Rein M. G. J. Houben

While a range of interventions exists for tuberculosis (TB), their potential impact and cost-effectiveness are seldom directly compared across settings with different TB epidemiologies and structural drivers. Here we calibrated a deterministic TB model to epidemiological indicators from Brazil, India and South Africa. We implemented seven interventions across countries focusing on prevention, screening and diagnosis and treatment, as well as prison screening (Brazil) and nutritional supplementation (India). We standardized scale-up (2025–2030), coverage (80% of the target population) and strength of evidence using published efficacy data. We estimated the epidemiological impact and incremental cost-effectiveness ratios (ICERs), expressed as costs per disability-adjusted life year (DALY) averted, through 2050. Only three interventions prevented >10% of incident TB episodes by 2050: vaccination (median 15–28% across countries), symptom-agnostic community-wide screening (31–38%) and prison screening (23%). Other interventions had limited impact, ranging from 0% (shorter drug-susceptible treatment) to 5% (nutritional supplementation). ICERs varied widely by intervention and setting. Shorter drug-resistant treatment was cost-saving across settings, with the next lowest ICERs for prison screening (US$146 per DALY) and nutritional supplementation (US$281 per DALY). Interventions with meaningful epidemiological impact can be cost-effective but must target populations beyond clinic-diagnosed individuals and their households. Achieving such potential requires a shift in priorities regarding funding, policy and product development.

The South Africa National Department of Health have set ambitious targets to scale up TB testing, focusing primarily on clinic attendees. In the context of declining funding for TB care and prevention, the most cost-effective approaches for targeting testing should be identified. We developed a mathematical model of TB in South Africa, explicitly incorporating clinic attendance by sex and HIV/ART status. We simulated six screening approaches over 2026–2035 (individually and in combination): three clinic-based (symptom screening, intensified targeted universal TB testing [TUTT, symptom-agnostic sputum testing of clinic attendees in key risk groups], and intensified TUTT allowing saliva samples) and three targeted community-based (community radiographic screening, symptom screening, and universal Xpert Ultra testing), each implemented at a range of coverage levels. Model outputs were combined with a mechanistic cost function to estimate potential impact and cost-effectiveness from a societal perspective. The most cost-effective standalone approach was community radiographic screening at 10% annual population coverage, with an incremental cost-effectiveness ratio (ICER) of $421 per disability-adjusted life year (DALY) averted. 10/11 scenarios along the expansion path included community radiographic screening at progressively higher coverage, combined with a clinic-based approach. Combining complementary approaches to reach both groups at increased risk of TB (e.g. clinic-based screening) and groups with lower screening coverage (e.g. community-based screening) may increase cost-effectiveness of TB screening, compared to standalone approaches. When designing TB screening strategies, both population risk and existing screening coverage should be considered.

Background: Tuberculosis remains the leading infectious cause of death worldwide. In the WHO African region, declining incidence has coincided with antiretroviral therapy (ART) scale-up, though whether this reflects reduced progression to disease or reduced transmission is unclear. We evaluated how ART and symptom status influence within-household Mycobacterium tuberculosis complex (MTBC) transmission risk. Methods: We conducted a case-contact household study in rural South Africa, enrolling index adults with bacteriologically-confirmed pulmonary tuberculosis. MTBC immunoreactivity was measured in all child household contacts (aged 2-14 years) as a proxy measure of within-household transmission. We assessed the influence of index person ART status and symptom status and explored effect-measure modification of the association between index person HIV status and transmission risk by sex. Results: Among 755 child contacts of 296 index persons, effective ART was not associated with within-household MTBC transmission risk (risk ratio [RR], 1.07; 95% CI, 0.66–1.74). Among PLHIV engaged in ART care, WHO TB four-symptom screen (WHO4SS) status was not associated with transmission risk (RR, 0.80; 95% CI, 0.43–1.47), although absence of reported cough reduced risk (RR, 0.61; 95% CI, 0.38–0.96). A pronounced interaction between sex and HIV status was observed: HIV-negative women had the highest within-household MTBC transmission risk (30.5% vs. 14.3% in women with HIV) whereas risks were similar between HIV-positive and HIV-negative men. Conclusions: We found no evidence that effective ART or WHO4SS status influenced within-household MTBC transmission risk, though confidence intervals were wide. Absence of reported cough was associated with lower risk, and transmission risk was highest among child contacts of HIV-negative women. These findings suggest reported cough is a useful marker of transmission risk and that routine tuberculosis screening within ART care may reduce transmission from PLHIV; intensified efforts are nonetheless needed to achieve earlier tuberculosis detection in HIV-negative individuals.

Background: Current tuberculosis (TB) prevention and care strategies have failed to reduce disease burden at the pace required to meet global targets. Community screening may enable more rapid declines in TB burden, but evidence is limited. We used mathematical modelling to evaluate approaches using different diagnostic algorithms, population coverage, and duration of screening. Methods and findings: We used a deterministic compartmental TB model, which recognised symptomatic and asymptomatic infectious TB (defined by whether an individual reported symptoms at screening), as well as noninfectious TB. We simulated diagnostic algorithms targeting symptomatic infectious TB (prolonged cough with confirmatory Xpert Ultra), infectious TB (Xpert Ultra), or all TB (chest X-ray), and we varied population coverage and duration of screening. Main outcomes were estimated reduction in symptomatic TB incidence and TB mortality over a 10-year horizon. Maximum coverage (100%) and duration (five annual rounds) was projected to reduce symptomatic TB incidence by 26.9% (UI 22.8, 31.5%) with the algorithm targeting symptomatic TB and 74.0% (UI 68.5, 79.1%) with the algorithm targeting infectious TB. However, incidence rebounded at the end of screening, erasing 9.8% and 15.9%, respectively, of those reductions within 5 years. The algorithm targeting all TB showed higher potential for rapid reductions—over 98%—with negligible rebound; however, low diagnostic accuracy of current tools led to prohibitive overdiagnosis, with 7.2 false positives per true positive in a single round of screening. Screening algorithms targeting broader disease definitions (infectious or all TB) generally achieved greater impact with lower population coverage and/or duration. Findings were broadly similar for mortality. As a modelling study, our approach assumed a homogeneous population for simplicity and required assumptions where data were lacking around algorithm performance, treatment acceptance, and treatment completion across disease states. Conclusions: We show that substantial reductions in TB morbidity and mortality can be achieved by community screening, highlighting the importance of symptom-agnostic algorithms and the need to balance population coverage and duration. To maximise and sustain epidemiological impact, accurate diagnostic tools and appropriate treatment regimens for individuals with noninfectious TB are needed.

Background: Tuberculosis (TB) remains a leading cause of infectious disease death. New TB vaccines are currently in late-stage trials and may be available before the end of the decade. Modelling predicts new TB vaccines may reduce global burden but rely on assumptions about vaccine efficacy by TB disease stage and TB natural history, which may be incorrect. We explored the sensitivity of estimates of the impact of new TB vaccines to uncertainties in efficacy by disease stage and natural history. Methods and findings: We developed a dynamic compartmental TB model for India, including early TB disease stages (non-infectious disease, infectious asymptomatic disease, and infectious symptomatic disease). Scenarios assumed 50% vaccine efficacy for 10 years and prevented progression to (a) only infectious symptomatic disease, or (b) any infectious disease (infectious asymptomatic disease and infectious symptomatic disease), or (c) any disease (non-infectious disease, infectious asymptomatic disease, and infectious symptomatic disease). We estimated impact on averting disease episodes over 2030–2050, compared to no-new-vaccine introduction. Results suggest, over 3 years, there was little difference in the proportion of cumulative symptomatic disease episodes averted by vaccines preventing only infectious symptomatic disease, any infectious disease, or any disease (1.6%, 2.3%, and 2.3%, respectively). However, over 20 years, compared to vaccines preventing only infectious symptomatic disease, vaccines preventing any infectious disease, or any disease, averted a markedly higher proportion of symptomatic disease episodes (7.3%, 19.4%, and 23.3%, respectively), due to preventing continued transmission from infectious asymptomatic disease. A key limitation with any mathematical modelling study is the uncertainty associated with the inputs, and further data collection is required to better understand the transmissibility, morbidity, and dynamics of asymptomatic disease, to improve modelling estimates and inform wider policy. Conclusions: Our modelling estimates that the population impact of new TB vaccines may depend on efficacy against infectious asymptomatic disease. TB vaccine trials should include analyses of participant sputum samples (collected during or at the end of trials and analysed at the end of trials) to enable better estimates of the potential value of new TB vaccines against infectious asymptomatic disease.

Background: Estimating the proportion of individuals currently infected with Mycobacterium tuberculosis ( Mtb ) is key for informing global health policies. Although a substantial portion of the global population exhibit tuberculous immunoreactivity, not all have a viable Mtb infection. Moreover, individuals with recent infections are at a higher risk of developing tuberculosis (TB). Here, we present estimates of the global burden of viable Mtb infection, using new insights into the natural history of TB. Methods and findings: We constructed country-specific trends in annual risk of infection considering estimates of TB burden, immunoreactivity reversion, and age-specific mixing. We applied these trends to a deterministic mathematical model incorporating reinfection and self-clearance to estimate recent (within 2 years) and total viable Mtb infections. Empirical data on self-clearance are limited, so rates were informed by modelling estimates. In 2022, we estimated that 133.7 million people (95% uncertainty interval [UI]: 104.0, 171.1) had a recent Mtb infection, representing 1.7% (95% UI: 1.3, 2.2) of the global population. In total, 288.9 million people (95% UI: 242.2, 342.7)—or 3.7% (95% UI: 3.1, 4.3) globally—were estimated to harbour a viable Mtb infection. Among those recently infected, 12.0% (95% UI: 11.4, 12.7) were children under 15 years of age. Most recent infections were found in the World Health Organization regions of South-East Asia (49.0%; 95% UI: 37.2, 62.4), the Western Pacific (19.7%; 95% UI: 12.6, 30.5), and Africa (17.9%; 95% UI: 12.9, 24.1). India, Indonesia, and China had the highest burden, with 39.1 million (95% UI: 18.0, 73.6), 12.0 million (95% UI: 5.8, 22.9), and 11.2 million (95% UI: 5.0, 25.5) people, respectively, recently infected with Mtb . Sensitivity analyses of varying self-clearance scenarios showed significant changes in global estimates of viable Mtb infection, particularly in total burden, with lower self-clearance rates. Overall uncertainty in the estimates was considerable, reflecting limitations in the underlying data informing key model parameters. Conclusions: Our findings offer global burden estimates of viable Mtb infection and reveal a sizable population recently infected with Mtb and at high risk of progression to disease. New diagnostic tools that can detect individuals with viable Mtb —particularly those who would benefit from TB preventive therapy—are urgently needed.

Bedaquiline (BDQ) is a cornerstone antibiotic for treating multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB). Resistance to BDQ (BDQR) can arise through three mechanisms: spontaneous mutation, acquisition during treatment, or transmission of a resistant strain. We developed a transmission threshold model to estimate the contribution of each mechanism to BDQR burden in MDR/RR-TB We integrated four data sources: (i) novel estimates of spontaneous resistance probability; (ii) updated estimates of acquired resistance during treatment probability; (iii) a systematic review of country-level BDQR prevalence in MDR/RR-TB (BR-MDR/RR-TB); and (iv) WHO MDR/RR-TB notification and treatment data. We estimated the proportion of BR-MDR/RR-TB attributable to transmission, using transmission threshold values defined as the ratio of BDQR observed in prevalence studies to expectations from spontaneous and acquired mechanisms alone. Analyses were conducted across hypothetical BDQR prevalence and treatment coverage scenarios, as well as country-specific data. We estimated spontaneous resistance among all MDR/RR-TB at 0.073% (95% CrI: 0.062-0.085%) and acquired resistance among MDR/RR-TB patients receiving BDQ at 3.6% (95% CrI: 2.8-4.4%). BDQR prevalence among MDR/RR-TB varied between 0-20% across 18 countries between 2015-2024. Scenario modelling suggested that spontaneous and acquired resistance alone could not account for BDQR prevalence among MDR/RR-TB above 1.9% in settings where ≤50% of MDR/RR-TB patients had received BDQ in the previous year-suggesting possible transmission. In Brazil, China, Mozambique, and South Africa, threshold values and associated uncertainty were consistent with BR-MDR/RR-TB transmission since 2020. Other countries had threshold values consistent with resistance primarily arising spontaneously or through acquisition. Determining country- and year-specific threshold values may help guide decisions on when to prioritise protecting a new antibiotic by preventing resistance acquisition versus when ongoing transmission requires interventions focused on interrupting transmission.

Background: Community-wide screening is a crucial strategy to end tuberculosis (TB), but a common concern is potential harm from overtreatment following false positive diagnoses. However, current reference standards determining test performance have limitations, with implications for prevalence thresholds and treatment decisions for community-wide screening. Methods: We estimated coverage of community-wide screening at a prevalence threshold of 0.5% (current global standard), 0.25%, and 0.1% for adult pulmonary TB. We considered test performance for Xpert Ultra against different reference standards (sputum culture, plus clinical evaluation, plus disease progression within two years). Potential harm was estimated through disability adjusted life years (DALYs) incurred or averted by treatment. We report net specificity, positive predictive value (PPV), the ratio of false positives to true positives, and DALYs averted for (non-)treatment based on different reference standards. Results: A lower threshold would increase screening coverage from the current 42% to 84% (0.25% threshold) and 89% (0.1% threshold) of the global TB burden. In a population of 100,000 with 0.5% prevalence, specificity was 99.5% for community screening, but increased to 99.7% using disease progression as reference standard, with PPV increasing from 45 to 66%. In addition, estimated harm of withholding appropriate treatment was approximately 1,200 times higher compared to providing inappropriate treatment, with treatment initiation after a positive Xpert Ultra increasing overall DALYs averted (median 5,977 versus 3,750). Discussion: The benefit of TB treatment following a positive molecular test in community-wide screening likely outweighs the harm associated with possible overtreatment, supporting expanding coverage of simplified community-wide screening. Brief summary: A concern with community-wide tuberculosis screening is the potential for overtreatment. We evaluated diagnostic reference standards and relative health costs of (non-)treatment, finding that after a positive molecular test, the benefit of initiating tuberculosis treatment likely outweighs its harm.