Phylo-epidemiology of extensively drug resistant tuberculosis in the Western Cape Province, South Africa

Extensively drug resistant tuberculosis (XDR-TB) is difficult to treat and poses a major threat to TB control. The transmission dynamics of XDR Mycobacterium tuberculosis (Mtb) strains has not been thoroughly investigated. We aimed to assess the geographic distribution of XDR-Mtb strains in the Western Cape Province of South Africa over a 10-year period (2006 to 2017) and investigate the association between Mtb sub-lineage, age, sex and geographic patient location with membership and size of XDR-TB clusters. Using whole genome sequencing data on 461 XDR-Mtb strains, a phylogenetic tree was generated and annotated with lineage, sex, age, and geographical patient location. Transmission clusters were identified based on the strains with less than 5 single nucleotide polymorphism differences between isolates. Cluster size was classified as small (2-4 isolates), medium (5-20 isolates), large (20-100 isolates) and very large (>100 isolates). We found that 85.5% of isolates were clustered and 14.5% of isolates were unique. Almost all (90.9%) of the clustered XDR-TB patients belonged to the very large cluster of 150 patients or to one of 3 large clusters of 66, 70 and 72 XDR-TB patients. All very large and large clusters were formed by lineage 2 strains, either the typical (lineage 2.2.1) or atypical (lineage 2.2.2) Beijing, and were spread across health districts of the Western Cape Province. We identified a significant association between district and cluster membership and cluster size, as well as between subdistrict and cluster size. There was no association between sex and cluster membership or cluster size. There was a significant association between age and cluster size, but not between age and cluster membership. In conclusion, our research indicates that the XDR-TB epidemic in South Africa is predominantly driven by transmission of XDR-Mtb strains rather than amplification of resistance, with multiple large XDR-TB outbreaks spread across the Western Cape Province. In addition to the prevention of amplification of resistance, rapid diagnosis of XDR-TB and timely initiation of appropriate treatment needs to be achieved in order to reduce the infectiousness of patients while they move for work, school, family and health care needs.