where much TB goes undiagnosed. We unpack the findings and implications of a recent study into such TB home testing.
One of the biggest challenges in combatting TB in South Africa is that many people who fall ill with the disease are diagnosed late, or not diagnosed at all.
The World Health Organization (WHO) estimates that 280 000 people fell ill with TB in the country in 2022. Of these, roughly 66 000 were not diagnosed, and accordingly also not treated. Apart from the damage to the health of the people who are not diagnosed and treated, this also has implications for the further spread of TB since untreated TB is often infectious TB – people become non-infectious within a few weeks of starting TB treatment.
Typically, people who fall ill with TB only get diagnosed once they turn up at clinics with TB symptoms – this is called passive case-finding. In recent years, there has been a growing recognition that passive case-finding alone is not good enough if we want to diagnose more people more quickly. As a result, many people in South Africa considered to be at high risk of TB are now offered TB tests whether or not they have symptoms – an approach called targeted universal testing. Screening for TB using new mobile X-ray technology has also been piloted in the country.
Now, in the latest such active case-finding innovation, researchers have been offering people TB tests in the comfort of their own homes.
Dr Andrew Medina-Marino, a senior investigator at the Desmond Tutu Health Foundation (DTHF), tells Spotlight no one in the world was testing for TB at home until they recently started doing so at the DTHF’s new research site in the Eastern Cape.
The testing is done using a molecular testing device, roughly the size of a two litre Coke bottle, called the GeneXpert Edge. The GeneXpert Edge is a portable version of the GeneXpert machines that have been used in labs across the country to diagnose TB for over a decade.
The GeneXpert Edge is a standardised testing device that detects TB DNA in sputum. (Photo: Nasief Manie/Spotlight)
One challenge with the device was that it needed to be plugged into a power outlet in a wall and not all homes in the area have power. “So what we did is, we hooked up a car-like battery to the device and we were able to take it into people’s homes,” says Medina-Marino.
‘Acceptable and feasible’
A study lead by Medina-Marino, and recently published in Open Forum Infectious Diseases, set out to determine the acceptability and feasibility of in-home testing of household contacts of people with TB.
The study was conducted among 84 households in Duncan Village, a township in the Buffalo City Metropolitan Municipality in the Eastern Cape. The Metro had an estimated TB incidence of 876 cases per 100 000 population in 2019, according to the National Institute for Communicable Diseases. This number is much higher than the latest WHO estimate of 468 per 100 000 for South Africa as a whole.
From July 2018 to May 2019, people diagnosed with pulmonary TB were recruited from six government health clinics in the area. They were asked for permission to visit their homes to screen their household contacts for TB. Household contacts were verbally assessed for signs or symptoms of TB, including night sweats, weight loss, persistent cough and a fever.
Households where people had any signs or symptoms of TB were randomised to either be referred to a local clinic for TB testing or tested immediately in their home. Of the eighty-four randomised households, 51 household contacts were offered in-home testing. Everyone accepted the offer for in-home testing.
For the test with the GeneXpert Edge, Medina-Marino says household contacts had to produce a sputum sample. About 47% (24/51) were able to produce sputum. This was then mixed with a reagent containing the required components for a polymerase chain reaction test. This solution was then loaded into a disposable cartridge/test module and inserted into the Edge device. Results were available in about 90 minutes. Anyone who received a positive test result in their home were immediately referred to a clinic for TB treatment.
Regarding the 47 household contacts referred for testing at the clinic, only 15% (7 people) presented for clinic-based TB evaluation, 6 were tested, and 4 out of 6 returned for their results.
Ultimately, the study found that in-home testing of household contacts for TB was acceptable and feasible.
“It’s feasible. If you compare the rate of uptake of treatment versus the rate of uptake for testing, it looks like it’s performing much better when you do home based testing versus referral for testing at the clinic,” says Medina-Marino.
Risk of stigma?
Similar to when HIV home-based testing studies were carried out, Medina-Marino says prior to their study, community members expressed concerns about stigmatising houses that were visited. “[A] lot of people were saying: ‘If you go to people’s houses, you’re going to stigmatise the household.’”
But what they actually found was that people didn’t feel stigmatised. Household contacts of people with TB felt that coming to the house to test people brought a sense of security in the home. He adds that it was easy for people to believe the results because everything was done in front of them.
In instances where people didn’t have TB, Medina-Marino says household contacts were comforted that they didn’t have to be scared of the person tested. In instances where people did have TB, he says the attitude of household contacts was supportive to start treatment.
How the test compares to other tests
Apart from testing for TB, the GeneXpert Edge can also detect whether someone’s TB is resistant to rifampicin. This is one of the medicines in the standard four-drug combination used to treat TB.
Unlike the latest lab-base GeneXpert tests, the GeneXpert Edge does not detect resistance to any TB medicines other than rifampacin. “It is hard to fit the probes needed to detect other forms of resistance into the cartridge,” says study co-author Professor Grant Theron, head of the Clinical Mycobacteriology and Epidemiology Research group at Stellenbosch University’s Molecular Biology and Human Genetics Unit.
Theron notes that the sensitivity and specificity of GeneXpert Edge is similar to that of lab-based GeneXpert machines if the tests are done on specimens from the same type of patient and the same test cartridge. (High sensitivity means the likelihood of false negatives is low wile high specificity means the likelihood of false positives is low.)
Performance may however differ because of differences between people who test at home and people who test at the clinic. Theron explains that in their study they tested people who did not yet feel sick enough to go to get tested at the clinic. People who are sicker, and who are accordingly more likely to go to the clinic, are likely to have more pathogen in their sputum samples and be easier to diagnose.
‘A breakthrough for TB’
Home-based tests is a significant breakthrough in TB because of its crucial role in detecting cases early and enabling timely tracing and testing of household contacts, says Dr Ntokozo Mzimela, a lecturer in integrated pathology in the Faculty of Health Sciences at Nelson Mandela University.
She tells Spotlight it also offers several advantages over clinic-based tests. “They are highly accessible, facilitate mass testing, reduce the risk of disease transmission, and address patient reluctance by allowing testing in the comfort and privacy of one’s home.”
Mzimela adds the GeneXpert Edge and portable X-ray screening serve complementary roles in TB diagnosis. “While the X-ray reveals lung abnormalities, the Edge confirms the presence of TB bacteria. Both tools are essential and should be used in conjunction to provide comprehensive diagnostic insights and ensure accurate and timely treatment for patients,” she says.
Professor Keertan Dheda agrees that home-based testing could link up neatly with portable X-ray, but adds it is still too early to determine where home-based TB testing will fit into the country’s TB testing programme. Dheda heads up the Division of Pulmonology at Groote Schuur Hospital and the University of Cape Town.
“We don’t yet know whether testing everyone is the right approach or whether reflex testing based on chest x-ray abnormalities is the right approach,” Dheda says. “Now that feasibility has been established, it means that more studies can be undertaken, and operational research can be commenced.”
Further studies are already underway, Medina-Marino tells Spotlight.
He says the study in Duncan Village found that about 60% of household contacts who had TB symptoms could not cough up a sputum sample. His team therefore decided to combine in-home testing with an oral swab.
“So in the study that we’re doing now in households, we found an additional 12 people who cannot produce sputum but on their swab test, they showed a positive swab result. Tongue swabs increase yield of case finding among those unable to produce sputum,” he says.
Besides preventing illness and death, tuberculosis prevention therapy is estimated to be highly cost effective. Yet, uptake of the medication is not what it could be in South Africa. Tiyese Jeranji asks how much has changed since the Department of Health last year decided to make TB prevention therapy much more widely available.
Many people who have the TB bug in their lungs are not ill with TB disease. Having the bug in your body, does mean however that you are at risk of falling ill, should the TB bacteria get the overhand in its battle with your immune system.
Fortunately, we have medications that can kill TB bacteria before one falls ill. A recent World Health Organization (WHO) investment case, suggests such TB prevention therapy, commonly called TPT, reduces the risk of falling ill with TB in those exposed to the bug by 60% to 90% compared to people who do not get the treatment.
In South Africa, TPT has been available in the public sector for years, but until the publication of new government guidelines last year, only kids aged five or younger and people living with HIV could get the medication. Under the new guidelines, everyone who has had close contact with someone with TB should be offered a TB test and if they test negative be offered TPT – if they test positive they should be offered TB treatment. These changes dramatically expanded the number of people in South Africa who are eligible for TPT.
The antibiotics used for TPT has also changed in recent years. For many years, the only option was a medication called isoniazid taken for six or more months. We now also have two three-month options – isoniazid and rifapentine given once weekly and rifampicin and isoniazid given daily. These shorter duration treatment courses should help more people complete the treatment.
Down and up?
Dr Norbert Ndjeka, Chief Director of TB Control and Management at the National Department of Health, tells Spotlight that in recent years, South Africa has seen a steady decline in the number of people initiated on TPT.
The decline has been substantial. In people living with HIV, initiation on TPT dropped from 454 000 in 2018 to around 241 000 in 2023. In children aged five and younger who have had contact with someone with TB, it fell from 25 357 in 2018 to 15 775 in 2023.
TPT enrolments per province for 2023
Province
People living with HIV
Contacts < 5 Years
Contacts > 5 Years
Eastern Cape
34 623
2 551
4 771
Free State
14 535
562
1 027
Gauteng
67 333
1 368
4 241
KwaZulu-Natal
62 362
3 168
8 519
Limpopo
15 871
391
452
Mpumalanga
25 618
669
2 006
Northern Cape
3 178
855
1 595
North West
9 433
596
1 425
Western Cape
8 532
5 615
1 278
South Africa
241 485
15 775
25 314
*Typically, provinces with higher numbers of people diagnosed with TB or those with high numbers of people living with HIV will report higher TPT initiations.
There are two significant reasons for this decline, according to Ndjeka. Firstly, declining TB incidence, and secondly, declining HIV incidence.
“With fewer people diagnosed with TB disease, fewer contacts will need TPT, and with fewer people being diagnosed with HIV, fewer people will initiate TPT regardless of TB exposure,” he says.
WHO figures have shown a significant downward trend in the estimated TB cases per year in South Africa and according to Thembisa, the leading mathematical model of HIV in South Africa, the number of people newly starting HIV treatment has dropped from a peak of over 700 000 in 2011, to well under 300 000 in 2023.
But the recent downward trend in people taking TPT may be coming to an end. “We believe that the implementation of the new guidelines within the current strategic framework will lead to increases in TPT enrolment,” says Ndjeka.
In line with the new guidelines, there are also changes to what TPT data is being collected. “For example, we never used to report on TPT provision to contacts 5 years and older, but now we do and in 2023 at least 25 314 TB contacts 5 years and older were initiated on TPT,” he says.
20% increase expected in 2024
Based on the data reported for January and February of this year, Ndjeka expects that overall TPT initiations will increase by at least 20% in 2024 compared to 2023. Moreover, as documented in the National Strategic Plan for HIV, TB and STIs 2023-2028, there is a plan to have a steady annual increase in TPT enrolments leading up to 2028.
Ndjeka says based on the NSP TPT targets, South Africa is exceeding TPT targets for people living with HIV, but reaching less than 25% of targets for TB contacts. He points out that performance varies by province, but that all provinces have a long way to go in terms of reaching TB contacts.
‘Cost saving over time’
“The aim of offering TPT is to reduce the TB incidence,” Ndjeka says. “So, if everyone eligible is offered TPT there will obviously be increased costs initially but cost saving over time. This looks at cost of treating people with TB, lives saved/ deaths prevented as well as costs to patients.”
For South Africa, he says, it is estimated that we can reduce the number of people with TB by 138 000 by 2050 at an estimated cost of R23 226.90 per TB episode prevented.
Ndjeka says it costs the health department an estimated at R1 498.51 to treat one person with drug-susceptible TB for 6 months and R16 612.82 to treat one person with the standard drug-resistant TB treatment for 6 months. “These costs are for medications alone, which can also go beyond R70 000 depending on the patient and the type of resistant TB. Moreover, when factoring in clinical consultations, hospitalisations, and costs to patients the costs go up considerably,” he says.
The cost of providing TPT also depends on the regimen. One person on TPT can cost as little as R608.77 for a course of three months of isoniazid and rifapentine given once weekly, and up to R1 358.02 for 12 months of isoniazid. “TPT also has much lower associated costs for example there is no hospitalisation, fewer clinic visits and consultations,” Ndjeka says.
“By preventing TB, the cost of TB treatment is avoided along with the costs of treating some of the acute and chronic conditions that someone with TB may experience even after being cured of TB. These include chronic obstructive pulmonary disease, bronchiectasis and pneumonia,” says Alison Best, communication manager at Cape Town-based NGO TB HIV Care.
“For children under five in particular, who are at increased risk of disseminated TB like TB meningitis, the cost of not preventing TB could be death or severe lifelong disability,” she says, adding that preventing TB in a single individual also prevents the costs associated with any onwards transmission of TB from that individual to others.
Questions over implementation
Expanded TPT eligibility has been widely welcomed, but questions have been raised over how well the new guidelines are being implemented.
Best says government austerity measures have made implementing new initiatives in the healthcare setting challenging.
“There is not much political will to implement the guidelines (to expand eligibility for TPT) at provincial and district levels and this has translated into the slow release of circulars, delays in training health workers, poor knowledge of the policy and its low prioritisation,” she says.
Ingrid Schoeman, Director of Advocacy and Strategy at TB Proof (a local advocacy group), says often when a national policy is released, there are delays at provincial-level in releasing circulars to enable health worker training.
“This results in these services not being available at district-level. In the Western Cape, civil society organisations, the [provincial] Department of Health, City of Cape Town and implementing partners are now all working together to support health worker training, and implementing community-led awareness campaigns so that all close TB contacts know they are eligible for TPT,” she says.
Best adds that tracking the data to show how many people are starting and completing TPT tends to be difficult. She notes there are many gaps in capturing the information. This includes, at times, the limited recording of information in patient folders by clinicians and suboptimal inputting of data by data capturers.
Ndjeka says the national department of health has been conducting training on the new guidelines with provincial and district TB and HIV programme managers, district support partners and other trainers.
“They are then responsible for training health care workers. The antiretroviral therapy guideline training also includes TPT. Webinars on the knowledge hub (an online training platform) have also conducted,” he says.
However, Ndjeka conceded that there is a lack of awareness about the value of TPT. “Additionally,” he says, “there is reluctance from clinicians to provide TPT. This result in poor demand for TPT. Treatment adherence is another problem especially for people on the long regimen (12 months)”.
Plans to address these challenges, among other things, include marketing TPT as treatment for TB infection rather than prevention, targeted communication strategies, community mobilisation, and ongoing training and mentoring of healthcare workers, says Ndjeka.
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
With resistance to chemical antibiotics on the rise, the world needs entirely new forms of antibiotics. A new study published in Microbiology Spectrum, a journal of the American Society for Microbiology, shows that an enzymatic cocktail can kill a variety of mycobacterial species of bacteria, including those that cause tuberculosis. The research was carried out by scientists at Colorado State University and Endolytix Technologies.
“We have a mycobacterial drug that works for Nontuberculous Mycobacteria and M. tuberculosis that is biological, not phage therapy, and not small molecule antibiotics,” said Jason Holder, Ph.D., a study coauthor and Founder and Chief Science Officer at Endolytix Technology.
“Mycobacterial infections are particularly hard to treat due to poor efficacy with standard of care drugs that are used in multidrug regimens resulting in significant toxicities and treatments lasting 6 months to years. This is often followed up by reemergence of the bacterial infection after a year of testing negative.”
In the new proof of principle study, the researchers took a biological approach instead of a chemical one to develop a cocktail of enzymes that attack the cell envelope of mycobacteria.
The cocktail of enzymes contains highly specific biochemical catalysts that target and degrade the mycobacteria cell envelope that is essential for mycobacterial viability.
To increase efficacy, the researchers delivered the enzymatic drug inside of host macrophages where mycobacteria grow. In laboratory experiments, the drug was effective against M. tuberculosis and Nontuberculous Mycobacteria (NTMs), both lethal pulmonary lung diseases (PD). TB kills roughly 1.5 million people per year.
“We characterised the mechanism of bactericide as through shredding of the bacterial cells into fragments,” Holder said.
“We’ve shown we can design and develop biological antibiotics and deliver them to the sites of infection through liposomal encapsulation. By combining drug delivery science with enzymes that lyse bacteria, we hope to open up treatment options in diseases such as NTM pulmonary disease, tuberculosis pulmonary disease and others.”
According to study coauthor Richard Slayden, PhD, a professor in the Department of Microbiology, Immunology and Pathology at Colorado State University, the new therapy complements current standard-of-care drugs and does not have many of the drug-drug interactions that are problematic with many anti-mycobacterial drugs in use. “Endolytix enzymes work powerfully with standard-of-care antibiotics to kill bacteria with lower drug concentrations,” Holder said. “This has the potential to reduce the significant toxicities associated with multi-drug regimens that are the standard for mycobacterial infections and hopefully lead to more rapid cures.”
A massive and long-awaited study of an experimental tuberculosis vaccine has kicked off in South Africa. Marcus Low reports.
Photo by National Cancer Institute
By Marcus Low for Spotlight
The first jabs in a much-anticipated clinical trial of an experimental tuberculosis (TB) vaccine have been administered at a clinical trial site at the University of the Witwatersrand in Johannesburg. Up to 20 000 people are anticipated to take part in the study, according to study sponsor, the Bill and Melinda Gates Medical Research Institute (Gates MRI).
The study will be conducted at 60 different sites in South Africa, Zambia, Malawi, Mozambique, Kenya, Indonesia, and Vietnam. The researchers estimate that between 50% and 60% of the study participants will be in South Africa.
The experimental vaccine called M72/AS01E (M72 for short) made waves in 2018 and 2019 when it was found to be around 50% effective at preventing people with latent TB infection from falling ill with TB over a three-year period in a phase 2b clinical trial. In June 2023, it was announced that, after some delays, $550 million in funding had been secured for a phase 3 study of the vaccine. Medicines or vaccines are typically only registered and brought to market after being shown to be safe and effective in large, phase 3 clinical trials.
While most cases of TB can be cured using a combination of four antibiotics for four or six months, TB rates are declining relatively slowly and it is widely thought that an effective vaccine would help bring TB rates down much more quickly. The World Health Organization estimates that at the level of protection seen in the phase 2b trial, the vaccine could potentially save 8.5 million lives and prevent 76 million people from falling ill with TB over a 25-year period. The one TB vaccine we already have, called bacille Calmette-Guerin (BCG), is over a century old and only provides limited protection against severe illness for children and no protection for adolescents or adults.
“Reaching Phase 3 with an urgently needed TB vaccine candidate is an important moment for South Africans because it demonstrates that there is a strong local and global commitment to fight a disease that remains distressingly common in our communities,” said Dr Lee Fairlie, national principal investigator for the trial in South Africa, in a media statement released by Gates MRI.
“South Africa also has considerable experience with TB- and vaccine-related clinical trials and a strong track record for protecting patient safety and generating high quality data essential for regulatory approvals.”
Fairlie is also the Director of Maternal and Child Health at the Wits Reproductive Health and HIV Institute at Wits University.
The initial response from TB activists was positive.
“TB Proof (a South African TB advocacy group) is delighted that the M72 phase 3 trial has been launched,” the organisation’s Ruvandhi Nathavitharana and Ingrid Schoeman told Spotlight. “Having an effective TB vaccine is critical for TB elimination efforts.”
While he said it is good to finally see the phase 3 trial of M72 get underway, Mike Frick, TB co-director at Treatment Action Group, a New York-based TB advocacy organisation, went on to say:
“The fact that we had to wait so long between phase II and phase III says everything one needs to know about the headwinds – financial, political, commercial – that TB research is up against.”
How the study will work
Half of the up to 20 000 study participants will receive the M72 jab and the other half a placebo. The vaccine is administered as two intramuscular injections given a month apart. After being jabbed, study participants, all aged 15 to 44, will be followed for four years from the date of the first study participant being enrolled to see if they fall ill with TB.
“The plan is to complete enrolment in 2 years,” Fairlie and Alemnew Dagnew, clinical lead for the trial, told Spotlight in response to written questions. They explained that the actual duration of the trial will depend on how long it takes for 110 people in the study to fall ill with TB. According to the Gates MRI statement, the study is expected to take around five years to complete.
According to Fairlie and Dagnew, the majority of study participants (around 18 000 people) will be people who are HIV negative and who have latent TB infection – that is to say people who have TB bacteria in their lungs, but who are not ill with TB. Latent TB infection is thought to be very common in South Africa and only around 10% of people with latent infection ever fall ill with TB. In the study, latent infection will be tested for using a type of test called an IGRA (Interferon-Gamma Release Assay).
Around 1000 HIV negative people with no TB infection will also be recruited to the study. This is being done to make sure the vaccine is safe and effective in this group of people – while latent infection will be tested for in the study, in the real world such testing may not always be feasible prior to vaccination.
It is anticipated that 1000 of the 20 000 study participants will be people living with HIV. Establishing how well the vaccine works in people living with HIV is important since around 13% of people in South Africa are living with HIV and HIV substantially increases the risk of falling ill with TB. The main phase 2b study of M72 did not include people living with HIV although another phase 2 study looked specifically at the safety and immunogenicity of M72 in people living with HIV – according to Fairlie and Dagnew, “that trial “was completed and supported the inclusion of such participants in a phase 3 trial”.
Smaller than previously thought
When funding for the phase 3 trial was announced last year, it was estimated that 26 000 people would participate in the study. That number has now been revised down to 20 000.
“As a result of ongoing discussions between the institute and our funders, the decision was taken to review the study protocol with the intent of simplifying the study given its size and complexity. This will not affect the safety of the trial. It is common to continue to refine a protocol. We found a way to expedite the study that would potentially allow us to offer the public health impact of this vaccine to those in need sooner. All partners, including the trial funders, are fully aligned to the protocol refinements,” Fairlie and Dagnew explained to Spotlight.
“Some assumptions used to inform the design of the first protocol were deemed overly conservative, so the clinical team used slightly less conservative assumptions on vaccine efficacy and TB incidence rate, thus allowing for a reduction in the number of participants in the trial, while still retaining the primary goal of confirming the safety and efficacy of the M72/AS01-E-4 vaccine for prevention of TB, guided by the final results of the phase 2b study completed several years ago.”
Planning for access
The development of M72 has taken a somewhat unusual path – with the pharmaceutical company GSK leading development up to the end of phase 2b and then largely passing the baton to Gates MRI with the conclusion of a licensing deal in 2020. GSK has come in for some criticism for not moving more quickly after the initial publication of the phase 2b results in 2018. A ProPublica article published last year suggested that the development of M72 slowed because GSK were focussing on more profitable vaccines.
According to the Gates MRI statement, GSK continues to provide technical assistance to the Gates MRI, supplies the adjuvant component of the vaccine for the phase 3 trial, and will provide the adjuvant post licensure should the trial be successful. An adjuvant is an agent included in the vaccine that improves the immune response elicited by the vaccine – in the case of M72/AS01E the AS01E refers to the adjuvant made by GSK.
This ongoing dependence on a single company for the adjuvant has some activists worried. “We are concerned about reports that scaling this vaccine may be difficult due to limited availability of the vaccine adjuvant. Access for everyone who needs it should be part of the early phases of the research process – not an afterthought,” said Nathavitharana and Schoeman.
“The press release announcing the study’s start in several places refers to the ‘complexity’ of ‘developing and ensuring access’ to a new vaccine. Part of the unspoken complexity here is the opaque licensing deal GSK and Gates MRI signed in 2020 in which GSK gave rights to develop and commercialise M72 to Gates MRI while retaining control over the AS01E adjuvant,” Frick told Spotlight. “There are legitimate concerns that the fine print of this arrangement could work against equitable access, but terms of the licence remain unknown to the public.”
When asked about supply concerns, Gates MRI told Spotlight: “Gates MRI collaboration with GSK includes provisions to ensure there is sufficient supply of adjuvant for the clinical development and first adoption in low-income countries with high TB burden, at an affordable price, should the vaccine candidate be successful in phase 3 trials and approved for use. For broader implementation, GSK has committed to working with its partners to ensure there is sufficient supply.”
Disclosure: The Gates MRI is a non-profit subsidiary of the Bill and Melinda Gates Foundation. Spotlight receives funding from the Bill and Melinda Gates Foundation. Spotlight is editorially independent and a member of the South African Press Council.
Few realise the extent of the global burden of tuberculosis (TB) or know how many people still succumb to this disease every year. The Centres for Disease Control in the United States estimates that two billion people – a quarter of the world’s population – may be infected with TB, with 10.6 million becoming ill each year. Although TB is preventable and treatable, around 3 500 people lose their lives to it every day, making up an annual mortality rate of 1.3 million people. This means that TB ranks third to only COVID-19 and HIV/Aids as the world’s most deadly infectious disease.
These statistics are alarming and demand immediate attention from all sectors of society. It is crucial to recognise the potential of technology and digital platforms in revolutionising treatment outcomes. By harnessing the power of innovation, we can transform the way in which TB is diagnosed, treated and managed, ultimately saving lives and reducing the burden of this disease.
Equally as sobering is the fact that around 30 percent of people who become ill with TB are missed by healthcare screenings and do not get the care they need, leading to poor outcomes and an increased spread of the disease, especially in remote, rural and underserved communities. People infected with TB do not necessarily become ill but can pass on the bacteria that causes the infection to between ten and fifteen other people through coughing, sneezing or the transfer of saliva. Approximately 10% of those infected go on to develop an active form of disease at some time in their lives.
TB in South Africa
In South Africa, the first-ever National Tuberculosis Prevalence Survey, published in 2018, found that the country is one of 30 countries with the highest prevalence of TB in the world. When adjusted for population size, it is often ranked as the country with the highest prevalence in the word.
The power of digital healthcare has the potential to change this scenario radically. The greatest challenges we face are the low rate of diagnosis and poor access to – and compliance with – treatment. That’s where digital platforms have such a significant role to play.
How digital can make a difference
Digital health platforms have the potential to revolutionise the fight against TB by improving early detection, enhancing treatment adherence and strengthening healthcare delivery systems. Through the integration of mobile applications, telemedicine, artificial intelligence (AI) and big data analytics, we can address the key challenges of TB diagnosis, treatment access and patient support.
Firstly, digital tools enable early detection and diagnosis of TB cases. Advanced imaging techniques, supported by AI algorithms, can swiftly identify TB-related abnormalities in medical images, facilitating prompt intervention and preventing the progression of the disease. Predictive analytics can also forecast TB outbreaks and hotspot areas, enabling healthcare authorities to take proactive measures to contain the spread of the disease.
Secondly, digital health platforms facilitate remote consultations and monitoring, which is particularly beneficial for patients in remote or underserved areas. By providing timely medical intervention and personalised support, these platforms promote treatment adherence and improve patient outcomes.
Thirdly, mobile health applications empower patients to actively participate in their care management. Through features such as medication reminders, digital health checks and access to educational resources, individuals can adhere to treatment protocols better, ultimately contributing to improved health outcomes.
In addition, digital health platforms streamline healthcare delivery by facilitating data interoperability and real-time monitoring of TB trends. Innovative technologies such as TB Check, the free service application of the South African National Department of Health, are revolutionising TB testing as they are being used to determine the risk of contracting TB and to provide guidelines on how to access testing and treatment.
Further, applications such as One Impact, a comprehensive digital health platform, connects individuals with TB support groups, provides access to TB services and enables the reporting of difficulties in accessing care. By leveraging such platforms, national TB programmes can gain valuable insights into the needs and concerns of affected communities, leading to more responsive and effective service delivery.
TB is treatable and curable, especially when patients are diagnosed early, have access to the medication they need and can be carefully monitored throughout their treatment programme.
As we observe World TB Day on 24 March, it is encouraging to know that the integration of digital health platforms provides immense promise in transforming TB outcomes. To realise this potential, collaboration among governments, healthcare providers, technology companies and civil society organisations is essential. By prioritising investment in innovative solutions and leveraging digital technologies, we can accelerate progress towards the elimination of TB and save countless lives. It is time to harness the power of technology to combat TB and create a healthier, TB-free world for all.
