Population-level impact of antiretroviral therapy and mixed strains of Mycobacterium tuberculosis infection on tuberculosis transmission

Current tuberculosis (TB) control measures face two challenges: the human immunodeficiency virus (HIV) co-epidemic and genotypic complexity of Mycobacterium tuberculosis (MTB) via exogenous reinfection. To address the former, antiretroviral therapy (ART) is known to be the single most effective TB prevention method among people living with HIV. Despite the substantial evidence supporting its clinical effects, ART has an unknown population-level impact on the TB epidemic. The second challenge–MTB reinfection—complicates management of the epidemic when multiple MTB strains infect a single host (mixed infection). Though mixed infection is known to be associated with poor clinical outcomes, the transmission mechanisms associated with mixed infection have not yet been explored. To better understand and overcome these two challenges for TB control, this dissertation aims to estimate and simulate the population-level impact of ART on TB incidence and to propose possible transmission mechanisms of mixed infections. The dissertation study setting is Botswana, a middle-income southern African country with high TB and HIV burden. Despite its limited resources, Botswana’s combination of high disease prevalence and progressive public health programs provide an ideal study setting to research TB and up-to-date TB control programs. This dissertation will provide implications that are relevant to Botswana’s current TB control practices and will deliver valuable insights for other high TB- and HIV-burden countries. Chapter 1 is a brief overview of TB. Chapter 2 examines community-level risk factors, including an ART intervention, for incident TB risk in individuals. Chapter 3 develops an individual-based model of TB transmission and HIV co-infection to simulate the long-term impact of ART scale-up interventions on TB incidence. Finally, Chapter 4 explores possible transmission mechanisms associated with mixed MTB infection