TORCH

Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment trial (SMARTT)

The SMARTT trial is a diagnostic phase IV study located in South Africa aiming to assess Whole Genome Sequencing (WGS) as a novel diagnostic utilized in the community at large. WGS allows the analysis of the entire Mycobacterium tuberculosis (Mtb) genome enabling the identification of all known mutations that confer drug resistance and mutations compensating for fitness cost in a single assay, overcoming most of the limitations of phenotypic drug susceptibility testing (pDST) and targeted molecular tests. In addition, WGS has an extremely high discriminatory power to measure the transmission of Mtb. The availability of WGS as a tool for the diagnosis and clinical management of rifampicing resistant tuberculosis (RR-TB) thus offers considerable promise.

Nevertheless, even though the cost of sequencing technologies has reduced substantially over the last decade, the use of WGS remains limited to research, reference laboratories, and high-income countries. The challenges to use WGS in routine care include the need for bioinformatics expertise, WGS infrastructure, and expertise in the interpretation of WGS data. The know-how on using ‘big’ Mtb WGS data for routine care is lacking, where medical doctors treating drug resistant (DR)-TB patients are not yet equipped with the knowledge needed to translate WGS Mtb data into individualized treatment regimens.

Therefore, the SMARTT trial aims to inform public health policy by evaluating the implementation of WGS for genotypic DST in patients diagnosed with RR-TB. The performance of a WGS-based DST strategy will be assessed by comparing the treatment outcome of patients in whom treatment was guided using a WGS DST strategy vs the South African standard of care DST strategy.