Martin Harker

Background: Tuberculosis preventive treatment (TPT) with levofloxacin reduces tuberculosis disease incidence in multidrug-resistant or rifampicin-resistant (MDR/RR)-tuberculosis household contacts. However, with age, disease progression risk falls and the frequency of adverse events (AE) rises. Methods: To inform decision-makers, we evaluated the cost-effectiveness of expanding the use of MDR/RR-TPT by age, with and without tests of tuberculosis infection. We modelled MDR/RR-household contact management (HHCM) in 189 countries, incorporating age-dependent risks of disease progression, death and AEs. Incremental cost-effectiveness ratios were calculated as USD/disability-adjusted life year (DALY) averted, and as a fraction of per capita gross domestic product (GDP). Findings: Compared to baseline of MDR/RR-HHCM with TPT for those M. tuberculosis infection were dominated by those without testing. Globally, full use of MDR/RR-HHCM with TPT for all would avert 11,900 (10,400 to 13,800) episodes of tuberculosis, 9,960 (9,100 to 10,900) deaths, and 289,000 (262,000 to 321,000) DALYs, but would result in 71,000 (68,000 to 74,000) SAEs and cost $359 million (294 to 449). Interpretation: Expanding MDR/RR-TPT use to older ages without testing appears cost-effective in most settings, but may require substantial resources and result in large numbers of AEs. Funding: Unitaid

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.

Population-wide screening may accelerate the decline of tuberculosis (TB) incidence, but the optimal screening algorithm and duration must weigh resource considerations. We calibrated a deterministic transmission model to TB epidemiology in Viet Nam. We simulated three population-wide screening algorithms from 2025: sputum nucleic acid amplification tests (NAAT, Xpert MTB/RIF Ultra) only; chest radiography (CXR) followed by NAAT; and CXR-only without microbiological confirmation. We determined the annual screening rounds required to reduce pulmonary TB prevalence below 50 per 100,000 people. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs), representing the additional costs (in US$) per disability-adjusted life year (DALY) averted compared to business-as-usual by 2050. Additionally, we evaluated the impact of NAAT cartridges costing US$1 each. NAAT-based algorithms required at least six rounds to reach the prevalence threshold, while CXR-only required three. NAAT-only achieved a prevalence reduction consistent with the ACT3 trial after three rounds. The CXR+NAAT algorithm averted 4.29m DALYs (95%UI:2.86-6.14) at US$225 (95%UI:85–520) per DALY averted compared with business-as-usual. The front-loaded investment of US$161m (95%UI:111–224) annually during the intervention resulted in average annual cost savings of US$12.7m (95%UI:6.7-21.4) up to 2050 compared to the business-as-usual counterfactual. Reducing the cost of NAAT to US$1 led to a 50% and 15% reduction in budget impact and a 63% and 26% reduction in the estimated ICER for the NAAT-only and CXR+NAAT algorithms, respectively. In Viet Nam, population-wide screening could achieve ambitious policy goals. Substantial front-loaded investment is immediately followed by persistent cost savings and could be further offset by more affordable NAATs.

Background: Population-wide screening may accelerate the decline of tuberculosis (TB) incidence, but the optimal screening algorithm and duration must weigh resource considerations. Methods: We calibrated a deterministic transmission model to TB epidemiology in Viet Nam. We designed three population-wide screening algorithms from 2025: sputum nucleic acid amplification tests (NAAT, Xpert MTB/RIF Ultra) only; chest radiography (CXR) followed by NAAT; and CXR-only without microbiological confirmation. We determined the annual screening rounds required to reduce pulmonary TB prevalence below 50 per 100,000 people. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs), representing the additional costs (in US$) per disability-adjusted life year (DALY) averted compared to business-as-usual by 2050. Additionally, we evaluated the impact of NAAT cartridges costing US$1 each. Findings: NAAT-based algorithms required at least six rounds to reach the prevalence threshold, while CXR-only required three. NAAT-only achieved a prevalence reduction consistent with the ACT3 trial after three rounds. The CXR+NAAT algorithm averted 4.29m DALYs (95%UI:2.86-6.14) at US$225 (95%UI:85-520) per DALY averted compared with business-as-usual. The front-loaded investment of US$161m (95%UI:111-224) annually during the intervention resulted in average annual cost savings of US$12.7m (95%UI:6.7-21.4) up to 2050 compared to the business-as-usual counterfactual. Reducing the cost of NAAT to US$1 led to a 50% and 15% reduction in budget impact and a 63% and 26% reduction in the estimated ICER for the NAAT-only and CXR+NAAT algorithms, respectively. Interpretation: In Viet Nam, population-wide screening could achieve ambitious policy goals. Substantial front-loaded investment is immediately followed by persistent cost savings and could be further offset by more affordable NAATs. Funding: European Research Council, National Health and Medical Research Council Australia. Research in context: Evidence before this study: Community-wide screening interventions for tuberculosis (TB) have historically been implemented in countries that are now considered low-burden. It has been hypothesised that such interventions could significantly alter TB epidemiology in current high-burden settings if applied with multiple screening rounds and broad coverage. A recent systematic review identified two contemporary cluster-randomised trials evaluating the effect of screening interventions on TB prevalence. The ACT3 trial in Viet Nam demonstrated a significant reduction in microbiologically confirmed TB prevalence after three annual rounds of screening with Xpert MTB/RIF for all, regardless of symptoms. In contrast, the ZAMSTAR trial in Zambia and South Africa, which used symptom-based screening with sputum smear microscopy, did not show a reduction in TB prevalence, highlighting that the screening algorithm employed plays a role in the impact of the intervention. Added value of this study: This study assessed the impact and cost-effectiveness of annual rounds of different population-wide screening algorithms using a mathematical model calibrated to TB epidemiology in Viet Nam. The model incorporated recent insights into the spectrum of TB disease, including self-clearance of Mycobacterium tuberculosis infection, the presence of unconfirmed, asymptomatic infectious, and symptomatic infectious TB, and the relative contribution of asymptomatic TB to transmission. We evaluated the epidemiological impact— assessed by cumulative TB incidence, TB deaths, and DALYs—along with the associated costs, including budget impact, the cost of front-loading for the duration of the intervention, and average annual cost savings over the time horizon, to inform policy decisions in a high TB burden setting. Additionally, sensitivity analyses allowed us to assess the impact of using alternative tests and reducing their associated costs. Implications of all the available evidence: A substantial reduction in TB prevalence may be achieved by repeated annual rounds of symptom-agnostic, population-wide screening. A two-step algorithm, which uses chest radiography as an initial screen followed by sputum nucleic acid amplification test, is expected to avert 1.31 million individuals developing incident TB and 171,000 dying from TB by 2050. Despite an estimated budget impact of US$1,478 million and annual intervention-specific costs of US$161 million, annual savings of US$12.7 million begin immediately after the intervention ends and are expected to be sustained well beyond 2050. These findings underscore the need to integrate proactive strategies into existing TB prevention and care practices and consider long term financial and health benefits. Furthermore, they illustrate how rapid achievement of ambitious policy goals can be accomplished through front-loaded investments.

Background: Digital adherence technologies (DATs) with associated differentiated care are potential tools to improve tuberculosis (TB) treatment outcomes and reduce associated costs for both patients and healthcare providers. However, the balance between epidemiological and economic benefits remains unclear. Here, we used data from the ASCENT trial to estimate the potential long-term epidemiological and economic impact of DAT interventions in Ethiopia. Methods: We developed a compartmental transmission model for TB, calibrated to Ethiopia and parameterised with patient and provider costs. We compared the epidemiological and economic impact of two DAT interventions, a digital pillbox and medication labels, to the current standard of care, assuming each was introduced at scale in 2023. We projected long-term TB incidence, mortality and costs to 2035 and conducted a threshold analysis to identify the maximum possible epidemiological impact of a DAT intervention by assuming 100% treatment completion for patients on DAT. Findings: We estimated small and uncertain epidemiological benefits of the pillbox intervention compared with the standard of care in Ethiopia, with a difference of −0.4% (95% uncertainty interval (UI) −1.1%; +2.0%) incident TB episodes and −0.7% (95% UI −2.2%; +3.6%) TB deaths. However, our analysis also found large total provider and patient cost savings (US$163 (95% UI US$118; US$211) and US$3 (95%UI: US$1; US$5), respectively, over 2023–2035), translating to a 50.2% (95% UI 35.9%; 65.2%) reduction in total cost of treatment. Results were similar for the medication label intervention. The maximum possible epidemiological impact a theoretical DAT intervention could achieve over the same timescale would be a 3% (95% UI 1.4%; 5.5%) reduction in incident TB and an 8.2% (95% UI 4.4%; 12.8%) reduction in TB deaths. Interpretation: DAT interventions, while showing limited epidemiological impact, could substantially reduce TB treatment costs for both patients and the healthcare provider.

Drug-resistant tuberculosis (DR-TB) threatens progress in the control of TB. Mathematical models are increasingly being used to guide public health decisions on managing both antimicrobial resistance (AMR) and TB. It is important to consider bacterial heterogeneity in models as it can have consequences for predictions of resistance prevalence, which may affect decision-making. We conducted a systematic review of published mathematical models to determine the modelling landscape and to explore methods for including bacterial heterogeneity. Our first objective was to identify and analyse the general characteristics of mathematical models of DR-mycobacteria, including M. tuberculosis. The second objective was to analyse methods of including bacterial heterogeneity in these models. We had different definitions of heterogeneity depending on the model level. For between-host models of mycobacterium, heterogeneity was defined as any model where bacteria of the same resistance level were further differentiated. For bacterial population models, heterogeneity was defined as having multiple distinct resistant populations. The search was conducted following PRISMA guidelines in five databases, with studies included if they were mechanistic or simulation models of DR-mycobacteria. We identified 195 studies modelling DR-mycobacteria, with most being dynamic transmission models of non-treatment intervention impact in M. tuberculosis (n = 58). Studies were set in a limited number of specific countries, and 44% of models (n = 85) included only a single level of “multidrug-resistance (MDR)”. Only 23 models (8 between-host) included any bacterial heterogeneity. Most of these also captured multiple antibiotic-resistant classes (n = 17), but six models included heterogeneity in bacterial populations resistant to a single antibiotic. Heterogeneity was usually represented by different fitness values for bacteria resistant to the same antibiotic (61%, n = 14). A large and growing body of mathematical models of DR-mycobacterium is being used to explore intervention impact to support policy as well as theoretical explorations of resistance dynamics. However, the majority lack bacterial heterogeneity, suggesting that important evolutionary effects may be missed.

### What you need to know Hearing loss is common— Over 9 million people in England123 have hearing loss and this is increasing with the ageing population (fig 1).4 Hearing loss ranks third for disease burden in England (years lived with disability).5 The average GP sees at least four patients every day who have hearing loss sufficient to interfere with their ability to communicate with ease. Fig 1 Estimated prevalence of people with hearing loss in the better hearing ear of ≥25 dB by age band in England4 Hearing loss is disabling— It affects communication at work and home, affecting educational attainment, employment opportunities, personal relationships, enjoyment of music, and social independence. It can lead to significant reduction in people’s quality of life and is associated with mental health problems including depression and dementia. Hearing loss is expensive— The overall economic burden associated with hearing loss in adults in the UK is estimated to be more than £30bn per year.67 Hearing loss can be managed successfully— Early and effective intervention can minimise the …