Background: South Africa, with an estimated annual tuberculosis (TB) incidence of 360,000 cases in 2019, remains one of the countries with the largest burden of TB in the world. The identification of highly burdened TB areas could support public health policy planners to optimally target resources and TB control and prevention interventions. Objective: To investigate the spatial epidemiology and distribution of TB mortality in South Africa in 2010 and its association with area-level poverty and HIV burden. Methods: The study analysed a total of 776,176 TB deaths for the period 2005-2015. Local and global and spatial clustering of TB death rates were investigated by Global and Local Moran's Indices methods (Moran's I). The spatial regression analysis was employed to assess the effect of poverty and HIV on TB mortality rates. Results: There was a significant decrease in TB mortality rate, from 179 per 100,000 population in 2005 to 60 per 100,000 population in 2015. The annual TB mortality rate was higher among males (161.5 per 100,000 male population; (95% confidence interval (CI) 132.9, 190.0) than among females (123.2 per 100,000 female population; (95% CI 95.6, 150.8)). The 35-44 age group experienced higher TB mortality rates, regardless of gender and time. Hot spot clusters of TB mortality were found in the South-Eastern parts of the country, whereas cold spot clusters were largely in the north-eastern parts. Tuberculosis death rates were positively associated with poverty, as measured by the South African Multidimension Poverty Index (SAMPI) as well TB death rates in the neighbouring districts. Conclusion: The findings of this study revealed a statistically significant decrease in TB deaths and a disproportionate distribution of TB deaths among certain areas and population groups in South Africa. The existence of the identified inequalities in the burden of TB deaths calls for targeted public health interventions, policies, and resources to be directed towards the most vulnerable populations in South Africa.

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