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New Weapons in the Fight against Tuberculosis


The Swiss doctor and researcher, Andreas Diacon, tests tuberculosis therapies in South Africa 



Zweni only reached the age of 21 years. He had the dangerous type of tuberculosis, which did not respond to several of the standard medications. The prospects seemed good for him initially; after six months of therapy he was no longer expectorating bacteria and was discharged from the Brooklyn Chest Hospital in the northwest of Cape Town.

However, Zweni was only able to walk with the help of crutches, and it was difficult for him to reach the health centre a few kilometres away where he was to be supplied with medicines daily over the next 12 months. He stopped the therapy, became gravely ill and refused to return to hospital. Instead of returning to fight the side effects of tuberculosis drugs for weeks and months on end behind the barbed wire fencing, he remained at home without treatment and died.

Andreas Diacon seems frustrated as he tells the story of Zweni. The Swiss pneumologist stands in front of a writing desk in the back room of his research station, a former ship container standing on a meadow at the Brooklyn Chest Hospital. Along with his team, Diacon is testing a new therapy for tuberculosis patients such as Zweni, who have bacteria that are resistant to several current drugs. Their disease is known as MDR (multi-drug resistant) tuberculosis. 

An estimated third of the world population is now infected with TB

Around 540,000 people contract tuberculosis (TB) each year in South Africa, of which 14,000 have MDR TB. For 400 to 1,400 patients the tuberculosis bacteria no longer respond to any of the therapies available, and this disease is known as XDR (extensively drug resistant) TB. It is currently barely treatable and will become increasingly common under the current treatment conditions, says Rob Warren, a colleague of Diacon at the University of Stellenbosch. He has examined the development of the resistance using genetic material from hundreds of TB bacteria.

In 1882 Robert Koch discovered the tuberculosis pathogen, mycobacterium tuberculosis. After the development of the antibiotic, streptomycin, doctors 50 years ago believed they would soon be able to eradicate tuberculosis. Researchers therefore turned their attention to diseases such as cancer, heart problems, and later HIV, which also affected financially solvent patients.

However, it did not turn out as expected: Since the spread of the Aids pathogen, HIV, from the 1990s, tuberculosis has been sharply on the increase. It is estimated that one third of the world population is infected with TB, and around two million people die from it each year. Today TB is the most frequent cause of death among those infected with HIV - almost half of HIV sufferers die from it worldwide.

And the battle to control it is being fought with obsolete weapons: The last new drug to combat tuberculosis came on to the market 33 years ago. Patients still have to take a combination of drugs over many months (see box), the side effects of which range from sickness to loss of sight and hearing and liver failure. It is not particularly attractive for pharmaceutical companies to develop new drugs because they can barely recover the development costs.

Nor has there been much change in its diagnosis: Where there are relevant symptoms, firstly smears of expectorated phlegm are examined under the microscope, just as they were 100 years ago - and around half of infections are not revealed in this way. A more precise method is bacterial cultures, where an attempt is made to allow bacteria from the phlegm to grow in the laboratory. As tuberculosis bacteria only multiply very slowly this procedure takes at least three weeks.

Diacon steps in front of the laboratory in the container. Wooden partition walls between the neighbouring building and the container keep the ceaseless summer winds at bay. Up to just a few months ago there was another building here where a few patients could sleep when their expectorated phlegm was being collected at night. "We had to demolish the temporary building", says Diacon. The ventilation of the neighbouring buildings was allegedly being obstructed by it.

She had lost 12kg in weight and coughed incessantly

He opens the door in the protective wall and braces himself against the wind outside. The hospital itself cannot accommodate the patients from the study. Diacon points to the meadow behind the container, where he consequently wants to put up a prefab for his patients, which will be financed by the Zürich Lung Association. After a tug-of-war lasting many months, he has finally received planning permission for this in the last few days. The new drug is called diarylquinoline or TMC 207, with which half of Diacon's study patients at the Brooklyn Chest Hospital have currently been treated for eight weeks - in addition to the five usual medicines. The drug was developed by the US pharmaceutical company, Tibotec. It was only recently that Diacon presented the results from the first 50 patients at a conference in Washington: In approximately half of TMC 207 patients there were no longer any tuberculosis bacteria in evidence in the bronchial phlegm after eight weeks. In the comparison group the phlegm was bacteria-free in only 8.7 per cent of participants.

Martha Simons is one of Diacon's patients. The 41 year-old grandmother has been in the Brooklyn Chest Hospital since the beginning of September. She is being treated for tuberculosis for the third time. She broke off the first therapy because she found it difficult to keep taking tablets over a period of months. The second time she was frightened of the daily injections that were necessary by that time. When Martha came to the hospital in September, the tuberculosis bacteria in her lungs no longer responded to two of the standard drugs. She was now an MDR patient, had lost 12kg in weight, coughed incessantly and when she took in air it hurt her chest. In the meantime Martha has started to recover but she is not yet over the worst of it, as a new resistance has manifested and she must continue to be treated in hospital.

The Brooklyn Chest Hospital is one of several places where Diacon conducts his research. On the other side of town in two areas called Delft and Mfuleni, there are two more white container stations next to state-run health centres, between tiny stone houses, tin huts and shacks. In the healthcare clinics nurses look after the basic medical needs of the mainly black inhabitants. One of their tasks is to examine and treat HIV and tuberculosis patients - according to a designated procedure. 

"It is rare for Swiss doctors to be able to see something like this"

If TB patients fulfil certain preconditions the nurses send them to the container. There they are offered treatment via a study - an arrangement from which it is not only the researchers who benefit. This alleviates the burden on the state and the patients are examined and cared for more intensively than would be possible via the normal budgets. It is also likely that the new therapy will be more effective than the old one.

According to Diacon that is how the results up to now are looking. In the study in Mfuleni and Delft, one of the standard drugs - Ethambutol or Isoniazide - has been replaced by the antibiotic Moxifloxacin for one group of patients. The Moxifloxacin patients are also being treated for only four months instead of the usual six. Neither the patients nor their doctors know which therapy they are being given.

Should the study show at its conclusion in 2011 that a four-month treatment is sufficient, that would be major progress, because the faster the therapy takes effect, the more of those infected with TB could receive complete treatment and be cured. 

The treatment of tuberculosis 

Up to now there has been no effective inoculation against tuberculosis.

Even the standard BCG inoculation of babies in many countries gives only limited protection. It is only in small children that it prevents the most life-threatening type of tuberculosis, where the pathogens are distributed around the whole body via the blood.

In South Africa normal tuberculosis is treated using a combination of four drugs in the first two months - as recommended by the WHO - Isoniazide, Rifampicin, Pyrazinamide and Ethambutol. This is followed by four months using the first two drugs. The taking of the drugs is overseen by the healthcare staff. If the second type of tuberculosis is diagnosed in a patient, the therapy usually lasts eight months. If the TB bacteria [MDR TB] no longer respond to Isoniazide and Rifampicin, then the so-called second line drugs are deployed. Alongside the so-called fluorochinolones, these usually also include aminoglycosides that have to be injected daily for several months. The therapy lasts for 21 months. The fixed standard procedure works for 90 per cent of those infected. However, MDR patients are often incorrectly treated for months for lack of expensive resistance checks - and they then infect dozens of people. 

Researchers at Harvard University have calculated that by 2012, a two-month rather than a six-month treatment could prevent 13 per cent of all new infections and 19 per cent of all deaths from TB in South East Asia.

Andreas Diacon initially worked as a pulmonary specialist when he came to Cape Town in 2000. It was almost by chance that the 46-year old ended up in tuberculosis research four years ago. On the lookout for a new assignment, he was sitting in the office of paediatrician and drugs expert, Professor Peter Donald, when the telephone rang. A representative of the company, Tibotec, was on the line and asked Donald if he wanted to take over the TMC 207 study. This provided Diacon with his new field of activity.

Since the beginning of 2008, he has also become a professor at the University of Stellenbosch, the medical faculty of which is housed at Tygerberg Hospital in Cape Town. 50% of the time Diacon works in the provincial hospital as a senior consultant, and looks after patients with pulmonary diseases and those on ventilators in intensive care. Many of them have tuberculosis. "Two or three times a week we treat patients who have life-threatening bleeding from the lungs due to tuberculosis", he says. "It is rare for Swiss doctors to be able to see something like this".

The massive spread of tuberculosis is leading to the growth of Cape Town as a research location. Diacon has been in charge of the most diverse tuberculosis studies; he employs 20 staff in his company, called Task Applied Science. He set this up in order to be able to act independently from the university, the authorities and the pharmaceutical companies.

The offices of the research company are in another part of Cape Town again, in the grounds of the Karl Bremer Hospital. Diacon shares the flat wooden building known as M2 with a charitable eye clinic, where those in need can obtain spectacles free of charge. There is a consulting room and offices in M2 but patients are not treated here.

However, Diacon intends to change this soon. One of his assignments is to test PA 824, another new TB drug, on patients. The drug, part of the Nitromidazole group, also kills dormant tuberculosis bacteria, which are then unable to multiply. This may considerably reduce the duration of therapy and the risk of relapse. In the first tests Diacon has discovered that an unexpectedly low dose of PA 824 achieves very promising results. 

Research results are entered into a central network

Even the Karl Bremer Hospital does not have the capacity to accommodate patients for Diacon's other studies. However, the hospital managers made an offer to the researcher a few days ago - not far from the M2 building, between an administration building and the fence of a German retirement home, there is a small, triangular flower meadow. The hospital is willing to allow Diacon to build a small ward on this piece of land. Diacon looks delightedly at the purple blooms: "We could have two patient areas here and a small laboratory there", he points with his peaked cap in his hand: "I will set about getting together the money for it straight away."

And the chances of this are not bad. Tuberculosis research is on the rise. "There are more drugs being developed than there have ever been", says Maria Freire, CEO of Global Alliance for TB Drug Development. The objective of the foundation is to make better and faster TB drugs available for as many people as possible. She therefore supports most of Diacon's projects. The research results are entered into a global network without which, in the opinion of experts worldwide, the control of epidemics such as tuberculosis would not be possible. 

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