22 March 2013

South Africa: Further Resistance to TB Drugs Identified in SA

Photo: Sue Valentine
The Lizo Nobanda TB Care Centre is run by Medecins Sans Frontieres. It is a short-stay facility with just 10 beds in the heart of Khayelitsha.

Researchers have identified a new strain of tuberculosis in 17 patients in the Eastern Cape which is totally resistant to the all current drug regimens.

When an earlier study of extensively drug resistant (XDR) TB in the Eastern Cape showed that patients weren't responding to treatment - 58 percent of patients died within a year and only 8.4 percent became un-infectious after more than four months of treatment – epidemiologists at Stellenbosch University (SU) decided to investigate the bacteria that seemed to be more resistant against the available drugs. The Eastern Cape cases are the first to be identified in South Africa, and the fourth country in the world to report totally drug resistant (TDR) TB – it was discovered in India last year, and in Italy (2003) and Iran (2009).

What they found was an emerging strain of TB even more resistant to drugs than XDR, which is already resistant to all first line drugs and some second line drugs. This new strain has shown resistance to at least 10 anti-TB drugs currently in use in the health sector.

According to Prof Tommy Victor, from SU's Division of Molecular Biology and Human Genetics, the World Health Organisation and many experts in the field, including him, think the name "totally drug-resistant" (TDR), which is currently used in scientific literature, is not appropriate. They believe there may be a cure for TDR among some of the new drugs currently being developed, or old medication not in use anymore.

"We really are facing bacteria that has become increasingly resistant, and there are now some bacteria that are hyper resistant, irrespective of the definition," said Victor who was one of the authors of the study.

In the scientific paper, which was published in the Emerging Infectious Disease Journal in March this year, they used molecular techniques to study cultures of the tuberculosis bacterium of just under 400 Multi-drug resistant (MDR) TB patients in the Eastern Cape. Among these a large number were pre-XDR and XDR's, and 17 cases of TDR.

There are approximately 18 000 new MDR cases diagnosed each year and "there may be be more TDR cases in South Africa ," says Victor, explaining that 17 cases emerged from only 400 MDR samples tested.

A shortcoming of the study, which was acknowledged by the authors, is that they only studied the cultures from the infected patients, and don't have any data on patient outcomes – so they don't know how long they may have survived, or if any have been cured. Although a related study on the Eastern Cape cohort showed that patients responded quite badly to even the fiercest treatment.

Like its precursors, MDR and XDR, TDR infection can develop in two ways: from a patient not taking medication as prescribed, or from being directly infected with the TDR bacterium from someone else with the disease.

"One can be infected with an already resistant strain, say MDR or XDR, which is already frightening, but if medication is not taken optimally (because it makes you feel terrible) then the resistance amplifies and the patient can progress to TDR," said Victor. "In this study only a relatively small number of TDR cases was identified, but as this pool becomes larger we predict that more transmission from person-to-person will occur. This would be similar to other forms of drug resistance (MDR, XDR) where the numbers are already large."

An important weapon in the fight against TB is to detect infected patients early and to treat them before they can spread the disease to others. Molecular based techniques to detect drug resistant TB are faster than the traditional cultures based tests. Currently the molecular Gene Xpert and Line Probe Assays has been implemented as a diagnostic standard in the public health sector to detect drug resistant TB but currently there is no test available to detect TDR-TB.

The only way to currently to diagnose TDR is through molecular testing which is currently only being done in research facilities, which will not be able to do molecular testing on a large scale to search for TDR cases.

However, the line probe assay already contains critical markers that will be indicative of the Atypical TDR Beijing strain. These suspicious cases can then be referred to research facilities such as Stellenbosch University for further testing.

Although the only confirmed cases of TDR were in the Eastern Cape, it is suspected that it may have already spread to other regions via migration, and cases of the atypical Beijing strain (which is susceptible to TDR) have been found in areas such as Khayelitsha.

A drug surveillance study will be done next year by the National TB Programme and will determine the extent of TDR.

Medecins Sans Frontieres TB specialist doctor Jenny Hughes said it was important to know that when the term TDR was first coined, the World Health Organisaton made it very clear that this was not an internationally accepted definition like MDR and XDR, and there is no clear standard for determining which drugs it is resistant to.

She added that there were always likely to be strains of TB which are resistant to a number of different drugs. MDR TB and XDR TB describe strains of TB resistant to particular classes of drugs. "We have not been looking for other resistance patterns and so have not found any, but now that people are looking for it, they are finding more and more. It is likely that these strains would be found in any environment in which there is MDR and XDR TB, we just don't know about it," said Hughes.

She added that the reason the outcomes for XDR TB are so bad is because the drugs are so ineffective. "If there were effective drugs available, then the TB could be treated, but it requires infrastructure to get a reliable supply of effective drugs, to be administered to the patient in the correct doses at the correct times, every day for a period of 2 years," said Hughes.

"This is why if we don't put efforts into getting better drug regimens for XDR TB now, then we will drive the development of more resistant strains like TDR TB, mainly through our healthcare policies and constraints rather than through the patient's unwillingness to take ineffective drugs with terrible side effects."

Professor Linda-Gail Bekker of the University of Cape Town said these cases may always have been around, but that for the first time there is better sensitivity surveillance.

"Hopefully there is a fitness cost to these mutants which may mean that don't transmit as easily. We need more surveillance to understand this all better," she said.

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