A study in Nature Communications reveals, for the first time, how the transcriptomic profile of human tuberculosis lung lesions is correlated with clinical data from the same patients. The work could potentially lead to improved prognosis by using personalised strategies.
Dr Cristina Vilaplana led researchers from the Experimental Tuberculosis Unit (UTE) at the Germans Trias i Pujol Research Institute (IGTP) and the Germans Trias i Pujol University Hospital.
The study applied RNAseq techniques to 44 fresh tissue samples from lesional and adjacent lung areas of patients with drug-sensitive and multidrug-resistant tuberculosis who underwent therapeutic surgery. The results show a clear separation between lesional and non-lesional tissue, with high expression of pro-inflammatory genes in the lesions.
Weighted gene co-expression network analysis (WGCNA) identified 17 differential transcriptomic modules and revealed a gradient of immune response elements depending on their location within the lesion.
Although lesion transcriptomics has been studied previously, this is the first work to associate these molecular profiles with clinical indicators from the same patients.
“Individuals with more severe forms of the disease present more inflamed lesions, while patients with better clinical outcomes show profiles compatible with tissue repair phases,” explains Dr Vilaplana.
The researchers used two clinical surrogates: a validated respiratory quality of life questionnaire (SGRQ) and sputum culture conversion.
“We confirmed that when a patient says they feel unwell, it is also reflected at the molecular level: their lesions show a stronger inflammatory response,” adds Vilaplana.
Furthermore, patients who take longer to achieve sputum culture conversion, a factor previously linked to worse prognosis, also show higher immune activation at the lesion site.
“These data open the door to personalised strategies: If after two months the patient hasn’t cleared the bacillus, we may need to adapt the treatment to modulate the inflammatory response and avoid a worse clinical outcome,” she concludes.
The international community must protect global responses to HIV, tuberculosis (TB), and malaria to serve humanity’s collective interests, according to an opinion article published May 14, 2025, in the open-access journalPLOS Global Public Health by Gorik Ooms from the Institute of Tropical Medicine, Belgium, and colleagues.
Within days of starting his second term as President, Donald Trump ended most United States (US) contributions to global health. Global responses to HIV, TB and malaria are not the only programs affected but were particularly dependent on US support. The US withdrawal from global health could result in 3 million additional HIV deaths and 10 million additional HIV infections, 107 000 additional malaria deaths and 15 million additional malaria infections, and 2 million additional TB deaths, all in 2025.
HIV, TB and malaria are global health security threats that require international collective action. The Global Fund to fight AIDS, TB and Malaria (Global Fund) entered its replenishment cycle for 2027–2029, with a target of $18 billion. A failure of this replenishment would make it impossible for many countries to compensate for decreasing US funding and decreasing Global Fund support.
The abrupt end of most US funding for global health comes at a crucial moment for the fight against the three epidemics. For HIV, funding cuts are disrupting treatment and prevention, and increasing morbidity, mortality and infections especially among marginalised groups. The transmission of TB remains high due to insufficient access to treatment, urbanisation and undernutrition. Control of malaria remains elusive due to emerging resistance to treatments, and insecticides, gaps in prevention, and limited access to healthcare.
According to the authors, the reduction of US bilateral aid calls for re-prioritisation and enhanced coordination of the global fights against HIV, TB and malaria. Currently, the Global Fund is uniquely positioned to undertake this endeavour, as it financially supports HIV, TB and malaria programs in most, if not all, countries affected by US spending cuts. This requires a successful replenishment, which seems improbable given uncertainty about the US position and considering the aid spending cuts announced by other high-income countries. Low- and middle-income countries need to step in, which necessitates an overhaul of the Global Fund governance.
The authors outline four action points. First, all countries, regardless of income level, should support the current replenishment of the Global Fund. Second, the replenishment mechanism should move toward agreed and fair assessed contributions, such as 0.01% of the annual gross domestic product of all countries. Third, the Global Fund should commit to overhauling its governance structures to promote equal representation among geographical constituencies. Fourth, the Global Fund should commit to adhere to the Lusaka Agenda, which captures consensus around five key shifts for the long-term evolution of global health initiatives and the wider health ecosystem.
As noted by the authors, these four actions would save essential elements of the global responses to HIV, TB and malaria and set a central and collaborative mechanism for global health security on a path toward the principles of global public investment.
Dr Gorik Ooms adds: “Richer countries still view global health cooperation primarily as aid, from them to poorer countries. They do not seem to realise how this cooperation also protects their own interests. We must not only find enough funding to sustain it; but also rethink how we work together. Through genuine international cooperation between equal partners.”
Co-author Dr Raffaella Ravinetto concludes: “It is not only a matter of keeping life-saving programs alive. It is also a matter of building and maintaining a solid ecosystem, encompassing health infrastructure, policies and human resources, to make quality health care feasible everywhere. Through solidarity we can serve common interests.”
Image Caption: A person holds medications. Limited access to diagnostics and medicines will worsen treatment quality, inducing resistance to antiretrovirals and medicines for infections.
For centuries, it was believed that tuberculosis spread primarily when a vulnerable person spends hours in a poorly ventilated space with someone infectious. But new findings suggest that much TB transmission also occurs through casual contact.
Conventional thinking held that enclosed spaces such as households, prisons, and shelters, where people spent long periods of time together, were where most TB transmission took place. But new data suggest that casual contact at social settings like shopping malls, restaurants, bars, and places of worship also account for much TB transmission.
A recent study found that close contact explained only 9% of TB transmission links, while casual contact accounted for 49%. The study, called CONTEXT (Casual Contact and Migration in XDR TB), was conducted in KwaZulu-Natal.
The study’s lead author, Professor Neel Gandhi of Emory University in Atlanta, recently presented the findings at the Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco. The work has not yet been published in a peer-reviewed medical journal.
The new findings come in the context of other research (much of which was conducted in Cape Town) that suggest TB could be transmitted through breathing, and growing evidence that people with asymptomatic TB can transmit the infection.
Where transmission occurs
Gandhi tells Spotlight that TB transmission has traditionally been linked to prolonged, close contact, with previous studies showing that 9 to 30% of cases could be attributed to this type of contact. A compelling alternative argument, he says, is that the remaining 70% of transmission occurs due to casual contact in community settings – which is what their research sought to explore.
He elaborates: “For much of history, we have thought that most TB transmission occurs through close and prolonged contact, meaning that a susceptible person is spending a lot of time in a poorly ventilated area with somebody who is infectious. And so most often we think of households as places where transmission occurs; or congregate settings, places like prisons or homeless shelters.”
On defining casual contact, he says: “In our research, we wanted to understand less intense forms of contact where transmission can occur. So, we understood where people lived, but we also asked them where they spent time in a typical week. The phrase we used was: ‘where do you spend two hours or more, most weeks?’ To try to identify the places people spend substantial amounts of time; and seeing whether they crossed paths with somebody else to whom their molecular fingerprints (of their TB bacteria infection) match.”
Genotyping, and geomapping
In their study, Gandhi and his colleagues made use of both genotyping and geospatial mapping to figure out where TB transmission likely occurred.
Genotyping, explains Gandhi, is a technology developed about 30 years ago that allows us to examine the genetic code of TB bacteria, and to compare similarity between patients’ bacteria.
“TB is a bacteria that keeps its genetic code similar across many generations of replication. In layman’s terms, we call this molecular fingerprinting. If I were to transmit TB to somebody else; my TB bacteria and that person’s TB bacteria’s genetic codes would look very similar – almost identical – so we could use this fingerprinting technique by sequencing the genomes of the two TB bacteria to try to fully get a sense of what the likelihood of transmission was.”
Commenting on their geospatial methodology, he says: “When our participants told us where they live or where they spend time in the community, or where they get outpatient healthcare; our team went to those sites and captured a GPS coordinates.
“Just like we use GPS for mapping when we’re trying to get around town, we would get specific coordinates… If two people went to the same shop, they might have used different names for that shop, or let’s say they went to a shopping mall, they may have used different names for those places; but we used GPS coordinates allowing us to determine whether they were at the same place or close to one another. And we used the concept of proximity to try to understand the likelihood that they may have crossed paths.”
In the study they used the metric of “community proximity” defined as a radius of 500 metres, or less.
Gandhi illustrates the nuance of geomapping, using his university campus: “So the example I like to give is; I work in a building called the School of Public Health. Across the courtyard is the School of Nursing. If you just asked me, where do you work? I would tell you, I work in this building. If you ask the next person where they work, they may say, I work in the School of Nursing. That wouldn’t match up in terms of place name. But if we used a radius of 100 metres or 500 metres, we can determine that we work very close to one another. And there’s a cafe in yet another building that we may have eaten lunch in at the same time. TB being an airborne disease, I don’t have to sit next to that person or even to know that person; if I’m infectious, I could have transmitted to them if they were sitting and eating in the same room.”
Essentially, the researchers used genotyping, particularly molecular fingerprinting to help understand the likelihood of transmission between people who have drug resistant TB. And once individuals with similar molecular fingerprints were found, they used geomapping to see whether these patients could be connected through close contact – and if not close contact, then through casual contact.
He adds: “The most common place people told us were friends and family members’ homes. Then the next most common was places of shopping so shopping malls.”
At CROI, Gandhi responded to a question from a conference delegate around risk, saying that there appears to be a greater risk of TB transmission in social settings than previously understood.
Symptoms and disease
To Spotlight, he says more work is needed to understand why casual contact transmission is happening. “And it connects to another topic in the TB community that is gaining a lot of attention currently, which is trying to understand what the association is between symptoms and having TB disease,” says Gandhi.
He notes that the challenge for researchers moving forward is understanding the link between infectiousness and symptoms – specifically, understanding when a person becomes infectious, even if they show no symptoms.
Most TB public health interventions are still based on the assumption that people with TB will present at health facilities with classic TB symptoms such as persistent cough, night sweats, fever, weight loss, and chest pain. South Africa has however in recent years been offering TB tests to asymptomatic people thought to be at high risk of TB, as part of its targeted universal testing strategy.
“So you may have heard of this concept of what some people have called subclinical TB or asymptomatic TB. And that is to say, if you were to test a group of people who didn’t come to a health clinic, but let’s say you were on a street corner and you tested everybody who went by for TB, we’re coming to appreciate that as many as 50% of people may not either have any symptoms or may not have symptoms that are worrisome enough for them to seek healthcare, but are actually testing positive for TB disease,” Gandhi adds.
Gandhi says this reminds him of the early days of COVID-19, when scientists weren’t sure if people only became infectious after showing symptoms.
“Eventually we learned that people were infectious probably for a few days before they developed symptoms. And in the TB world, this may be an area we need to investigate. If there’s the possibility that somebody is infectious when they have absolutely no symptoms, they would go about their regular activities; going to work, going to school, going shopping, going to religious ceremonies, going to restaurants, and they may unknowingly be infectious with TB. So this is the challenge.”
The bigger picture
Commenting on the findings, Robert Wilkinson, Honorary Professor in the Department of Medicine at the University of Cape Town and director of the Centre for Infectious Diseases Research in Africa, says: “It is interesting, and the proportion of transmission estimated to occur outside the household is a low estimate, but not incompatible with other estimates.”
He notes that the phenomenon of transmission occurring after brief casual contact is not novel though, and has been investigated in previous studies.
Asked how the findings presented by Gandhi might affect the outlook on TB interventions, Wilkinson says: “Whilst close household exposure to infectious tuberculosis should prompt clinical evaluation especially if there are symptoms, finding a close contact by conventional contact tracing approaches is far from invariable. Therefore, in high incidence environments like South Africa more attention needs to be placed on mass radiographic (X-ray) and, or microbiological screening of asymptomatic persons.”
In a recent public lecture called ‘Hunting Bosons, Finding the Bummock’, Emeritus Professor in Medicine at the University of Cape Town, Robin Wood, former CEO of the Desmond Tutu Health Foundation, states: “I think we are changing the paradigm of tuberculosis.” He notes that research now targets “hidden reservoirs of TB transmission beyond visible, symptomatic cases… [as] TB silently spreads within communities through carriers who exhibit no symptoms yet contribute to transmission.” Asked about Gandhi’s findings, Wood told Spotlight he would reserve comment until the data is submitted for further peer review and publication.
Study details
The 305 respondents in the CONTEXT study were patients with extensively drug-resistant TB or pre-extensively drug-resistant TB. They were diagnosed between 2019 and 2022 in the eThekwini, Ilembe, Umgungundlovu, and Ugu regions. The average age was 36 years, with 137 (45%) women and 216 (73%) people living with HIV.
The study was conducted in collaboration with the Durban-based Centre for the AIDS Programme of Research in South Africa (CAPRISA).
“CAPRISA played a leadership role in conceptualising the science, development of the protocol and data collection instruments, oversight of all aspects of field work, including screening and enrolling patients, obtaining informed consent from patients or their proxy’s, field and laboratory data collection, data verification and data clean-up activities for all data used in this study,” says CAPRISA’s deputy director, Professor Kogieleum Naidoo.
CONTEXT was funded through the United States National Institutes of Health (NIH), the world’s largest health research funder which has in recent weeks terminated several grants in South Africa and elsewhere. “The funding period has ended,” says Gandhi. “Now we’re analysing all of the data, so it won’t be impacted by any changes happening at NIH.”
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
By Catherine Tomlinson
Both TB treatment and TB preventive therapy involve taking lots of pills, usually for several months. Researchers are working on new long-acting formulations that might, for example, reduce an entire course of TB preventive therapy to a single injection.
The biggest HIV news of last year was that an injection containing an antiretroviral called lenacapavir provides six months of protection against HIV infection per shot. While it will be several years before the jabs become widely available, experts nevertheless hailed the development as a potential game-changer. In some countries, HIV treatment is already available as injections – containing the antiretrovirals cabotegravir and rilpivirine – administered every two months.
Scientists working on tuberculosis (TB) are trying to replicate the successes of the HIV field and develop similarly long-acting formulations of TB medicines. The good news is that they have several exciting products under development – the bad news is that the research is still at a very early stage and the pivotal studies that will tell us if these products work are likely still years away.
But if they work, they could make a big difference to patients. That is because TB treatment and TB preventive therapy mostly still requires swallowing lots of pills over a long period of time. There is some good evidence that many people would prefer long-acting injections.
The case for long-acting TB medicines
TB preventive therapy is used to stop someone suspected of having latent TB infection from falling ill with TB. In South Africa, such preventive therapy is recommended for all close contacts of someone sick with TB. Typically, it involves taking tablets for three or six months (a one-month course has been shown to work, but is not widely available). There is research that shows that the shorter the regimen the more likely it is to be completed.
The hope is that a long-acting product might do away with swallowing tablets altogether and reduce an entire course of preventive therapy to a single injection. This is likely to be more convenient for patients as well as come with the benefit of perfect treatment completion rates.
TB preventive therapy is a simpler target for long-acting formulations than TB treatment since it typically involves only one or two drugs and treatment durations are shorter. TB treatment typically takes six or more months to complete and usually involves taking four different drugs – often four for two months and then only two for the remaining four months in what is called the continuation phase. Some of the current thinking is that the continuation phase could potentially be replaced by long-acting formulations of TB medicines. This could shorten the duration of TB treatment to just two months of taking tablets.
Not an easy nut to crack
As explained by Dr Eric Nuermberger of Johns Hopkins University, not all TB medicines available as tablets make good candidates for translation to long-acting injectable formulations. He was presenting on long-acting TB drugs at the Conference for Retroviruses and Opportunistic Infections (CROI), recently held in San Francisco.
Nuermberger outlined three key characteristics that are needed for long-acting formulations. These are low water solubility (so the drug doesn’t dissolve to quickly), low clearance in plasma (so that the body doesn’t clear the drug too quickly), and high drug potency (so that a small volume of drug can be effective for a long period of time).
One key challenge, according to Nuermberger, is that scientists do not yet have reliable biomarkers to measure the effectiveness of long-acting TB preventive therapy in phase II trials. Biomarkers, such as blood levels of certain proteins, could in theory offer scientists a faster way to assess if TB preventative therapy is working, without having to monitor clinical trial participants for long periods of time to determine treatment outcomes.
Writing in the journal Clinical Infectious Diseases, scientists working to develop long-acting TB products explained: “The inability to culture or otherwise quantify viable bacteria during latent TB infection and the lack of validated surrogate biomarkers mean that there is no opportunity to obtain initial proof of efficacy… which is usually the domain of phase 2 trials. Instead, the development of new TPT regimens requires bridging directly from preclinical studies and phase 1 trials to phase 3 trials, which are themselves long and require large numbers of participants.”
However, they added that “[t]he search for biomarkers that act as prospective signatures of risk for developing TB disease is a very active research area and an important scientific priority for the field”.
Back at CROI, Nuermberger also told participants that most products in the pipeline remain at pre-clinical stages and are still being tested in mice. He explained that differences in how depot drugs — drugs released slowly over time — work in mice and humans make it hard to apply findings from mice to humans. But modeling is being done to help bridge this gap.
‘Expanded remarkably’
Despite these challenges, Nuermberger said “the number of long-acting drug formulations in development [for TB] has really expanded remarkably in the last few years, which is a very promising development”.
The product that is furthest along in the development pipeline, but still at a very early stage of research, is a long-acting form of bedaquiline. This drug is currently used for the treatment of drug-resistant forms of TB and falls in a class of antibiotics known as diarylquinolines.
The Belgian pharmaceutical company Janssen is currently running a phase I trial of long-acting injectable bedaquiline in Austria. Phase I trials are conducted in a small group of healthy individuals to assess the safety and tolerability of an experimental medicine. In the phase 1 bedaquiline trial, researchers are investigating the safety and tolerability of different doses of long-acting injectable bedaquiline.
Several other long-acting TB medicines are being investigated in preclinical research, including long-acting versions of the TB medicines rifabutin and rifapentine, as well as the second generation diarylquinolines, TBJ-876 and TBA-587, which are under development by the TB Alliance. The second generation diarylquinolines are being tested on their own and in combination with pretomanid and telacebec.
In addition, the University of Liverpool, Johns Hopkins University, University of Southern Denmark, University of North Carolina and the US pharmaceutical company Inflamamasome Therapeutics, are all involved in pre-clinical research on long-acting formulations. These efforts are supported financially by Unitaid, the US National Institutes of Health, and the Gates Foundation.
The treatments being developed include aqueous nanoparticle suspensions, in-situ forming implants, and rod implants. Aqueous nanoparticle suspensions are drugs turned into tiny particles and delivered in a water-based solution via injection. In-situ forming implants are injected as a liquid that then solidifies into an implant under the skin. Rod implants are small, rod-shaped devices inserted under the skin with a needle-like tool after numbing the area with a local anaesthetic.
What users prefer
At CROI, delegates also learned about patient and provider preferences for long-acting TB treatment.
Dr Marcia Vermeulen from the University of Cape Town presented the results of a survey involving over 400 patients in South Africa and India, as well as 94 healthcare providers.
Seventy-five percent of healthcare workers said they would prescribe a long-acting injectable product rather than pills for tuberculosis preventative therapy if it was priced the same or lower. Similarly, 75% of patients said they would try an injectable product for TB prevention if it became available.
“As a TB survivor, I am excited about long-acting TB treatment as it doesn’t require frequent facility visits, saving a person’s time and money, and can thereby increase adherence and improve treatment outcomes,” TB Proof’s Phumeza Tisile told Spotlight.
She added that communities should be at the heart of rollout plans because they understand the needs of people affected by TB and know how to communicate effectively to encourage involvement and adoption.
Disclosure: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
An international clinical trial has found three new safe and effective drug regimens for tuberculosis that is resistant to rifampin, the most effective of the first-line antibiotics used to treat TB. The research, published in the New England Journal of Medicine, was led by researchers at Harvard Medical School and other members of the endTB project.
The newly identified regimens take advantage of recently discovered drugs to expand the treatment arsenal and give physicians new ways to shorten and personalise treatment, minimise side effects, and treat patients using only pills instead of daily injections. They also offer alternatives in case of drug intolerance, medication shortages or unavailability, or drug resistance, the researchers said.
The endTB trial is one of four recent efforts to use randomised controlled trials to test new, shorter, less toxic regimens for drug-resistant TB. endTB uses two new drugs – bedaquiline and delamanid — which, when brought to market in 2012-2013, were the first new TB medicines developed in nearly 50 years.
To find shorter, injection-free drug combinations for people infected with TB resistant to rifampin, endTB tested five new, all-oral 9-month regimens using the two new drugs in combination with older medications.
A third drug, pretomanid, received emergency authorisation from the FDA for specific use within a regimen against highly drug-resistant TB in 2019, after the endTB clinical trial was underway, and is not included in the regimens used in these trials.
Trial regimens were considered effective if they performed at least as well as the control group, which received a well-performing standard of care composed in accordance with a stringent interpretation of World Health Organization (WHO) recommendations.
The three successful new regimens were successful for between 85 and 90% of patients, compared with 81% success for people in the control group. The control group was treated with longer treatments, which also included the recently discovered medicines.
The trial launched in 2017 and enrolled 754 patients across seven countries: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa. The goal was to improve treatment for patients with tuberculosis resistant to rifampin. The WHO estimates that some 410 000 people become sick with rifampin-resistant TB each year, including people who have multidrug-resistant TB (MDR-TB). Only 40% are diagnosed and treated, 65%of them successfully.
The study population included children as well as people infected with HIV or hepatitis C, both common in populations with high rates of TB. In another innovation, women who became pregnant while on treatment were included in the endTB trial. These groups are often excluded from clinical trials. In a special report published in August 2024, the WHO added the three noninferior regimens from the endTB trial to the list of treatment options for rifampin-resistant and multidrug-resistant TB (MDR-TB) treatment; the recommendations extend to these neglected groups as well as to pregnant women.
With recent efforts to end patent exclusivity on bedaquiline, two of the endTB regimens and the WHO-recommended pretomanid-containing regimen can all be purchased for less than $500, an access target set by activists more than 10 years ago, which has only just now been achieved. All of these innovations together mean the new shortened, all-oral regimens are available to more people than ever.
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
Multidrug-resistant tuberculosis (MDR-TB) poses a particular threat to global health. A study led by the Swiss Tropical and Public Health Institute (Swiss TPH) shows that resistance to the new MDR-TB treatment regimen recently recommended by the World Health Organization is already spreading between patients. The findings, published in NEJM, highlight the urgent need for better surveillance and infection control to counteract the rise in antimicrobial resistance.
The traditional treatment regimen for MDR-TB is lengthy, expensive, and comes with severe adverse event. In 2022, the World Health Organization (WHO) endorsed a new 6-month regimen, the BPaL(M), based on evidence of its improved safety and efficacy from numerous clinical studies, including TB-PRACTECAL.
Monitoring the implementation of a new treatment regimen
“While this new regimen is a game changer for patients suffering from MDR-TB, we knew that it will be difficult to outsmart Mycobacterium tuberculosis, the bacteria causing TB,” said Sébastien Gagneux, Head of the Department Medical Parasitology and Infection Biology at Swiss TPH and senior author of the study. “It was therefore crucial to study how the TB bacteria would react to the global roll-out of this new regimen.”
This new study led by Swiss TPH in collaboration with the National Centre for Tuberculosis and Lung Diseases in Tbilisi, Georgia, now examined in detail whether resistance to the drugs in the new regimen has already emerged since its introduction, and whether this resistance is transmitting between patients.
Over a quarter of resistant strains result from transmission between patients
The researchers analysed the genomes of close to 90 000 M. tuberculosis strains from Georgia and many other countries around the world. They identified a total of 514 strains that were resistant to TB drugs, including both the old and the new treatment regimens. These highly drug-resistant strains were found in 27 countries across four continents.
Alarmingly, 28% of these strains were transmitted directly from one patient to another. “We already had anecdotal evidence of resistance emerging to the new regimen, but we did not know to what extent transmission was responsible for the spread of these highly drug-resistant strains,” said Galo A. Goig, postdoctoral collaborator at Swiss TPH and first author of the study.
“The good news is that the total number of these cases is still low. However, the fact that more than a quarter of these highly drug-resistant cases are due to patient-to-patient transmission, only two years after WHO endorsed the new regimen, is worrying,” added Goig.
Call for better surveillance and infection control
These findings have important implications for public health policy and interventions. “These new drugs have taken many years to develop, and to prevent drug resistance from emerging, it is essential to combine the deployment of these new regimens with robust diagnostics and surveillance systems,” said Chloé Loiseau, postdoctoral collaborator at Swiss TPH and co-author of the paper.
The authors emphasise the need for improved diagnostic tools, better infection control and robust surveillance systems to curb the spread of these highly drug-resistant strains, and to safeguard the efficacy of the new treatment regimen.
Tackling antimicrobial resistance
While there are already new TB drugs in the pipeline, experts worry that M. tuberculosis will continue to find ways to evade new drugs. “The example of these highly drug-resistant TB strains further illustrates that antimicrobial resistance is one of the most critical threats to global health today,” said Gagneux. “We must stay ahead in this constant race between drug development and bacterial resistance, and take proactive steps to prevent a ‘post-antibiotic era’ for TB and other diseases.”
Though several South African companies are producing HIV and TB medicines, the active ingredients that go into these medicines are usually imported from India or China. Now, a local company is planning to break new ground by making the active ingredients for two important TB medicines in Pretoria. We zoom in on the company’s efforts and outline some of the obstacles to getting such local production off the ground.
South Africa has a relatively robust pharmaceutical sector. Approximately 60% of the medicines sold in South Africa are locally produced, according to Dr Senelisiwe Ntsele, writing in an opinion piece for the Department of Trade, Industry and Competition (dtic).
But most of the time we are not producing these medicines from scratch. In fact, like most countries in the world, we mostly import the ingredients that make the medicines work – commonly referred to as active pharmaceutical ingredients, or APIs. In addition to APIs, medicines contain other inactive substances that maintain their form and structure and assist in their delivery: such as binders, stabilisers, and disintegrants.
Around 98% of the APIs used in locally formulated medicines are imported and South Africa spends around R15 billion a year importing APIs, according to Ntsele.
Government has tried to address South Africa’s dependence on imported APIs as part of its broader strategy to bolster the local pharmaceutical industry, which is identified as a priority sector for investment in the country’s Industrial Policy Action Plan. Several government departments provide support to the local pharmaceutical sector, including for local establishment of API manufacturing capacity. These departments include the dtic, the Department of Science and Innovation (DSI), the Technology Innovation Agency (TIA), and the Industrial Development Corporation (IDC) – South Africa’s development finance instrument.
In a bid to reduce the country’s reliance on imported APIs, Ketlaphela – a state-owned API manufacturing company – was announced in 2012. The plan was that Ketlaphela would produce APIs used in HIV medicines, but after multiple setbacks the initiative never got off the ground. Spotlight reported on the history of Ketlaphela in more detail here.
Turning to the private sector
Less well known than Ketlaphela, are government’s efforts to support API manufacturing capacity in the private sector. One private company that has received such government support and seem set to start delivering is Pretoria-based Chemical Process Technologies Pharma (CPT Pharma) that was established in 2014.
CPT Pharma is a subsidiary of Chemical Process Technologies, a company with many years of experience in chemical manufacturing and synthesis, including manufacturing of APIs for animal medicines. Human medicines, CPT Pharma’s core business, have stricter production management and quality control standards than those for animal medicines.
Dr Hannes Malan, Managing Director of CPT Pharma, told Spotlight that the company has 14 APIs in its pipeline, with a strong focus on TB medicines.
CCPT Pharma is a subsidiary of Chemical Process Technologies. (Photo: Supplied)
In 2023, the company secured a license from USAID to produce API for rifapentine, a drug widely used for TB prevention, and in 2022 they secured a licence from the Medicines Patent Pool to produce API for molnupiravir, a treatment for COVID-19. Malan pointed out that these two licenses were agreed with organisations aiming to expand the presence of API manufacturers in Africa – unlike typical arrangements driven by pharmaceutical companies looking to secure their own supply chains.
“For all the other APIs that we’re working on [beyond molnupiravir and rifapentine], we’re either working on technical packs [technical information about the API] that were available in the public domain or technologies that we’ve developed ourselves,” said Malan.
“Our approach has always been to look at the molecules, look at the market value, look at the technology, and then see if there’s an opportunity for us to develop technology that allows us to produce these compounds cost competitively,” he said.
“We really believe that to be competitive and independent, you have to have your own technology. Doing a technology transfer from Big Pharma does not make you independent,” Malan added.
How to fund it all?
In 2017, the company completed a pilot plant for making APIs. Then in 2020 it received approval from the South African Health Products Regulatory Authority (SAHPRA) to produce APIs for human use. The plant was built for R50 million, funded jointly by the IDC, TIA, and CPT Pharma.
Malan said that that the IDC and TIA also supported trial runs to test CPT Pharma’s manufacturing processes and technology. These tests included several APIs in development, such as isoniazid, a drug commonly used to prevent and treat TB.
The company has also secured funding from several international donors. The Gates Foundation provided support to develop manufacturing technology for the anti-malarial drug amodiaquine, as well as tuberculosis medicines bedaquiline and pretomanid. GIZ, a German development agency involved in a European Union project to boost vaccine and health product production in Africa, supported the company’s work on molnupiravir and dolutegravir – a widely used HIV medicine. USAID and the DSI are supporting the company’s work on developing rifapentine API manufacturing capacity.
Most of this financial support has been in the form of grants.
Still building new plants
While CPT Pharma has secured local and international funding to help construct a pilot plant and to develop its API manufacturing technology and processes, Malan said more investment is needed to support the construction of two commercial-scale manufacturing facilities: an isoniazid API manufacturing plant and a multiple API manufacturing facility.
Construction of the isoniazid manufacturing plant has already commenced using existing land and infrastructure with support from the IDC, but it is short of around R20 million to complete it, said Malan.
Although the plant is not yet operational, he said a company has already expressed interest in buying CPT Pharma’s locally produced isoniazid API. This company, said Malan, is contracted to supply isoniazid to government. The plan is to initially supply the company with isoniazid API produced at its pilot plant
Malan said the commercial plant, when built, will be able to manufacture enough isoniazid API to supply around 60% of local demand.
Things are less far down the road with plans for a plant to produce multiple different APIs at commercial scale, and more work is needed to understand the financing requirements for this type of facility, said Malan. “We want to do a bankable study and a concept design for such a plant,” he said. Based on CPT Pharma’s own experience, published data, and the required complexity and capacity of the plant, Malan said it is estimated that construction for the multi-API plant will cost around US$100 million or R1.8 billion.
Plans to commercialise
Meanwhile, the company is moving forward with plans to commercialise isoniazid and rifapentine API from its pilot plant. Isoniazid and rifapentine is increasingly used together as TB preventive therapy.
“For rifapentine, our pilot plant is seen as the commercial plant,” said Malan. “At this stage, we can use the pilot facility and the pilot reactor to produce enough rifapentine to get into the market and to grow the market.” But in the long term he said the company hopes to transfer rifapentine manufacturing to a larger commercial plant.
The company is also planning to apply for World Health Organization (WHO) pre-qualification status for its rifapetine API. The goal is to conduct demonstration runs in the pilot plant by June 2025 and validate the WHO pre-qualification application in September 2025.
If achieved, WHO pre-qualification of CPT Pharma’s rifapetine API would show that the company’s APIs meet high-quality standards. It would also allow CPT Pharma to supply rifapentine API to companies producing medicines for the broader African market, for which a significant proportion of medicines are procured by donors requiring WHO PQ approval.
Note: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation. Spotlight is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
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.
