Genomic approaches to drug-resistant tuberculosis in South Africa

Despite significant reductions across much of the developed world, tuberculosis (TB) is now ranked alongside HIV as the leading cause of death from infectious disease worldwide.

There are many challenges to the control and management of TB, one of which is the emergence of drug resistance. TB treatment comprises a six month long regimen, which involves patients taking a combination of drugs. Even more complicated is the treatment of drug-resistant TB infections, usually comprises at least 18 months of treatment using less effective second-line drugs that have many side effects.

The KwaZulu-Natal Institute for TB and HIV research (K-RITH) in Durban is located in a province that has the highest rates of TB drug resistance in South Africa, and a high prevalence of HIV. The province has a high burden of extensively drug-resistant TB (XDR-TB). XDR-TB is not only resistant to first-line drugs but also the key second-line drugs, fluoroquinolones and aminoglycosides. Infection with an XDR-TB has been associated with 75% mortality.(1) In KwaZulu-Natal, XDR-TB was first reported in 2006 and its emergence was assumed to be linked to the high prevalence of HIV.(2) Surprisingly, however, a recent study from K-RITH found that XDR-TB had not emerged recently but rather had evolved over 50 years.

The study used whole genome sequencing of M. tuberculosis (the bacteria that causes TB) strains, taken from across the province, to determine the origins of XDR-TB(3). As each new combination of drugs was introduced to treat TB, starting with isoniazid and streptomycin in the 1950’s, M. tuberculosis had rapidly developed resistance to them, resulting in the emergence of XDR-TB in the 1990’s, before the explosive HIV epidemic.

The study highlights the importance of antibiotic stewardship. It is also a reminder that bedaquiline(4) and delamanid(5), the first new TB drugs to have been developed in the last 40 years, will require careful management when they are introduced into clinical care in South Africa. Failure to do so will rapidly render these drugs obsolete.

K-RITH is now focussing on incorporating genomics into the TB clinic. Recent studies have shown that through the use of genomics we can successfully identify mutations conferring drug resistance. These can be used to predict resistance to first-line TB drugs;(6) however less is known about second-line drug resistance. Current phenotypic drug susceptibility testing to second-line drugs takes at least six weeks due to the extremely slow growth of M. tuberculosis. However, the combined use of genome wide association studies (GWAS) and molecular genetics can help to identify all possible drug resistance-conferring mutations. The next step will be to carry out genome sequencing of M. tuberculosis direct from sputum, which in a matter of days, would give clinicians the full resistance profile to all drugs and would allow us to select the optimal drug combination to treat TB patients. This would be an enormous improvement on current methods of drug susceptibility testing.

TB, and particularly XDR-TB, is a worldwide global public health concern. Using advanced genome sequencing technologies we are able to better understand the resistance profile of M. tuberculosis and use this information to inform antimicrobial stewardship practices and patient care in an effort to reduce TB, not just in South Africa, but worldwide.

References

1. Pietersen E, Ignatius E, Streicher EM, Mastrapa B, Padanilam X, Pooran A, Badri M, Lesosky M, van Helden P, Sirgel FA, Warren R, Dheda K. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet. 2014;383(9924):1230-9.
2. Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, Zeller K, Andrews J, Friedland G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006;368(9547):1575-80.
3. Cohen KA, Abeel T, Manson McGuire A, Desjardins CA, Munsamy V, Shea TP, Walker BJ, Bantubani N, Almeida DV, Alvarado L, Chapman SB, Mvelase NR, Duffy EY, Fitzgerald MG, Govender P, Gujja S, Hamilton S, Howarth C, Larimer JD, Maharaj K, Pearson MD, Priest ME, Zeng Q, Padayatchi N, Grosset J, Young SK, Wortman J, Mlisana KP, O’Donnell MR, Birren BW, Bishai WR, Pym AS, Earl AM. Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal. PLoS medicine. 2015;12(9):e1001880.
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5. Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, Gao M, Awad M, Park SK, Shim TS, Suh GY, Danilovits M, Ogata H, Kurve A, Chang J, Suzuki K, Tupasi T, Koh WJ, Seaworth B, Geiter LJ, Wells CD. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012;366(23):2151-60.
6. Bryant JM, Lipman M, Breuer J. Personalizing therapy for multidrug resistant TB: the potential of Rapid Whole Genome Sequencing. Expert Rev Anti Infect Ther. 2016;14(1):1-3.