Carel Pretorius

Background: Global investments to combat HIV, tuberculosis, and malaria (HTM) have delivered substantial health gains and may have reduced the burden placed by these diseases on the routine health system. We estimated the reduction in primary healthcare (PHC) utilization resulting from the scale-up of HTM services over 2000–2023 in 108 low- and middle-income countries. Methods and findings: For each disease, we applied established mathematical models to quantify PHC utilization (outpatient visits and inpatient bed-days provided outside of HTM programs) by individuals with symptomatic HIV, tuberculosis, or malaria unable to access HTM-specific services. For each country, we estimated averted PHC utilization by comparing a scenario describing the actual scale-up of HTM services to a counterfactual scenario holding HTM service coverage constant at year 2000 levels. We applied published unit costs to estimate the averted costs resulting from reduced PHC utilization. Over 2000–2023, scale-up of HTM services averted an estimated 6.9 (95% uncertainty interval (UI) [4.4, 10.5]) billion outpatient PHC visits and 3.9 (95% UI [2.5, 5.9]) billion inpatient bed-days, representing US$135 (95% UI [71, 250]) billion in averted costs. These reductions were greatest in sub-Saharan Africa and East Asia and Pacific regions. Across study countries, these reductions represented a median of 4.4% of hospital bed capacity and 1.6% of government health spending in 2023. These percentages were 22.9% and 5.1%, respectively, for low-income countries. Our analysis did not consider changes in PHC services beyond utilization. Also, several inputs were missing in some countries, with missing values estimated using regression imputation. Conclusions: Over recent decades, sustained investments in HTM services in high-burden settings have averted substantial PHC utilization and associated costs. These benefits should be considered when assessing investment impact.

The recent withdrawal of U.S. financial support threatens essential TB service delivery, including diagnostics, treatment, TB-HIV co-infection interventions and research initiatives critical to eradicating TB. This study analyses the dependency of and potential impact of funding cuts to 26 high-burden TB countries (HBCs). We modelled three recovery scenarios: (1) minimal impact (services recover within three months), (2) moderate impact (recovery within one year), and (3) worst-case scenario (long-term service reduction). Extrapolations were made for all 26 HBCs based on representative countries from each dependency category. Across all 26 HBCs, additional TB cases between 2025 and 2030 are estimated at 0.63 million (CI 0.45–0.81) (minimal impact), 1.66 million (CI 1.2–2.1) (moderate impact), and 10.67 million (CI 7.85–13.19) (worst-case). Corresponding TB deaths are projected to increase by 99,900 (CI 65,200–130,000), 268,600 (CI 185,800–337,900), and 2,243,700 (CI 1,570,800–2,807,300), respectively. The loss of U.S. funding endangers global TB control efforts, jeopardizing progress towards End TB and SDG targets, and potentially puts millions of lives at risk. While some nations may adapt, short-term disruptions will severely impact vulnerable populations. Urgent alternative funding is needed to sustain critical TB prevention and treatment efforts.

Rationale Tuberculosis (TB) remains a global health crisis, disproportionately affecting low- and middle-income countries. Strategic resource allocation is essential to achieving the WHO End TB targets. Existing TB costing tools have limitations in conducting global analyses, prompting the development of a novel model tailored to address these gaps. Methods We developed a new, open-source TB costing model that simulates detailed TB care cascades comprising steps of screening, diagnosis, treatment, and prevention for those eligible - according to WHO guidelines for 20 distinct population groups. These include 10 groups each from patient-initiated and provider-initiated pathways, capturing variations in pulmonary status, age, HIV/ART status, and drug sensitivity. The model captures the cost of a large-scale vaccine. We demonstrate the model’s functionality through a case study that informed the Global Fund’s Investment Case for its 8th replenishment (2027–2029). Results In the case study, the model was first used to estimate the cost of implementing the TB Global Plan 2023 - 2030. This scenario incorporated intervention targets, normative standards of care, and the availability of new TB tools. An optimization routine applied to 29 high-burden countries estimated maximal TB impact under constrained funding scenarios. The results were also used to assess the potential impact and contribution of innovation within the Global Fund’s 8th replenishment. Discussion This new TB costing model offers improved representation of TB care complexity across diverse populations, with enhanced transparency, flexibility, and policy relevance. Its application in global TB strategy analysis highlights its value in informing investment cases and prioritizing interventions for maximal impact under resource constraints.

Background: Tuberculosis (TB) remains one of the deadliest infectious diseases globally. Despite the World Health Organization’s (WHO) End TB Strategy targets for 2035, progress has been hindered by structural, financial, and implementation barriers, including recent cuts in global funding. Strategic use of mathematical modelling is useful for prioritizing high-impact interventions and optimizing limited resources. A new global TB infection transmission model was developed to address limitations in existing tools with respect to these applications. Methods: The model includes enhanced features such as age-specific mixing, explicit representation of asymptomatic TB, stratification by drug resistance, HIV status, and new vaccine status, and inclusion of both public and private care pathways. It was calibrated to country-specific data using Bayesian adaptive Markov Chain Monte Carlo (MCMC) methods. The model was used to assess the impact of national strategic plans and the Global Plan to End TB, using a Target Population (TP) component to map interventions to WHO guidelines. Results: Model calibration showed good agreement with historical TB data from 29 high-burden countries, with case studies for Indonesia and Nigeria presented here. In Indonesia, comprehensive implementation of Global Plan interventions - including public-private mix efforts, modern diagnostics, improved treatment for drug-resistant TB, and a post-exposure vaccine - could enable the country to achieve End TB targets by 2035. In Nigeria, implementing its National Strategic Plan could reduce TB incidence by 27% and mortality by 37% by 2030, even without a vaccine. The model highlighted the additional efforts that are needed to meet the End-TB goals. Conclusions: The enhanced TB model provides a flexible, policy-relevant framework for assessing the epidemiological impact of TB interventions at both national and global levels. Its open-source design and alignment with WHO recommendations make it a valuable tool for guiding evidence-based investments amid tightening global health budgets.

Background Investments to combat HIV, tuberculosis, and malaria (HTM) have delivered substantial health gains in high-burden settings. There is limited evidence on how this has affected primary health care (PHC). We estimated the changes in PHC utilization and associated cost savings resulting from scale-up of HTM interventions in 108 low- and middle-income countries over 2000–2023. Methods For each disease, we applied validated mathematical models quantifying the incremental differences in PHC outpatient visits and inpatient bed-days by individuals with untreated symptomatic HIV, tuberculosis, or malaria. By country and year, we compared the actual scale-up of HTM services scenario against a counterfactual scenario holding HTM intervention coverage constant at year 2000 levels. We estimated the cost savings associated with these utilization reductions, and compared results to national hospital capacity and health expenditure. Findings Over 2000–2023, scale-up of HTM services averted an estimated 6·9 (95% interval: 4·4–10·4) billion PHC outpatient visits and 3·9 (2·5–6·1) billion inpatient bed-days, equivalent to US$135 (77–225) billions in total cost savings. Reductions in utilization and cost savings were greatest in the Sub-Saharan Africa and East Asia and Pacific regions. For 2023, a median of 4·4% of hospital bed capacity and 1·6% of government health expenditures were freed-up across study countries. These percentages were 22·9% and 5·1% respectively for low-income countries. Interpretation Sustained investments in HTM services in high-burden settings generated substantial cost savings over recent decades through reduced PHC utilization. These benefits should be considered when assessing investment impact. Funding The Global Fund.

Background The abrupt discontinuation of U.S. government funding for global tuberculosis (TB) programs has created significant challenges in TB care and prevention. In 2023, external funding accounted for 21% of total TB expenditures, with the U.S. contributing over 55% of these funds. The withdrawal of U.S. support threatens essential TB services, including diagnostics, treatment, TB-HIV co-infection interventions, and research initiatives critical to achieving the 2030 Sustainable Development Goals (SDGs) for TB eradication. Methods This study analyses the dependency of 26 high-burden TB countries (HBCs) on U.S. funding and models the potential impact of funding cuts on TB incidence and mortality. Countries were classified into low (0–22%), moderate (23–37%), and high (>37%) dependency groups based on three-year expenditure data. A deterministic compartmental model simulated service disruptions under three recovery scenarios: (1) minimal impact (services recover within three months), (2) moderate impact (recovery within one year), and (3) worst-case scenario (permanent service reduction). Extrapolations were made for all 26 HBCs based on representative countries from each dependency category. Findings Funding cuts are projected to result in substantial increases in TB cases and deaths across the three scenarios. In a high-dependency country, cumulative TB cases could rise by 2.1% (CI 1.5 – 2.5), 5.4% (CI4 – 6.5), or 36% (CI 25 – 47), and TB deaths by 2.9%(CI 2.2 – 3.5), 7.8%(CI 5.9 – 9.2), 68%(CI 45 - 86), depending on the severity of service disruptions. Across all 26 HBCs, additional TB cases are estimated at 0.63 million (CI 0.45 – 0.81) (minimal impact), 1.66 million (CI 1.2 – 2.1) (moderate impact), and 10.67 million (CI 7.85 – 13.19) (worst-case). Corresponding TB deaths are projected to increase by 99,800 (CI 65,200–130,000), 268,600 (CI 185,800–337,900), and 2,243,700 (CI 1,570,800–2,807,300), respectively. The findings underscore the catastrophic consequences of the funding cut, particularly in countries highly reliant on U.S. support. Interpretation The loss of U.S. funding endangers global TB control, jeopardizing End TB and SDG targets. While some nations may adapt, short-term disruptions will severely impact vulnerable populations. Urgent alternative funding is needed to sustain TB prevention and treatment efforts and mitigate the effects of aid withdrawal. Funding None for this specific work

The 2018 United Nations High-Level Meeting on Tuberculosis (UNHLM) set targets for case detection and TB preventive treatment (TPT) by 2022. However, by the start of 2022, about 13.7 million TB patients still needed to be detected and treated, and 21.8 million household contacts needed to be given TPT globally. To inform future target setting, we examined how the 2018 UNHLM targets could have been achieved using WHO-recommended interventions for TB detection and TPT in 33 high-TB burden countries in the final year of the period covered by the UNHLM targets. We used OneHealth-TIME model outputs combined with the unit cost of interventions to derive the total costs of health services. Our model estimated that, in order to achieve UNHLM targets, >45 million people attending health facilities with symptoms would have needed to be evaluated for TB. An additional 23.1 million people with HIV, 19.4 million household TB contacts, and 303 million individuals from high-risk groups would have required systematic screening for TB. The estimated total costs amounted to ~USD 6.7 billion, of which ~15% was required for passive case finding, ~10% for screening people with HIV, ~4% for screening household contacts, ~65% for screening other risk groups, and ~6% for providing TPT to household contacts. Significant mobilization of additional domestic and international investments in TB healthcare services will be needed to reach such targets in the future.

Background Routine services for tuberculosis (TB) are being disrupted by stringent lockdowns against the novel SARS-CoV-2 virus. We sought to estimate the potential long-term epidemiological impact of such disruptions on TB burden in high-burden countries, and how this negative impact could be mitigated. Methods We adapted mathematical models of TB transmission in three high-burden countries (India, Kenya and Ukraine) to incorporate lockdown-associated disruptions in the TB care cascade. The anticipated level of disruption reflected consensus from a rapid expert consultation. We modelled the impact of these disruptions on TB incidence and mortality over the next five years, and also considered potential interventions to curtail this impact. Results Even temporary disruptions can cause long-term increases in TB incidence and mortality. We estimated that a 3-month lockdown, followed by 10 months to restore normal TB services, would cause, over the next 5 years, an additional 1.92 million TB cases (Crl 1.74 - 2.15) and 488,000 TB deaths (CrI 449 - 541 thousand) in India, 48,000 (33,400 - 72,320) TB cases and 16,800 deaths (11.9 - 21.9 thousand) in Kenya, and 9,100 (6,980 - 11,200) cases and 1,960 deaths (1,620 - 2,350) in Ukraine. However, any such negative impacts could be averted through supplementary 'catch-up' TB case detection and treatment, once restrictions are eased. Interpretation Lockdown-related disruptions can cause long-lasting increases in TB burden, but these negative effects can be mitigated with targeted interventions implemented rapidly once lockdowns are lifted.

This paper presents two approaches to smoothing time trends in prevalence and estimating the underlying incidence of remissible infections. In the first approach, we use second order segmented polynomials to smooth a curve in a bounded domain. In the second, incidence is modeled instead and the prevalence is reconstructed using the recovery rate which is assumed to be known. In both approaches, the number of knots and their positions are estimated, resulting in non-linear regressions. Akaike Information Criterion is used for model selection. The method is illustrated with Syphilis and Gonorrhea prevalence smoothing and incidence trend estimation in Guinea-Bissau and South Africa, respectively.