Whole genome sequencing for drug-resistant tuberculosis management in South Africa: What gaps would this address and what are the challenges to implementation?

Global control of tuberculosis (TB) has been seriously impacted by the emergence and transmission of its drug-resistant forms. Delayed detection and incomplete characterisation of drug-resistant tuberculosis (DR-TB) contributes to morbidity and mortality, and to ongoing transmission of drug-resistant strains. Current culture-based and molecular diagnostic tools for TB present numerous disadvantages that could potentially lead to misdiagnosis, inappropriate treatment initiation and the amplification of drug resistance. The detection of drug-resistant tuberculosis (DR-TB) in South Africa relies on molecular diagnostic assays such as the Xpert MTB/RIF and line probe assays (MTBDRplus and MTBDRsl). However, these molecular assays are limited to detecting resistance to only a few first-line and second-line drugs. It is for this reason that next-generation sequencing (NGS) and bioinformatics pipelines have been developed for rapid detection of M. tuberculosis drug resistance, with the added advantage that sequence data could also have public health applications through understanding transmission patterns. This review highlights some of the challenges that are currently hampering the diagnosis and control of DR-TB in a high burden setting of the KwaZulu-Natal (KZN) province in South Africa. Shortfalls of current diagnostic techniques for DR-TB are discussed in detail and we also propose how these might be overcome with an accurate and rapid NGS system.

Mycobacterium tuberculosis Next-Generation Whole Genome Sequencing: Opportunities and Challenges.

Mycobacterium tuberculosis drug resistance is a threat to global tuberculosis (TB) control. Comprehensive and timely drug susceptibility determination is critical to inform appropriate treatment of drug-resistant tuberculosis (DR-TB). Phenotypic drug susceptibility testing (DST) is the gold standard for M. tuberculosis drug resistance determination. M. tuberculosis whole genome sequencing (WGS) has the potential to be a one-stop method for both comprehensive DST and epidemiological investigations. We discuss in this review the tremendous opportunities that next-generation WGS presents in terms of understanding the molecular epidemiology of tuberculosis and mechanisms of drug resistance. The potential clinical value and public health impact in the areas of DST for patient management and tracing of transmission chains for timely public health intervention are also discussed. We present the current challenges for the implementation of WGS in low and middle-income settings. WGS analysis has already been adapted routinely in laboratories to inform patient management and public health interventions in low burden high-income settings such as the United Kingdom. We predict that the technology will be adapted similarly in high burden settings where the impact on the epidemic will be greatest.