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The Rat Race Against The silent Killer

Tuberculosis is a silent killer; now there is a greater chance of people dying from it. A strengthening superbug is defying drugs and sending African hospitals into the red. Doctors are calling it a ticking time bomb and all that stands in its way are new pills, new technology and a rat pack.

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Seven months ago, Daniel, not his real name, was so tired he couldn’t walk and at night he would wake up sweating. He was so thin people thought he was on tik (crystal meth). He hadn’t worked for two years.

At the time, Daniel thought he had a bad cold, so he went to his clinic in Bonteheuwel, a township in Cape Town, to get medicine. To his horror the nurses told Daniel he was suffering from what they call extensively drug resistant tuberculosis (XDR-TB) – a virulent strain of multidrug resistant tuberculosis (MDR-TB). A mere four years ago, this would have been a death sentence.

In Africa, tuberculosis (TB) is called the poor man’s disease – it strikes in overcrowded homes and overcrowded taxis.

Professor Andreas Diacon

“I didn’t know anything about TB. I didn’t know anything about MDR or XDR. I didn’t realize TB was a disease that could kill you… [Death] hung at the back of my mind. I wouldn’t sit next to people who had it… I was scared of them. Now, it’s the opposite. I was the one who had it,” says Daniel.

It hit home hard over Christmas. Daniel was allowed out of hospital, but his family refused to sit with him. Many others are ostracized by their own people largely because of the relationship between HIV/Aids and TB; half of South Africa’s TB patients also have HIV.

“In my community people believe TB can change to HIV. But that’s not true. TB stays TB and those who have HIV can get TB. They told me to sit outside and drink by myself, alone,” says Daniel.

Daniel is one of millions in a worldwide TB epidemic. It’s been called the world’s number one infectious killer disease, taking more lives than HIV and malaria in 2015, according the World Health Organization (WHO). In that year alone, 1.8 million people died from TB. That is a third of the people living in Cape Town and more than a small country like Gabon.

The problem is, over the last 40 years, TB has sharpened its teeth, yet hospitals haven’t. In 2015, an estimated 480,000 people developed MDR-TB alone, according to the WHO.

This is because MDR-TB has become a superbug.

For those who do survive, it means up to two years of expensive treatment; in which you swallow almost 15,000 pills and in which you take daily injections that can make you deaf.

Thanks to a revolutionary drug called bedaquiline, Daniel’s death sentence has been stayed.

It was discovered in 2005 by Belgian veterinarian Koen Andries, a pharmacist at Janssen pharmaceutical company. This was the first TB drug to be registered in 40 years in 2012.

It proved so promising that a mere month later it was being handed out in South Africa at the behest of the country’s Minister of Health, Aaron Motsoaledi.

Just 15 kilometers from where Daniel still lies in hospital, Motsoaledi sits in the oak-furnished offices of Parliament, in Cape Town. Motsoaledi is keen to push his point for the war against TB – he is a qualified doctor who has seen its effect firsthand.

Bedaquiline is helping to save the lives of 4,385 people living in South Africa, like Daniel. To this day 60% of all the people taking bedaquiline are treated in South Africa, according to Motsoaledi.

The effectiveness of TB treatment is measured by a patients’ sputum culture – infections in the respiratory system – converting from positive to negative. The South African government says the number of people with MDR-TB cured is 79.7% for those on bedaquiline; up from 39%.

“[TB] is a silent killer that does so in an undramatic way, so nobody notices. In 2009, 80 members of the National Union of Mineworkers died in rock falls, everybody knew about it. But in that same year 1,500 of their members died of TB. They are all deaths, it’s a loss. But the 80 made the most noise. The 1,500 died a silent death in a bed,” says Motsoaledi.

Motsoaledi is trying to convince the world as board chair of the Stop TB Partnership, a United Nations project. He is exasperated that TB has not been debated in a general assembly of the United Nations, based in New York. Even though it is part of the Millennial and Sustainable Development Goals, which hopes to eradicate TB by 2030, it was only recently amended to be on the agenda for 2018.

 

“TB is not bringing a lot of fear to people. But look at the figures, when Ebola broke out it killed 11,000 people during its time of existence. But almost every human being on the planet heard about Ebola and got worried. But during the same period TB killed 1.5 million. I am not trying to say Ebola was not a big scare, but these 1.5 million hardly made a blip on the radar screen,” he says.

In the yellow hallways of the Brooklyn Chest Hospital, in Cape Town, is the grim proof of the statement. Here, Doctor Paul Spiller is one of the people standing against the tide. He looks laidback, in an open neck shirt, but his job is far from so. He has been Manager of Medical Services at Brooklyn Chest Hospital for six years and says the new drug has transformed treatment.

“Before these new drugs became available, [Brooklyn] was a very depressing place. XDR-TB survival was less than 10%, we had a 90% mortality rate. It was like trying to fight a war with a peashooter,” says Spiller.

The downside is XDR-TB could also bankrupt a country.

“The difference in costs are oceans apart. To treat a person with normal TB you spend between R300 ($20) to R400 ($30) for treatment. Once you get MDR-TB its goes to R400,000 ($30,000) per patient. Once you get XDR-TB its R800,000 ($60,000) per patient. It’s a 1,000 times more expensive to treat someone who has MDR-TB than a person with ordinary TB,” says Motsoaledi.

The expensive battle continues.

 

An Idea Born Of A Sheet Of  Paper And A Fist Full Of Bucks

What makes Daniel’s story even more remarkable is that it all started with a flimsy piece of paper, R200 ($15) and a doctor-turned-entrepreneur with a truckload of perseverance.

The proving ground was a company called TASK Applied Science, headquartered in Bellville, Cape Town. It was the brainchild of the full-of-life Professor Andreas Diacon, a Swiss-born lung doctor – pulmonologist – who came to Africa looking for a job. He is every inch the eccentric nutty professor with a joke on his lips and hope in the eyes. He is also a man on a mission.

“If you read in the newspaper that bedaquiline is reducing the mortality by many many percent. Then we know, without [TASK], all these people would have died,” says Diacon.

Diacon deals firsthand with South Africa’s overburdened public health system. He is a consultant in pulmonology who works in the Internal Medicine and ICU units at Tygerberg Hospital, in Cape Town. It was here that Diacon came across the Afrikaans saying ‘a farmer makes a plan’ – it became his mantra in taking down TB.

“As opposed to being a doctor in Switzerland, being a doctor here in an intensive unit, in a public hospital, people die. This is a job that drains you… There is too much disease for too little resources. The system is just not big enough.”

APOPO laboratory

The idea to start TASK came by chance in a fast crowd. Diacon came across retiring Professor Peter Donald, a renowned TB researcher also living in Cape Town, at a lecture in 2002.

“I had seen all his work. I was fascinated by it. I, in Europe, in my medical training, had read about it. He is the leading researcher of TB for the last 30 years. Suddenly this man is here and he is giving a lecture in front of five people, and I was one of them.”

On the day, Diacon asked who would continue Donald’s research. Donald’s reply was straight forward and bleak: there was little future for research in a disease where there was no money; no revolutionary new drugs and no interest.

“Two weeks later, Donald gets a phone call from a drug company called Tibotec (now known as Janssen). They said they had this new drug called bedaquiline, at the time it was called TMC207. It was a completely experimental compound. They were desperately looking for someone to test it in people. Donald had just cleaned up his office, so… he called me,” says Diacon.

It was the sort of challenge Diacon had been looking for. Donald handed Diacon a pamphlet with trial protocols; the rest was up to him.

“[South African hospitals] needed new TB drugs, why should I ever say no? From my point of view it’s imperative that every drug that people have, that might work, must be tested. It’s the only way we can get control of the problem.”

It wasn’t easy. Diacon struggled to find the beds; hospitals turned him down saying they had no space and they didn’t want TB to spread. After months of looking, Diacon found the sympathetic ear of Professor Frans Maritz, who was head of the Karl Bremer Hospital, also in Cape Town.

“It didn’t take longer than five minutes. He said to me ‘Andreas, this is the most important research I’ve ever heard of in my career. You can have my private ward here,'” says Diacon.

Then there was the matter of finding the budget. Diacon secured upfront funding and with R200 ($15) – enough to put petrol in your car – opened a bank account to pay his four employees.

“Then we got this drug. It was the first time I did anything like this. And somehow we did [the trials] well. And then the drug worked. And we could show that the drug works. It was the first new TB drug that showed some signs that it could do something. It was not as strong as people had hoped, but it was there,” says Diacon.

TASK’s bedaquiline trials started with 180 patients, on a two-week course in 2010. It took seven years, five months and five days to go from discovery to FDA approval – Diacon counted. What is significant is that drugs can take up to 15 years to develop, but in this case bedaquiline was fast-tracked, because of its necessity. Without Diacon’s research, the drug could have taken a lot longer to make it to FDA approval by 2012.

“For a drug manufacturer, getting FDA approval is like being knighted. If you are a chemist, that leads to marketing approval of a drug. It gives them patent protection for 10 years,” says Diacon.

“But for TB drugs it’s a bit of the opposite because nobody has any money to buy it. The development cost will never be covered. So in return the FDA offer a voucher system, whereby if [a drug company] develop a drug under these circumstances, then the FDA agrees to fast-track another drug they develop.”

“With only data from 180 patients, there I was presenting the story to the FDA… it wasn’t a strong case. [The FDA] agreed to a special situation where people with really drug resistant TB would be allowed to be registered, under the condition that it was researched further.”

TASK began tests with more patients over longer periods with bedaquiline.

“Suddenly we became the hub where everyone went to with their new TB drugs,” says Diacon.

Still, hospitals were reluctant to trial the drug. Diacon managed to eke out eight beds in an empty building at the Brooklyn Chest Hospital, in Milnerton.

“We renovated [the building] ourselves. We even went to an old bed store in Brooklyn and welded the beds together out of broken parts. We didn’t have the money to buy beds… Then one morning the groundsman came and took four of our beds saying the head nurse needed them elsewhere in the hospital.”

As the drug showed signs of working, he needed more patients to test over longer periods of times. So he walked the hallways of the hospital looking for candidates that met the trial’s rigid requirements.

TASK’s current MDR facility is on site at Brooklyn, and can accommodate up to 10 patients overnight.  Daniel is one of hundreds to have undergone trials and on the road to being cured.

The company has grown from four employees to more than 150, and so have the facilities. Among them, Diacon converted an abandoned mosque into a trial center in Bellville. TASK also opened sites in Delft and Mfuleni, and is building one in Scottsdene, which are extremely rural townships on the fringes of Cape Town. You could say that he is building up his own clinical empire in TB.

“TB is curable. It’s a bacterium that can be killed. If the shortest time it can be killed is six months, then there will always be people not sticking to treatment. We need to get a once-off injection, or a two-week course of antibiotics. It needs to be affordable and we need to be able to make sure people are swallowing the drugs and not infecting anybody else,” says Diacon.

Diacon’s company has emerged as the leading clinical trial company to do research into this overlooked killer. Thanks to R200, a pamphlet and making a plan like a farmer.

 

The Ticking Time Bomb That Kills

The fight against TB in Africa has only just begun and it will be rats and machines on the frontline.

New research on TB resistance was published in the New England Journal of  Medicine by a team led by Dr Sarita Shah, of United States-based Centers for Disease Control and Prevention (CDC). The study was done in KwaZulu-Natal, a province with many cases of XDR-TB. Findings suggested at least 69% of XDR-TB patients caught it in an overcrowded house or an overcrowded taxi.

The research contradicts previous opinion where it was believed patients acquired XDR-TB though failing to take their pills. The research also shows why South Africans, like Daniel, are suffering from a tenfold increase in XDR-TB cases since 2002, says the CDC. Key statistics have led researchers to call XDR-TB a ticking time bomb.

Early detection is key to diffusing this bomb. According to the WHO, more than a third (4.3 million) of people with TB go undiagnosed or unreported, some receive no care at all and for others, access to care is questionable.

Dr Florian von Groote-Bidlingmaier

“After one week, [patients] would disappear forever. Then the person who is diagnosed with TB wouldn’t come back and is spreading it. You try to track the person down but by the time you have tracked them down, they have infected many more people,” says Motsoaledi.

To combat the spread, scientists have racked their brains to find ways of detecting the disease faster. One of them is the diagnostic machine, the GeneXpert, deployed by the South African government since 2011. This can test for TB in just two hours, instead of weeks in a laboratory.

“Our figures of TB are very high. In terms of what we had five or seven years ago, the numbers are going down. We used to be the number one country in the world with TB. Now, we are sixth. In 2008, we had 70,000 dying of TB, now the number is below 40,000. Obviously, that is very significant. In 2008 the cure rate was 67% [for normal TB]. It is now 85%,” says Motsoaledi.

“Because of the GeneXpert, we are picking up more people and it is helping to pick up the people who would not have been diagnosed before.”

By 2016, just over 10 million specimens have been processed, says the South African National Health Laboratory Service.

The GeneXpert is expensive. The most common model is the GX4 which costs $17,000 per unit. This machine can test four cartridges in two hours; the subsidized cost for each cartridge is around $10.

“In terms of rand for rand, the GeneXpert is more expensive. But it’s faster and more efficient. Also, for microscope testing, you have got to be a qualified medical technician, or microbiologist. [With] the GeneXpert, you can be trained in 15 minutes. The machine does the work for you,” says Motsoaledi.

Motsoaledi says the results of combining this early warning system with advanced trial treatment of bedaquiline has been a game changer.

If cost is the problem, TB detection can border on the bizarre. African scientists at APOPO, an NGO in Tanzania, have found the African giant pouched rat to be very good at sniffing it out.

“By using rats alongside conventional methods we have raised partner clinic detection rates by 40%. One rat can take 20 minutes to test up to 100 samples, this would take a clinic technician, using conventional microscopy, up to five days,” says James Pursey, Head of Communications at APOPO, from their TB research and training facilities in Morogoro, Tanzania.

Since 2005, APOPO has trained over 80 rats to sniff out TB in the sputum of patients. Each one costs $6,500 and takes nine months to train. Once trained, they can screen as much as 1,500 sputum samples a month.

The rats are trained on a click-reward system. They learn to associate the smell of TB with a click in its ear and are given a bite of a banana as a reward. The rats are given samples and when TB is detected they hover or scratch over the sample for three seconds. The sputum is then verified at APOPO’s laboratory within 24 hours for the patients to given their results – much faster than standard microscopic testing.

“A clinic technician usually gets through 10 to 20 samples a day. The difference is that conventional microscopy is 20 to 60% accurate so around 50% of TB patients in sub-Saharan Africa go home misdiagnosed, where they can infect up to 15 other people in a year. The rats are an addition to the current method and they are effective because they are so fast at screening the samples that the clinic already tested. This gives doctors time to then check a much reduced sample base using better methods (concentrated smear LED microscopy) which the clinics can’t afford in time or cost,” says Pursey.

March saw the opening of a new TB-detection program in Addis Ababa, Ethiopia, funded by the Skoll Foundation. It aims to increase the number of identified TB patients by at least 35% in the short term, in the heart of the city, with 30 rats in training.

In addition to Morogoro, APOPO operates out of Dar es Salaam, Tanzania, and Maputo, Mozambique. To date the rats have found over 11,000 TB-positive patients missed by clinics.

It’s not all good news – the rats do have their limitations. Pursey says they can’t tell the difference between types of TB. Using rats is also a new science, there are many questions surrounding how or what the rats are smelling and whether they are able to detect the TB.

“The smell is a bouquet of volatile organic compounds and we are currently carrying out research to find out exactly what the rats are targeting,” says Pursey.

Their scientists have also been left bemused when their research showed that a number of rats were picking up a bunch of seemingly false positives in samples of many patients who went on to develop TB.

“It turned out the rats might be able to detect the TB up to six months in advance. [Our scientists’] working theory is the rats may be more sensitive to the volatile organic compounds released by the TB,” says Pursey.

African solutions to world problems – an expensive machine in South Africa that can tell you have TB in a matter of hours and rats in Dar es Salaam that can sniff out in a trice. Where else but in Africa?

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