Comorbidities such as HIV, diabetes and other chronic illnesses that require the use of immunosuppressants for treatment or control can increase the likelihood of progression to TB after infection [44]. HIV increases the risk of TB and vice versa [69]. The cellular targets of HIV and M. tuberculosis play a key role in the effect HIV infection has on TB risk. Macrophages are the primary cells infected by M. tuberculosis, and are cleared with the help of CD4+ T-cells. HIV-1 infection is associated with CD4+ T-cell depletion, which increases the risk of TB in individuals living with HIV-1 [70]. Pro-inflammatory cytokines, such as INF-γ, TNF and IL-2, which are assumed to be key to CD4+ T-cell protection against M. tuberculosis, are also reduced in individuals with HIV-1 [69, 70]. A recent review by SHARAN et al. [71] summarised different mechanisms through which TB has been shown to exacerbate HIV. HIV is the second largest contributor to TB after undernourishment, accounting for 0.86 million cases in 2021 (figure 3). In that same year, ∼187 000 deaths among PLHIV accounted for 11.7% of all TB deaths [1]. TB incidence decreases for HIV patients on ART, but even with treatment, the risk of TB remains higher for PLHIV [69, 72]. Diabetes mellitus affects the integrity of the immune system, thereby increasing the risk of TB [73]. Metabolic changes in diabetic patients affect the function of neutrophils, macrophages, dendritic cells and natural killer cells, compromising the ability of the innate immune system to fight off M. tuberculosis infection [74]. The adaptive immune system is also affected by impaired antigen-presenting cells, along with an imbalanced cytokine profile that impacts T-cell differentiation in people with diabetes [74]. In 2021, 0.37 million TB cases were attributable to diabetes [45]. Diabetes has an effect on multiple stages of the course of TB, including faster progression to TB, an increase in symptom severity and an escalated likelihood of relapse, treatment failure and death [74–76]. Several studies have shown an association between vitamin D deficiency and increased TB risk [77–83]. Vitamin D deficiency has been linked to an increased risk of diabetes and could therefore have a deteriorating effect on the interaction between diabetes and TB [73]. The mechanism behind this is potentially through both the regulatory influence of vitamin D on insulin secretion and signalling, and the immunomodulatory effect of vitamin D, which involves binding to the macrophage receptor, thereby activating a cascade to kill intracellular M. tuberculosis. Vitamin D deficiency is a risk factor for both progression to TB and TB treatment outcomes [73]. Smoking and chronic use of alcohol Tobacco and alcohol consumption have long been known to be risk factors for TB, with reports published as early as 1961 [84, 85]. Globally, in 2021, 0.74 and 0.69 million cases were attributable to alcohol-use disorders and smoking, respectively (figure 3) [45]. Tobacco smoking, passive smoking and exposure to indoor air pollution from burning biomass fuels are all risk factors for TB infection and disease [86, 87]. Both first- and second-hand smoking are risk factors for subclinical TB, unsuccessful treatment and TB-related death. The risk of TB shows a linear relationship with years of smoking [88]. Furthermore, smoking is associated with delayed smear and culture conversion, along with an increased probability of cavitary lesions [87, 89, 90]. Recent studies have shown elevated cure rates, reduced transmissibility, and reduced TB recurrence after smoking cessation compared with persistent smokers [91–93]. Alcohol use increases the rate of TB, treatment default, development of DR-TB and TB-related death [94–96]. Alcohol is also associated with a higher likelihood of adverse treatment outcomes in both drug-susceptible TB and MDR-TB patients [97]. The risk of TB increases as https://doi.org/10.1183/2312508X.10023922 27 EPIDEMIOLOGY |R. VERSTRAETEN ET AL.