Transmission of Extensively Drug-Resistant Tuberculosis in South Africa

Abstract

Background: Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions.

Methods: We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission.

Results: Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).

Conclusions: The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Figures

Figure 1. Geospatial Coordinates of Participants with Extensively Drug-Resistant (XDR) Tuberculosis in KwaZulu-Natal Province, South Africa

Panel A shows the homes (red dots) of all 404 enrolled participants. Panel B shows the 53 hospitals (blue squares) where the participants were admitted before or after XDR tuberculosis was diagnosed.

Figure 2. Single-Nucleotide Polymorphism (SNP)–Based Maximum Likelihood Phylogenetic Tree

Isolates are labeled according to study identification number and color coded according to restriction-fragment– length polymorphism (RFLP) group. Single-isolate RFLP groups are shown in black. The tree is rooted to the lineage 7 isolate Percy256. L2 denotes lineage 2, and L4 lineage 4. The other abbreviations (MH, W, AH, BW, BH, GY, CC, and HP) denote common RFLP patterns seen between isolates. The letters were assigned according to the first time that a particular RFLP pattern was seen (often many years before the current study). The blue circular band shows that all the isolates on the branches on the tree below it are from lineage 4. The orange band shows that the isolates under it belong to lineage 2. At the center of the circular tree, one large branch separates all the isolates below the orange band from those below the blue band. All internal nodes separating RFLP groups are supported by 100 of 100 bootstrap replicates. Publicly available sequences (not sequenced for this study) are marked with asterisks. The scale bar indicates the maximum-likelihood estimate of the number of substitutions per site.

Figure 3. Social Networks in Homes and Communities, Derived from Name-Based Person-to-Person Links

A social network of 59 participants with direct person-to-person links is shown. Large black circles indicate study participants. Small circles indicate 450 close contacts named by participants. Lines between two large circles indicate 2 study participants who named each other as a close contact. Lines between a large circle and a small circle show contacts named by each participant. Contacts’ circles are shaded according to their history of tuberculosis, as reported by the study participant (white denotes no previous active tuberculosis, gray previous active tuberculosis, and black previous XDR tuberculosis). Additional details are provided in Figure S3A in the Supplementary Appendix.