Project: Early comprehensive genetic drug susceptibility testing to guide treatment of rifampicin resistant tuberculosis

Acronym	sECRET (Reference Number: TMA2018CDF-2374)
Duration	01/10/2019 - 30/09/2022
Project Topic	Despite recent data indicating a worldwide decline in tuberculosis incidence, the disease continues to present serious public health challenges. Drug resistance further complicates treatment. To protect the limited repertoire of anti-tuberculosis drugs available, treatment strategies rely on the use of combination therapy to reduce the risk of antibiotic selection of resistance. It is therefore essential to ensure that the treatment regimen contains four to five effective drugs, which can only be assessed when comprehensive drug susceptibility testing is done: a situation that is rarely accomplished when new treatment regimens are introduced. Furthermore, diagnosis of tuberculosis is a slow process and drug susceptibility testing is heavily dependent on culture of Mycobacterium tuberculosis. Knowing how to optimise the treatment regimen for patients with drug-resistant tuberculosis is dependent on knowledge of genetically encoded resistance. M. tuberculosis develops drug resistance through mutations in target genes implying that identification of these mutations can be used as a means to describe the drug susceptibility profile of the infecting pathogen, as has been done in a number of WHO-endorsed tests. Sequencing the genome of M. tuberculosis offers a unique opportunity to record variants relative to a standard genome sequence to identify mutations conferring drug-resistance in all genes known to be involved in resistance. This technology has been implemented in the United Kingdom and by the CDC in the USA to provide insight into patient management, informing diagnostic policy and surveillance. In South Africa, whole genome sequencing (WGS) has been used to describe the epidemiology of extensively drug-resistant tuberculosis with particular emphasis on transmission and the evolution of resistance. WGS has also questioned the reliability of routine drug susceptibility testing in a high throughput laboratory, as well as confirming the presence of additional resistance markers not detected by the routine laboratory. We propose to harness the resolution of WGS to provide comprehensive genetic drug resistance profiles on all rifampicin resistant tuberculosis isolates from patients resident within the Western Cape Province with the view to provide clinicians with this information such that therapy changes can be made at their discretion to improve treatment outcome. The WGS data generated will also provide the opportunity to longitudinally measure the impact of policy changes on the drug-resistant tuberculosis epidemic.
Network	EDCTP2
Call	Career Development Fellowships 2018

Project partner

Number	Name	Role	Country
1	Stellenbosch University	Coordinator	South Africa