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.

The authors have declared no competing interest.

This work was supported by the European Research Council [grant number 757699 to AS, JCE, KCH, and RMGJH]. KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK Aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government's official policies. GJF was supported by a Leadership Fellowship from the Australian National Health and Medical Research Council.

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