Pillar One

Tuberculosis (TB) remains a leading infectious disease killer globally despite the availability of robust diagnostics, effective prevention, and treatment. Poor implementation of comprehensive TB programs and HIV infection remain drivers of ongoing elevated TB rates in high burden countries such as South Africa. In South Africa there are many losses in the TB care cascade; an estimated 95% of individuals with TB access testing, yet only 82% are diagnosed, 70% initiate treatment, and 53% successfully complete treatment. However, it is also imperative to screen and treat subclinical TB infection to lessen the vast reservoir of people at risk of progressing to TB disease, especially recent contacts of TB patients and people living with HIV (PLH). Using implementation science methods and building on the success of the improvements in the HIV care cascade “90-90-90” targets, our team has recently piloted two TB care cascades for drug-resistant and drug-sensitive TB and a TB prevention program in which 922 household contacts of patients with TB were screened.

This R01 award will adapt the Systems Analysis and Improvement Approach (SAIA), an evidence-based implementation strategy combining systems engineering tools into a clinic-level package for TB (SAIA-TB), expanding upon successful SAIA models trialed across a range of clinical settings in sub-Saharan Africa and the USA, and leverage the PI’s preliminary TB cascade analysis data in this setting. SAIA-TB will evaluate five comprehensive TB indicators (screening, diagnosis, linkage to care, treatment, and TB-free survival) to aid frontline healthcare workers and managers to optimize cascade performance through the use of a cascade analysis tool, process flow mapping, and continuous quality improvement cycles.

Our specific aims are to: (1) Evaluate the effectiveness of SAIA-TB on cascade optimization for patients with TB and high-risk contacts, specifically people living with HIV. We will use a stepped-wedge crossover trial to evaluate the impact of SAIA-TB on comprehensive TB care in 16 rural clinics. We hypothesize that SAIA-TB implementation will lead to a 20% increase in both screening and TB preventive treatment or TB disease treatment initiation during the 3-year intervention period. (2) Determine the drivers of SAIA-TB implementation variability across clinics. The implementation process will be evaluated using focus group discussions and key informant interviews with clinic staff and analyzed using the consolidated framework for implementation research, with additional data gathered from study logs to describe fidelity to SAIA-TB. (3) Assess the acceptability of comprehensive TB care among patients accessing care at clinics implementing SAIA-TB at each step of the cascade. We will use the theoretical framework for acceptability and the socioecological model to define acceptability and compare individual-, family- and systems-level barriers and facilitators to completing TB cascade steps among patients with and without HIV infection.

The study has been paused since May 2025. However, eight of the 16 clinics have entered the intervention phase and facility staff have been trained on SAIA-TB principles through day-long workshops in Joubertina, Kareedouw, Loutewater, Addo, and Kirkwood. We had a successful launch in Gqeberha in November 2024 with sub-district, district, and provincial participation and our team has captured data from 18,623 patients across these 16 clinics.

Annually, 1.2 million children globally develop tuberculosis (TB) disease which has been treatable for more than 70 years. However, if children are diagnosed and treated appropriately, mortality is <1%. Unfortunately, many children have delays in diagnosis and treatment, and fall out of care once initiated on treatment, and little is known about the long-term effects of TB disease on lung functioning and quality of life in children, known as post-TB lung disease (PTLD). Risk-factors for poor TB treatment outcomes and PTLD are poorly described for children. Therefore, the purpose of this study is to determine gaps in the TB care cascade among children, define PTLD in children, and assess risk-factors for poor TB outcomes in children in order to improve lung health globally.

Specifically, we propose to study children <15 years in the Eastern Cape, South Africa to:

1. Determine gaps in the TB care cascade stratified by age, sex and HIV status.

2. Assess changes in lung function and quality of life throughout the course of TB treatment to 1) identify an optimal threshold to predict post-TB lung disease (PTLD) and 2) develop a robust child-specific definition of PTLD aligned with clinical standards.

3. Assess whether air pollution exposure, nutritional status, and distance to clinic are associated with identified gaps in the TB care cascade, stratified by age, sex and HIV status.

This study is collecting data from children in Gqeberha, South Africa, a high TB prevalence setting, and longitudinally follow-up with a subset of these children to repeatedly measure lung function and quality of life and collect robust air pollution exposure and nutrition-specific laboratory data. Overall, we will examine the TB care cascade at screening, diagnosis, treatment, and post-TB follow-up inclusive of spirometry, laboratory, and air pollutant data to improve pediatric lung health and quality of life.

As of August 2025, we have enrolled 62 children with TB and are starting to conduct six-month follow-up visits with children completing treatment.  We have also received additional funding and have added additional implementation science aims to better understand the barriers and facilitators to participating in the study from the patient and caregiver perspective as well as conduct focus groups with healthcare providers, study staff, and stakeholders about the setting and context in which this study is taking place and how that impacts implementation using the Context and Implementation of Complex Interventions (CICI) framework.