TB's tight grip: Why this curable disease is so hard to treat

Daily Maverick

2 days ago

TB can be cured, but ridding the body of the bug often takes many months and usually requires taking four or more medicines. In this special briefing, Spotlight zooms in on what makes the TB bacterium so hard to beat.
There are many things we've learned from studying the ancient Egyptians. One especially fascinating discovery was evidence of skeletal deformities in mummies, which serve as silent markers of a tenacious bug still stalking us today: tuberculosis (TB).
With about 10.8 million people around the world getting sick with TB in 2023, it remains the leading infectious disease on the planet, according to the World Health Organization (WHO). In just South Africa, it claims more than 50,000 lives a year.
In this Spotlight special briefing, we take a closer look at the bacterium that causes TB and why, even now in an era where TB is curable, beating it still requires months of treatment with multiple medicines.
Adapted for survival
The mystery of TB's staying power starts with the bug itself. As explained by Dr Jennifer Furin, Mycobacterium tuberculosis is well adapted to survive on multiple fronts. Furin is an infectious diseases clinician and medical anthropologist who specialises in TB.
First, she explains, there is its size. TB is spread through the air when someone who has the bacterium in their lungs coughs it up. It's then contained in small amounts of fluid called droplet nuclei. This droplet is precisely the right size to hang in the air, allowing TB to survive for hours and even days. These droplets can then be inhaled by other people and are just the right size to travel to their lungs.
'It is really amazing from an evolutionary point of view and would be absolutely fascinating if it did not lead to such a horrible disease,' says Furin.
Secondly, the bacteria themselves are well adapted to avoid being killed, sporting a thick, slimy coating called mycolic acid. This coating makes it difficult for drugs or immune system cells to get into the organism to kill it.
The bacteria also have some clever ways of getting around the human immune system, which allows them to 'persist in the body for years and years'. Furin says one way it's able to stay in the body for so long is the bacterium's ability to go into a 'metabolically quiet state' when the immune system starts coming after it. In this state, it stops multiplying until the pressure from the immune system quiets down.
It is this combination of being able to pass from person to person and lay dormant in the body when challenged by the immune system that enables TB to thrive in humans.
How the body fights back
Though hard to estimate with great accuracy, it is thought that only in the region of one in 10 people who inhale the TB bacterium and become infected actually fall ill with TB disease. In fact, some people's immune response is so good that even though they've been exposed to TB, there's no evidence that it was ever able to establish an infection in the lungs. For everyone else exposed to TB, one of two things happens. Either the body mounts an immune response that contains and may eventually kill the bug, or the bacteria get past the immune system and cause illness.
To make people ill, the bug needs to get past the first line of defence and get a foothold in the lungs. Unfortunately, the antibodies relied on to kill other bacteria or viruses don't work against TB. Instead, Furin explains, special pulmonary macrophages recognise TB as a threat and 'gobbles it inside them'. Macrophages work by 'swallowing' bugs and then neutralising them by 'digesting' them.
But the bacterium's thick, slimy mycolic acid layer prevents the macrophages from killing it. The macrophages with the TB inside, along with other essential immune system cells called CD4 and CD8 cells, then signal more macrophages to help out. These cells then work together to build a wall around the bacteria to keep it contained.
Furin compares the CD4 and CD8 cells to foremen who oversee the building of a wall called a granuloma, while the macrophages are like the bricks and cement that form the actual structure. This wall around the TB bacteria needs to be constantly maintained by the immune system.
If the immune system is weakened, Furin says the walls break down and the bacterium escapes, coming out of its dormant state and starts multiplying again. If this happens, TB could spread beyond the lungs to other parts of the body.
If the walls are built right and maintained, then eventually the bacterium is starved to death. Yet, this process can take a long time, sometimes years, because of the bacterium's ability to go dormant.
'Double-edged sword'
The 'interaction between TB and the immune system is a double-edged sword', says Professor Graeme Meintjes, an infectious diseases specialist with a research interest in HIV and TB at the University of Cape Town.
'The immune system is trying to contain and kill TB. But at the same time, TB is using the immune system to perpetuate infection from one person to the other,' he says.
Meintjes explains that TB has evolved alongside people and developed special proteins and molecules that cause the immune system to react to it. It needs this reaction to cause damage in the lungs, leading to its being released during coughing or even breathing, which helps spread it to other people.
'The TB excites the immune response that causes damage [to the lungs] and that allows it to be released into the airway and either coughed or breathed out. So, there's some evidence that TB has evolved to elicit the immune response in order to achieve that,' he says.
Adding to this, for some people cured of TB, Furin says that a condition known as post-TB lung disease can in part be caused by the granulomas grouping together, which causes cavities to form in the lungs. This can lead to scarring and sometimes surgery is required to remove these areas of destroyed lung tissue.
The immune system can also start 'over-functioning' if it senses the bacterium has escaped from the granulomas and is spreading. This causes the immune system to send out special chemicals called cytokines that can cause indiscriminate killing of the lung cells around it. She says this is like the immune system going after one target with the intention to kill it, but then blowing up the whole neighbourhood.
TB works differently in different people
The complex interplay between the immune system and TB makes it difficult to predict which individuals will become sick with TB and who won't, although there are some clear trends. Meintjes says factors like malnutrition, poverty, overcrowded living or working conditions and multiple exposures to TB are some of the biggest drivers of infection and disease. Factors like genetics, the amount of TB someone is exposed to, or a person's initial immune response are also thought to play a role.
'But still, in a given setting where you have two people living in a household, one of them might go on to develop TB disease with the same exposure and the other not. And there are factors that are not fully explained about why some people will develop TB and others won't,' he says.
Probably the most important risk factor for TB in South Africa over the past three decades has been untreated HIV. Because HIV targets specifically CD4 cells, it was the worst thing that could have happened in a world with TB, Furin says. HIV infiltrates and kills a person's CD4 cells, which means the immune system then has fewer of the cells ready to fight TB.
In 2024, over half (58%) of all adults receiving TB treatment in South Africa were also living with HIV, according to estimates from Thembisa, the leading mathematical model of HIV and TB in the country.
Another group that is at high risk of TB disease is children, particularly those younger than two. The good news is that there is a vaccine that reduces this risk. As Furin explains, the BCG (bacillus Calmette-Guérin) vaccine works by showing the CD4 and CD8 cells how to build the 'protective wall' against TB, because the immune systems of children are still too 'immature' to know how to do it without help.
'It [the BCG vaccine] only works for a little bit of time, but it works great to protect kids against those very severe forms of disease, while their own immune systems are learning [how to fight TB],' says Furin.
Because the vaccine protects children only for a short time, the WHO recommends that one dose be given at birth for children in countries with a high TB burden. Despite many research efforts to find another vaccine, and a promising candidate being studied in a phase 3 trial, BCG remains the only TB vaccine in use for now.
A brief history of TB treatment
Though TB has been making humans sick for many centuries, the bug that causes the illness was identified only in 1882, by the German physician and microbiologist Robert Koch. It would be roughly another 60 years before the first effective treatments would become available. Until the 1940s, TB treatment mainly involved staying in a sanatorium.
The first drugs to treat TB with any success were the antibiotics streptomycin and para-aminosalicylic acid. These two drugs had significant side effects, and using only two drugs often led to TB becoming resistant to the treatment. As described in this excellent overview, what followed was a 'great flurry of drug discovery research' that lasted from the 1940s to the 1960s. The four drugs used to treat most cases of TB today – isoniazid, rifampicin, pyrazinamide, and ethambutol – were all first used to treat TB in this period.
After the 1960s, there was a lull in investment in TB research for several decades, probably because TB rates in wealthy countries had declined, and what cases there were could generally be cured with the new treatments.
'The Global North was very much of the perspective that it's [TB] a disease that's waning and 'it's no longer our problem',' Meintjes says. 'It was seen as a disease of poverty; a disease of other countries, and money was put into diseases that are common in the Global North.'
This all changed around the turn of the century with the HIV epidemic and a resurgence of TB, particularly drug-resistant TB (DR-TB) in Europe and North America, says Meintjes. By definition, DR-TB means that some of the standard drugs used to treat TB no longer work.
The renewed interest in TB resulted in a new flurry of TB drug discovery. Maybe most notably, in the 2010s, a drug called bedaquiline replaced older DR-TB drugs that were associated with hearing loss. A slightly older antibiotic called linezolid also became a cornerstone of DR-TB treatment.
Today, in South Africa, 'normal' drug-susceptible TB (DS-TB) in adults is treated with a six-month treatment course – consisting of four drugs for two months and then two drugs for the next four months. A four-month treatment course has been shown to work in a clinical trial, but is not yet routinely provided in the country. Kids are typically treated for four or six months. DR-TB is treated with anything from three to six drugs, for any time from six to 24 months.
How someone's TB is classified is largely determined by which drugs their particular strain of TB is resistant to. Lindsay McKenna, co-director of the TB Project at the Treatment Action Group, suggests thinking of it as a ladder. If the standard four drugs all work for your TB, then you don't have to climb any rungs. If rifampicin doesn't work for you, you have rifampicin-resistant TB (RR-TB) and must climb to the first rung to find drugs that work. If both rifampicin and isoniazid no longer work, you have multi-drug-resistant TB (MDR-TB) and must climb another rung. If you have resistance to even more drugs and you have pre-extensively drug-resistant TB and after that, extensively drug-resistant TB. (In practice, TB programmes often classify RR-TB and MDR-TB together since the same medicines are used to treat them.)
All of the above treatments are for people who are ill with TB disease. There is also so-called TB preventive therapy, which aims to kill the TB bacteria in the lungs of someone who is infected, but who hasn't yet become ill with TB disease. These preventive treatments typically involve taking one or two medicines for one to six months, depending on the specific treatment regimen. It is possible that new long-acting formulations could allow for an entire course of preventive therapy to be administered as a single injection, though that research is still at an early stage.
How the treatments work
One reason for the complexity of TB treatment is the bacterium's large and complex genome. Meintjes says that HIV has nine genes, while TB has around 4,000. Having so many genes means the bug has lots of potential to bypass the effect of drugs targeting certain molecules or pathways and still survive. On the other hand, the many genes, at least in theory, provide many potential targets for antibiotics to attack.
As noted, to cure TB, one typically has to attack the bug with at least three or four drugs. Meintjes says it is like a group of lions taking down a large buffalo – each one targeting a different part of the buffalo.
Along these lines, TB drugs can broadly fit into different categories based on which part of the bacterium they target. Some drugs attack the way the bacterium builds its cell wall, others disrupt how the bug makes its protein, yet others interfere with how the bacterium produces or gets energy, and finally, some sabotage the way TB replicates.
As Meintjes explains, isoniazid targets the cell wall of the bacterium by affecting the formation of molecules within the wall, ultimately causing it to leak and die. Rifampicin targets the genetic mechanisms of the TB bacterium, which prevents it from replicating. Bedaquiline works by targeting the mechanisms that allow the bug to metabolise energy, essentially starving it of fuel.
A class of antibiotics called fluoroquinolones, specifically levofloxacin and moxifloxacin, target the TB bacteria's DNA while it's trying to copy itself and stops that process, explains Furin. Another drug, linezolid, interferes with how the bacterium makes proteins, which it needs to survive. It is not entirely clear how some other drugs, like clofazimine and pyrazinamide, work, says Furin.
Even when attacking TB with several drugs and from multiple angles like this, it can still take months for all the bacteria in someone's body to be killed and for them to be cured. This is because, according to Furin, sometimes the protective wall formed by the immune system to contain the TB becomes too thick for the drugs to get through. And the environment inside the wall is often very acidic and deactivates some of the drugs that do manage to get in.
How treatment could improve
Novelist George Orwell, who was diagnosed with TB in 1947, was one of the first people to be treated with streptomycin. 'I am a lot better, but I had a bad fortnight with the secondary effects of the streptomycin. I suppose with all these drugs it's rather a case of sinking the ship to get rid of the rats,' he wrote in a letter at the time.
More than 75 years later, TB treatments have improved massively, but drug side effects remain a real problem, especially when treating DR-TB. Some older treatments for TB involved injections of toxic drugs and had horrible side effects, including hearing loss and kidney damage. While newer drugs are better, there are still issues. Linezolid, for example, can cause peripheral neuropathy (painful tingling in the hands and feet) and anaemia.
McKenna says none of the TB drugs is 'necessarily a walk in the park' and all come with side effects. This is because of the drugs themselves, the dosages required to kill the TB bacterium, and how long the drugs need to be taken.
Because of this, much of the focus in TB research has been on finding drug combinations that can reduce the duration of treatment and the severity of side effects. For Furin, an ideal future regimen includes 'fewer pills' – she's hoping for one pill once a day for no more than eight weeks, 'fewer side effects', and doing away with the one-size-fits-all approach.
Her reference to the 'one size fits all approach' points to one of the central tensions in TB treatment programmes. People with TB often do not get optimal treatment based on the specific characteristics of their own illness. For example, in countries with limited testing for drug resistance, people might be treated with medicines that their specific strain of TB is resistant to. They might thus suffer the side effects of that medicine without any of its benefits. This is less of an issue in South Africa than elsewhere, since the country's health system provides routine testing for resistance against several of the most important TB drugs.
There are also questions about whether everyone really needs to be treated for six months to be cured. A landmark study called Truncate has shown that many people can be cured in two months. The difficulty is that we can't currently predict who will be cured after two months and who will need the full six months, or even longer. Figuring this out, as McKenna points out, would enable more personalised care that would mean fewer people are over- or under-treated.
Some in the TB world have argued for the development of a pan-TB regimen – a combination of three or so drugs that nobody is resistant to and that accordingly could be given to everyone with TB, no matter what strain of TB they have.
The benefit of such a pan-TB regimen would be that it would dramatically simplify the treatment of TB if it worked. But the experts interviewed by Spotlight agree that resistance is likely to develop against the drugs in such a regimen, and as such, testing people for drug resistance will remain necessary, as will alternative treatment regimens.
Furin also points out that pharmaceutical companies have a greater incentive to invest in a pan-TB regimen since its potential market share is bigger than for drugs in a more fragmented treatment model.
A hard task, getting harder
One of the biggest obstacles in the way of finding new TB treatments is that there really aren't any reliable shortcuts when it comes to doing the research. With HIV, one can get a good idea as to whether a treatment is working by looking at biomarkers such as a person's viral load and CD4 count. TB, by contrast, doesn't have any similarly clear biomarkers that tell us whether a treatment is working or not.
Arguably, the most promising biomarker for TB is bacterial load – essentially, how many bacteria are left in someone's sputum a while after treatment has begun. Having a high TB bacterial load is associated with a poor treatment outcome, but the problem is that it is difficult to measure reliably.
Without a good biomarker, the only way to measure how well treatment is working is to follow patients for a long time and see if they are cured, and if they are, whether they suffer a relapse. Because of this, TB treatment trials often take several years to complete.
Despite these challenges, there has been a good deal of activity in recent years. 'There are about 20 different new drugs in clinical trials at the moment – either early or later phase,' says Meintjes.
But much of that momentum might now be lost because of the United States' abrupt slashing of research funding, including much TB research. The US government has until now been the largest funder of TB research by some distance. It spent $476-million or over R8.7-billion through its agencies on TB research in 2023, according to a report by TAG. Many ongoing US-funded TB clinical trials have already been affected, according to McKenna, although there have recently been indications that some research funding might be restored.
Where does this leave us?
That most people with TB can be cured is something worth celebrating. That treatment for DR-TB has become a lot better and shorter over the past two decades is also something to be grateful for.
But as we have shown in this Spotlight special briefing, TB is a tough and ancient adversary and keeps adapting. The treatments at our disposal today are far from as good as we'd like them to be. The treatment side effects are often horrible, and many people find it very hard to take these drugs for month after month. We didn't linger on it, but many people who are cured struggle with post-TB lung disease for the rest of their lives – meaning the bug might be gone, but that person's lungs are never the same again.
The scientific search for better TB treatments is not a matter of convenience. It is critical to reducing the suffering that several million people will endure just this year. It is also vital for reducing the number of lives that are still being claimed by this age-old disease. And of course, TB will keep mutating, and we will likely see more and more resistance developing against the drugs that we are depending on today.
That is why it is imperative that governments, donors, and pharmaceutical companies all maintain and increase their investment in the search for better TB treatments. After all, TB claims more lives than any other single infectious agent on the planet. If that alone doesn't warrant more investment, what does?
But there is also a case to be made that we should change the way we conduct TB research.
Ideally, more research should be driven, and informed by, what actually matters to people with TB and to people in the communities where TB is rampant. After all, when given the choice, who wouldn't opt for more personalised and more respectful treatment and care?
'The TB community keeps making the same mistakes over and over and then acts mystified when things do not turn out the way they want,' says Furin. 'All the new drugs and new regimens in the world will never be enough if we do not listen to what impacted communities need, and follow their lead.' DM
Additional reporting by Marcus Low.