Modelling the South African tuberculosis epidemic: the effect of HIV, sex differences, and the impact of interventions

The South African tuberculosis (TB) epidemic is driven mainly by HIV, and the TB disease burden is greater in males than females. Additional factors that drive the epidemic include undiagnosed and untreated TB, contributing to transmission; and highly prevalent TB risk factors such as alcohol misuse, smoking, diabetes, and undernutrition, which increase the risk of progression to TB disease. These factors are distributed differently by sex and likely explain the observed sex disparities in TB. The South African TB control programme has implemented multiple interventions, including directly observed therapy strategy (DOTS), antiretroviral therapy (ART), intensified screening activities, the provision of isoniazid preventative therapy (IPT) and the implementation of Xpert MTB/RIF as a first-line diagnostic tool. However, few analyses have quantified the historical impact of HIV and the combined impact of TB interventions on the South African TB epidemic at a national level. In addition, factors that influence sex disparities in the South African TB burden have not been explored thoroughly. Also, it remains uncertain whether, with existing interventions, it would be feasible for South Africa to meet the End TB targets to reduce TB incidence and mortality by 80% and 90% respectively (relative to 2015 levels) by 2030. This thesis aims to address the abovementioned gaps in knowledge and provide insights into understanding the population-level TB dynamics, using a mathematical model. The first objective is to quantify TB incidence and mortality due to HIV and assess the impact of interventions mentioned above on TB incidence and mortality between 1990 and 2019. The second objective is to explore the extent to which the following factors contribute to sex differences in TB: HIV, ART uptake, smoking, alcohol abuse, undernutrition, diabetes, health-seeking patterns, social contact rates and TB treatment discontinuation. The third objective is to project the future impact of increasing screening, improving linkage to TB care and retention, increasing preventative therapy, and reducing ART interruptions. An age- and sex-stratified dynamic tuberculosis transmission model for South Africa was developed. To dynamically model the effect of HIV and ART on TB incidence and mortality, the TB model was integrated into the Thembisa model, a previously developed HIV and demographic model. In addition, age- and sex-specific relative risks were applied to rates of progression to TB disease to capture age and sex differences in tuberculosis incidence. The model also included a diagnostic pathway representing health-seeking patterns and the sensitivity and specificity of the diagnostic algorithm. A Bayesian approach was used to calibrate the model to the numbers of people starting treatment from the electronic tuberculosis register, deaths from the vital register, microbiological tests, and the national tuberculosis prevalence survey. The model estimated rapid increases in TB incidence and mortality in the mid-to-late 1990s, influenced by HIV. Between 1990 and 2019, approximately eight million people developed tuberculosis, and two million died from TB; HIV accounted for at least half and two-thirds of the TB incidence and mortality, respectively. The TB epidemic peaked in the mid-to-late 2000s, followed by declines until 2019. The ART program and TB screening efforts, which were expanded in the mid-2000s, contributed the most to reductions in TB incidence and mortality, while other interventions had minor impacts. Due to the heavier HIV burden in women than men, women experienced greater HIV-associated TB incidence and mortality than men. However, because of the higher ART uptake among women than men, women experienced greater relative reductions in TB incidence and mortality over the period 2005– 2019. Consequently, the higher TB burden among men has been sustained; the estimated male-to-female ratios of TB incidence and mortality in 2019 were 1.7 and 1.65, respectively. Additional factors explaining the excess TB in men are smoking, alcohol abuse and delays in health-seeking patterns. Sex differences in undernutrition, social contact patterns, and treatment discontinuation had minimal effect on TB sex disparities. Projections of the model to 2030, considering the effects of COVID-19-related disruptions to TB care, suggest that increasing TB screening would be the most impactful among all interventions explored. However, the model also suggests that the 2030 End TB milestone is unlikely to be met by scaling up existing interventions. Other interventions that need to be explored include targeted universal TB testing and other diagnostic tests such as digital chest x-rays, urine Lipoarabinomannan, and biomarkers to identify individuals at risk of TB disease. Accelerating progress toward TB incidence and mortality reductions will require developing affordable and efficient rapid diagnostic tools to identify potential and active TB cases. Research and innovation efforts towards finding a vaccine effective in preventing TB disease are also critical. In addition, it is essential to improve the uptake of TB preventative therapy in HIV-positive individuals and perhaps further expand provision to other TB risk group

The prevalence and risk factors of diabetes mellitus among tuberculosis patients at Ubuntu clinic, Khayelitsha

Summary: There is strong evidence suggesting that diabetes mellitus (DM) triples the risk of tuberculosis (TB) disease and worsens TB outcomes. South Africa carries a heavy burden of TB which is primarily driven by the human deficiency virus (HIV). The burden of non-communicable disease is also growing rapidly in South Africa. There is however lack of up to date data on the burden of DM and the associated risk factors among TB patients. This dissertation is based on a cross-sectional study which sought to assess the prevalence of DM and impaired glucose tolerance (IGT) and determine the risk factors associated with DM among TB patients. Methods: This cross sectional study forms part of a case control study that aimed to assess the association between DM and TB and the population attributable risk of TB due to DM in Khayelitsha, a high HIV and TB setting. The TB patients recruited in the case control study formed the population of this current cross-sectional study. Based on oral glucose tolerance test, fasting blood glucose, glycated haemoglobin and self-report the prevalence of DM was determined. Bivariate and multivariate logistic regression analyses were performed to assess risk factors associated DM among TB patients. Due to significant differences between male and females with respect to various characteristics, we also stratified the data by sex during analysis

An agent-based model of binge drinking, inequitable gender norms and their contribution to HIV transmission, with application to South Africa

Abstract Background Binge drinking, inequitable gender norms and sexual risk behaviour are closely interlinked. This study aims to model the potential effect of alcohol counselling interventions (in men and women) and gender-transformative interventions (in men) as strategies to reduce HIV transmission. Methods We developed an agent-based model of HIV and other sexually transmitted infections, allowing for effects of binge drinking on sexual risk behaviour, and effects of inequitable gender norms (in men) on sexual risk behaviour and binge drinking. The model was applied to South Africa and was calibrated using data from randomized controlled trials of alcohol counselling interventions (n = 9) and gender-transformative interventions (n = 4) in sub-Saharan Africa. The model was also calibrated to South African data on alcohol consumption and acceptance of inequitable gender norms. Binge drinking was defined as five or more drinks on a single day, in the last month. Results Binge drinking is estimated to be highly prevalent in South Africa (54% in men and 35% in women, in 2021), and over the 2000–2021 period 54% (95% CI: 34–74%) of new HIV infections occurred in binge drinkers. Binge drinking accounted for 6.8% of new HIV infections (0.0–32.1%) over the same period, which was mediated mainly by an effect of binge drinking in women on engaging in casual sex. Inequitable gender norms accounted for 17.5% of incident HIV infections (0.0–68.3%), which was mediated mainly by an effect of inequitable gender norms on male partner concurrency. A multi-session alcohol counselling intervention that reaches all binge drinkers would reduce HIV incidence by 1.2% (0.0–2.5%) over a 5-year period, while a community-based gender-transformative intervention would reduce incidence by 3.2% (0.8–7.2%) or by 7.3% (0.6–21.2%) if there was no waning of intervention impact. Conclusions Although binge drinking and inequitable gender norms contribute substantially to HIV transmission in South Africa, recently-trialled alcohol counselling and gender-transformative interventions are likely to have only modest effects on HIV incidence. Further innovation in developing locally-relevant interventions to address binge drinking and inequitable gender norms is needed

Tuberculosis, Human Immunodeficiency Virus, and the Association With Transient Hyperglycemia in Periurban South Africa

Abstract Background Diabetes mellitus (DM) increases tuberculosis (TB) risk. We assessed the prevalence of hyperglycemia (DM and impaired glucose regulation [IGR]) in persons with TB and the association between hyperglycemia and TB at enrollment and 3 months after TB treatment in the context of human immunodeficiency virus (HIV) infection. Methods Adults presenting at a Cape Town TB clinic were enrolled. TB cases were defined by South African guidelines, while non-TB participants were those who presented with respiratory symptoms, negative TB tests, and resolution of symptoms 3 months later without TB treatment. HIV status was ascertained through medical records or HIV testing. All participants were screened for DM using glycated hemoglobin and fasting plasma glucose at TB treatment and after 3 months. The association between TB and DM was assessed. Results Overall DM prevalence was 11.9% (95% confidence interval [CI], 9.1%–15.4%) at enrollment and 9.3% (95% CI, 6.4%–13%) at follow-up; IGR prevalence was 46.9% (95% CI, 42.2%–51.8%) and 21.5% (95% CI, 16.9%–26.3%) at enrollment and follow-up. TB/DM association was significant at enrollment (odds ratio [OR], 2.41 [95% CI, 1.3–4.3]) and follow-up (OR, 3.3 [95% CI, 1.5–7.3]), whereas TB/IGR association was only positive at enrollment (OR, 2.3 [95% CI, 1.6–3.3]). The TB/DM association was significant at enrollment in both new and preexisting DM, but only persisted at follow-up in preexisting DM in patients with HIV-1 infection. Conclusions Our study demonstrated high prevalence of transient hyperglycemia and a significant TB/DM and TB/IGR association at enrollment in newly diagnosed DM, but persistent hyperglycemia and TB/DM association in patients with HIV-1 infection and preexisting DM, despite TB therapy. This work was supported by the Wellcome Trust (grant numbers 084323, 104873, and 203135), a Carnegie Corporation Postdoctoral Fellowship, and a Harry Crossley Senior Clinical Fellowship. R. J. W. is supported by the Francis Crick Institute, which receives funding from Cancer Research UK (grant number FC001010218), Research Councils UK (grant number FC0010218), and the Wellcome Trust (grant number FC0010218). He also receives support from the National Institutes of Health (NIH) (grant number U1 AI115940), NIH (grant number WILK116PTB), and European and Developing Countries Clinical Trials Partnership (grant number SRIA 2015–1065). M. K. is supported by the South African Centre for Epidemiological Modelling and Analysis, the International Epidemiology Databases to Evaluate AIDS, and the NIH (grant number U01AI069924)

The impact of HIV and tuberculosis interventions on South African adult tuberculosis trends, 1990-2019: a mathematical modelling analysis

Objectives: To quantify the South African adult tuberculosis (TB) incidence and mortality attributable to HIV between 1990 and 2019 and to estimate the reduction in TB incidence due to directly observed therapy, antiretroviral therapy (ART), isoniazid preventive therapy, increased TB screening, and Xpert MTB/RIF. Methods: We developed a dynamic TB transmission model for South Africa. A Bayesian approach was used to calibrate the model to South African-specific data sources. Counterfactual scenarios were simulated to estimate TB incidence and mortality attributable to HIV and the impact of interventions on TB incidence. Results: Between 1990 and 2019, 8.8 million (95% confidence interval [CI] 8.3-9.3 million) individuals developed TB, and 2.1 million (95% CI 2.0-2.2 million) died from TB. A total of 55% and 69% of TB cases and mortality were due to HIV, respectively. Overall, TB screening and ART substantially reduced TB incidence by 28.2% (95% CI 26.4-29.8%) and 20.0% (95% CI 19.2-20.7%), respectively, in 2019; other interventions had minor impacts. Conclusion: HIV has dramatically increased TB incidence and mortality in South Africa. The provision of ART and intensification of TB screening explained most recent declines in TB incidence

Drivers of sex differences in the South African adult tuberculosis incidence and mortality trends, 1990–2019

Abstract Males have higher tuberculosis incidence and mortality rates than females. This study aimed to assess how sex differences in tuberculosis incidence and mortality could be explained by sex differences in HIV, antiretroviral treatment (ART) uptake, smoking, alcohol abuse, undernutrition, diabetes, social contact rates, health-seeking patterns, and treatment discontinuation. We developed an age-sex-stratified dynamic tuberculosis transmission model and calibrated it to South African data. We estimated male-to-female (M:F) tuberculosis incidence and mortality ratios, the effect of the abovementioned factors on the M:F ratios and PAFs for the tuberculosis risk factors. Over the period 1990–2019, the M:F ratios for tuberculosis incidence and mortality rates persisted above 1.0, and the figures reached 1.70 and 1.65, respectively, by the end of 2019. In 2019, HIV contributed greater increases in tuberculosis incidence among females than males (54.5% vs. 45.6%); however, females experienced more reductions due to ART than males (38.3% vs. 17.5%). PAFs for tuberculosis incidence due to alcohol abuse, smoking, and undernutrition, in men were 51.4%, 29.5%, and 16.1%, respectively, higher than females (30.1%, 15.4%, and 10.7%, respectively); the PAF due to diabetes was higher in females than males (22.9% vs. 17.5%). Lower health-seeking rates in males accounted for a 7% higher mortality rate in men. The higher burden of tuberculosis in men highlights the need to improve men’s access to routine screening and ensure earlier diagnosis. Sustained efforts in providing ART remain critical in reducing HIV-associated tuberculosis. Additional interventions to reduce alcohol abuse and tobacco smoking are also needed