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Majority of XDR TB Cases Are Due to Transmission in a High-HIV-Prevalence Setting
N. Sarita Shah1, James C. Brust2, Barun Mathema3, Thuli Mthiyane4, Nazir Ismail5, Pravi Moodley6, Koleka Mlisana8, Salim Allana7, Jonathan Smith7, Neel R. Gandhi7
1 Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, United States. 2 Division of General Internal Medicine, Montefiore Medical Center & Albert Einstein College of Medicine, Bronx, NY, United States. 3 Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, United States. 4 University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa. 5 Centre for Tuberculosis, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa. 6 Department of Virology, University of KwaZulu-Natal & National Health Laboratory System, Durban, South Africa. 7 Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States. 8 Department of Medical Microbiology, University of KwaZulu-Natal & National Health Laboratory Service, Durban, South Africa.
Background: Drug-resistant TB threatens gains made in the control of TB and HIV worldwide. In South Africa, there has been a ten-fold increase in the number of MDR and XDR TB cases over the past decade. Factors driving this rapid rise in caseload have not been fully elucidated. We sought to determine the proportion of XDR TB cases resulting from primary transmission versus inadequate treatment of MDR TB (i.e., acquired resistance).
Methods: Cross-sectional study of 400 culture-confirmed patients with XDR TB diagnosed during 2011–2014 from KwaZulu-Natal province, South Africa. Participants were interviewed about demographics, previous TB and HIV history, healthcare utilization, and potential TB exposures. Medical records were reviewed for prior treatment with first- and second-line TB medications and previous hospitalizations. All M.tuberculosis isolates underwent IS6110 RFLP genotyping and targeted sequencing of nine resistance-conferring genes. Isolates from genotypic clusters with more than 20 participants also underwent whole genome sequencing.
Results: To date, 377 patients with XDR TB have been enrolled. The median age was 33 (IQR 29-43) and 57% were female. 78% were HIV-infected, with a median CD4 count of 275 cells/mm3 (IQR 149 – 433); 90% were on antiretroviral therapy at the time of enrollment and 79% had a viral load <400 copies/ml. Participants were identified from all 11 districts in the province. Only 33% of participants had been previously treated for MDR TB, and an additional 7% had received fluoroquinolones or injectable TB medications for non-TB illnesses. Based on genotypic analysis, 87% of participants had an isolate that belonged to one of 16 clusters; only 13% had isolates that were unique. One large cluster (LAM4/KZN) accounted for 47% of participants, while the remaining cluster sizes ranged from 2–16 participants. Whole genome sequencing confirmed the highly clonal nature of the large LAM4/KZN cluster.
Conclusions: In this high HIV prevalence setting, the majority of XDR TB cases occurred due to transmission of drug-resistant TB strains, rather than prior inadequate treatment of MDR TB. Analysis of epidemiologic and geospatial data also collected in this study will provide valuable insights into identifying potential locations of transmission and opportunities to intervene. TB control efforts must focus on curbing transmission through improved TB case-finding, infection control and enhanced treatment programs.