Page Content: In a paper, published in the Centres for Disease Control and Prevention's journal Emerging Infectious Diseases in March this year, scientists of the SU Faculty of Medicine and Health Sciences (FMHS) reported the emergence of a TB strain in the Eastern Cape which is resistant to all first- and most second-line TB drugs.
"These hyper-resistant bacteria can actually be called TB strains that are 'XDR-TB and beyond' and have been referred to as Totally Drug Resistant TB (TDR-TB) in the literature since they are resistant to all ten of the drugs that are currently available for the treatment of the TB," says one of the authors of the paper, Prof Tommie Victor of the SU division of Molecular Biology and Human Genetics.
Thus South Africa has became the fourth country to report the emergence of this virtually untreatable strain of TB – a discovery that further complicates the TB crisis in this country where the disease already poses an serious threat for the large population of South Africans suffering from HIV and Aids. Although TB can infect anyone – even healthy people – it is particularly easy to contract by people whose immune systems are compromised by HIV infection.
Other countries reporting TDR-TB include India, Iran and Italy but none of them has reported TDR as prevalent as it is in South Africa.
According to TB experts, it is just a matter of time before TDR-TB is discovered in other countries where multiple drug-resistant TB (MDR) and extensively drug resistant TB (XDR-TB) is being treated. Globally, about four per cent of new TB cases and some 20 per cent of previously treated cases are resistant to the two first-line TB drugs, isoniazid and rifampicin (MDR-TB). XDR-TB, on the other hand, is defined by resistance to these two first-line drugs, as well as fluoroquinolones and the second-line injectable drugs. MDR with resistance only to fluoroquinolones or injectables is called pre-XDR. According to the World Health Organisation (WHO), XDR-TB has already been identified in 84 different countries.
Drug resistant TB emerges due to inadequate treatment, poor drug quality and poor adherence and is spread through droplet infection. The authors estimate that 75.6% of XDR-TB cases in the Eastern Cape (with complete data) were the result of ongoing transmission. One of the authors of the SU paper, Prof Paul van Helden of the Department of Biomedical Sciences, warns that it is just a matter of time before TDR-TB spreads. Furthermore, he emphasises, "Where there is currently MDR and XDR, there may also be undetected TDR as drug resistance is only tested for a limited number of drugs".
A concurrent study conducted by the SU team in the Eastern Cape showed that treatment outcomes of XDR-TB were dismal: 58% of patients died after one year of treatment, while culture-conversion rates were only 8.4% over a follow-up period of 143 days.
"This raises the concern that these patients had an untreatable form of TB. This situation is similar to the Tugela Ferry outbreak in KwaZulu-Natal province, which highlighted the need for improved basic control measures, including rapid diagnosis and infection control methods," Prof Tommie Victor says.
Despite this discovery of TB strains that are extremely difficult to treat in SA, and the emergence of similar TB strains in other countries, the WHO has been cautious of recognising the definition of TDR-TB. Victor agrees that the term, 'totally drug-resistant' may be inappropriate since there may still be cure for TDR among the new drugs which are currently in development, or amongst medicines no longer in use.
New drugs, new hope
Prof Andreas Diacon of Stellenbosch University has been testing new TB drug candidates for the Global Alliance for TB Drug Development and other drug developers for a number of years. In December last year, the US Food and Drug Administration (FDA) approved the first of these drugs, bedaquiline, for the treatment of MDR-TB in special situations. This is the first new class of TB drug to be developed in more than 40 years. There are indications that the drug will be approved in South Africa sometime this year.
"Thanks to our active participation in the evaluation of these drugs, we were fortunate enough to be able to give bedaquiline to one of the first patients in
South Africa, Dr Dalene van Delft, a Tygerberg paediatrician, long before it was approved for use by the FDA (see article on page 15).
Van Delft had contracted MDR- TB from a patient in 2010 and was treated with bedaquiline for six months last year. Today she credits the drug for saving her life.
"We have several new drugs in clinical testing but only bedaquiline (TMC207) is currently available for compassionate use by certain centres in South Africa. However, tuberculosis is very quick to develop resistance against drugs that are given alone or in combination with ineffective drugs. Any drug, including new drugs, should only be used as part of a regimen of at least three effective drugs to prevent resistance developing to the new drug. Such a combination might be difficult to put together in patients that have resistance to many drugs already, such as those with TDR- TB. The policy for compassionate access to bedaquiline requires that at least two other effective drugs must be available," says Diacon.
There is not yet any evidence that the drug is effective against TDR-TB, "but since bedaquiline has a new mechanism of action and no common mechanism of resistance with other drugs, it is highly likely that it may be effective."
Experts agree that bedaquiline is a good start, but that more new drugs with new mechanisms of action to protect against new resistances should be developed quickly to prevent TB resistance to bedaquiline as well. At present, there are three drugs in phase 2 and phase 3 trials that look promising.
Meanwhile, TB experts agree that drug susceptibility testing for TB is not always accurate or comprehensive enough to determine optimal treatment regimens. South Africa is rolling out the so-called GeneXpert countrywide but this test identifies resistance to only one drug, namely rifampacin, and this needs to be confirmed by an additional assay. Second-line drug resistance is still being tested, using culture-based methods, thereby delaying the initiation of appropriate treatment.
According to Victor, the mutations and resistance mechanisms against many TB drugs are unknown and large investments in research are needed to understand these mutations to enable scientists to develop assays that will detect a complete spectrum of mutations to all the currently used drugs. Scientists at Stellenbosch University, like others across the world, are concentrating research efforts on rapidly identifying TB strains that cause MDR-, XDR- and TDR-TB.
The Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa, by Marissa Klopper et al, of the SU Molecular Biology and Human Genetics division – www.cdc.gov/eid, Vol. 19, No. 3, March 2013.
Members of the research team from the Molecular Biology and Human Genetics are from the left: Drs Lizma Streicher, Frik Sirgel, Profs Rob Warren, Nico Gey van Pittius and Paul van Helden. Seated in front are Prof Tommie Victor and Ms Marissa Klopper.