Estimating tuberculosis drug resistance amplification rates in high-burden settings.

BACKGROUND: Antimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used epidemiological data to develop a mathematical model of Mycobacterium tuberculosis (Mtb) transmission. METHODS: A four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministic Mtb transmission model was developed to explore the progression from DS- to MDR-TB in The Philippines and Viet Nam. The models were calibrated using data from national tuberculosis prevalence (NTP) surveys and drug resistance surveys (DRS). An adaptive Metropolis algorithm was used to estimate the risks of drug resistance amplification among unsuccessfully treated individuals. RESULTS: The estimated proportion of INH-R amplification among failing treatments was 0.84 (95% CI 0.79-0.89) for The Philippines and 0.77 (95% CI 0.71-0.84) for Viet Nam. The proportion of RIF-R amplification among failing treatments was 0.05 (95% CI 0.04-0.07) for The Philippines and 0.011 (95% CI 0.010-0.012) for Viet Nam. CONCLUSION: The risk of resistance amplification due to treatment failure for INH was dramatically higher than RIF. We observed RIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which allow for early detection of INH-R.

Revisiting the Natural History of Pulmonary Tuberculosis: A Bayesian Estimation of Natural Recovery and Mortality Rates.

BACKGROUND: Tuberculosis (TB) natural history remains poorly characterized, and new investigations are impossible as it would be unethical to follow up TB patients without treatment. METHODS: We considered the reports identified in a previous systematic review of studies from the prechemotherapy era, and extracted detailed data on mortality over time. We used a Bayesian framework to estimate the rates of TB-induced mortality and self-cure. A hierarchical model was employed to allow estimates to vary by cohort. Inference was performed separately for smear-positive TB (SP-TB) and smear-negative TB (SN-TB). RESULTS: We included 41 cohorts of SP-TB patients and 19 cohorts of pulmonary SN-TB patients in the analysis. The median estimates of the TB-specific mortality rates were 0.389 year-1 (95% credible interval [CrI], .335-.449) and 0.025 year-1 (95% CrI, .017-.035) for SP-TB and SN-TB patients, respectively. The estimates for self-recovery rates were 0.231 year-1 (95% CrI, .177-.288) and 0.130 year-1 (95% CrI, .073-.209) for SP-TB and SN-TB patients, respectively. These rates correspond to average durations of untreated TB of 1.57 years (95% CrI, 1.37-1.81) and 5.35 years (95% CrI, 3.42-8.23) for SP-TB and SN-TB, respectively, when assuming a non-TB-related mortality rate of 0.014 year-1 (ie, a 70-year life expectancy). CONCLUSIONS: TB-specific mortality rates are around 15 times higher for SP-TB than for SN-TB patients. This difference was underestimated dramatically in previous TB modeling studies, raising concerns about the accuracy of the associated predictions. Despite being less infectious, SN-TB may be responsible for equivalent numbers of secondary infections as SP-TB due to its much longer duration.

Timing of Mycobacterium tuberculosis exposure explains variation in BCG effectiveness: a systematic review and meta-analysis.

RATIONALE: The heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure. METHODS: We updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context. MAIN RESULTS: Of 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings with longer follow-up showed no protection, sometimes with higher case rates in the vaccinated than the controls in the later follow-up period. CONCLUSIONS: The most plausible explanatory hypothesis for these results is that BCG protects against TB that results from exposure shortly after vaccination. However, we found no evidence of protection when exposure occurs later from vaccination, which would be of greater importance in trials in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection observed for many years thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines with repeated exposure to Mycobacterium tuberculosis or other pathogens.

Modelling direct and herd protection effects of vaccination against the SARS-CoV-2 Delta variant in Australia.

OBJECTIVES: To analyse the outcomes of COVID-19 vaccination by vaccine type, age group eligibility, vaccination strategy, and population coverage. DESIGN: Epidemiologic modelling to assess the final size of a COVID-19 epidemic in Australia, with vaccination program (Pfizer, AstraZeneca, mixed), vaccination strategy (vulnerable first, transmitters first, untargeted), age group eligibility threshold (5 or 15 years), population coverage, and pre-vaccination effective reproduction number ( Reffv¯ ) for the SARS-CoV-2 Delta variant as factors. MAIN OUTCOME MEASURES: Numbers of SARS-CoV-2 infections; cumulative hospitalisations, deaths, and years of life lost. RESULTS: Assuming Reffv¯ = 5, the current mixed vaccination program (vaccinating people aged 60 or more with the AstraZeneca vaccine and people under 60 with the Pfizer vaccine) will not achieve herd protection unless population vaccination coverage reaches 85% by lowering the vaccination eligibility age to 5 years. At Reffv¯ = 3, the mixed program could achieve herd protection at 60-70% population coverage and without vaccinating 5-15-year-old children. At Reffv¯ = 7, herd protection is unlikely to be achieved with currently available vaccines, but they would still reduce the number of COVID-19-related deaths by 85%. CONCLUSION: Vaccinating vulnerable people first is the optimal policy when population vaccination coverage is low, but vaccinating more socially active people becomes more important as the Reffv¯ declines and vaccination coverage increases. Assuming the most plausible Reffv¯ of 5, vaccinating more than 85% of the population, including children, would be needed to achieve herd protection. Even without herd protection, vaccines are highly effective in reducing the number of deaths.

Vaccines and variants: Modelling insights into emerging issues in COVID-19 epidemiology.

Mathematical modelling has played a pivotal role in understanding the epidemiology of and guiding public health responses to the ongoing coronavirus disease of 2019 (COVID-19) pandemic. Here, we review the role of epidemiological models in understanding evolving epidemic characteristics, including the effects of vaccination and Variants of Concern (VoC). We highlight ways in which models continue to provide important insights, including (1) calculating the herd immunity threshold and evaluating its limitations; (2) verifying that nascent vaccines can prevent severe disease, infection, and transmission but may be less efficacious against VoC; (3) determining optimal vaccine allocation strategies under efficacy and supply constraints; and (4) determining that VoC are more transmissible and lethal than previously circulating strains, and that immune escape may jeopardize vaccine-induced herd immunity. Finally, we explore how models can help us anticipate and prepare for future stages of COVID-19 epidemiology (and that of other diseases) through forecasts and scenario projections, given current uncertainties and data limitations.

Ethics of selective restriction of liberty in a pandemic.

Liberty-restricting measures have been implemented for centuries to limit the spread of infectious diseases. This article considers if and when it may be ethically acceptable to impose selective liberty-restricting measures in order to reduce the negative impacts of a pandemic by preventing particularly vulnerable groups of the community from contracting the disease. We argue that the commonly accepted explanation-that liberty restrictions may be justified to prevent harm to others when this is the least restrictive option-fails to adequately accommodate the complexity of the issue or the difficult choices that must be made, as illustrated by the COVID-19 pandemic. We introduce a dualist consequentialist approach, weighing utility at both a population and individual level, which may provide a better framework for considering the justification for liberty restrictions. While liberty-restricting measures may be justified on the basis of significant benefits to the population and small costs for overall utility to individuals, the question of whether it is acceptable to discriminate should be considered separately. This is because the consequentialist approach does not adequately account for the value of equality. This value may be protected through the application of an additional proportionality test. An algorithm for making decisions is proposed. Ultimately whether selective liberty-restricting measures are imposed will depend on a range of factors, including how widespread infection is in the community, the level of risk and harm a society is willing to accept, and the efficacy and cost of other mitigation options.

Profiling Mycobacterium tuberculosis transmission and the resulting disease burden in the five highest tuberculosis burden countries.

BACKGROUND: Tuberculosis (TB) control efforts are hampered by an imperfect understanding of TB epidemiology. The true age distribution of disease is unknown because a large proportion of individuals with active TB remain undetected. Understanding of transmission is limited by the asymptomatic nature of latent infection and the pathogen's capacity for late reactivation. A better understanding of TB epidemiology is critically needed to ensure effective use of existing and future control tools. METHODS: We use an agent-based model to simulate TB epidemiology in the five highest TB burden countries-India, Indonesia, China, the Philippines and Pakistan-providing unique insights into patterns of transmission and disease. Our model replicates demographically realistic populations, explicitly capturing social contacts between individuals based on local estimates of age-specific contact in household, school and workplace settings. Time-varying programmatic parameters are incorporated to account for the local history of TB control. RESULTS: We estimate that the 15-19-year-old age group is involved in more than 20% of transmission events in India, Indonesia, the Philippines and Pakistan, despite representing only 5% of the local TB incidence. According to our model, childhood TB represents around one fifth of the incident TB cases in these four countries. In China, three quarters of incident TB were estimated to occur in the ≥ 45-year-old population. The calibrated per-contact transmission risk was found to be similar in each of the five countries despite their very different TB burdens. CONCLUSIONS: Adolescents and young adults are a major driver of TB in high-incidence settings. Relying only on the observed distribution of disease to understand the age profile of transmission is potentially misleading.

Cost-effectiveness of 3 months of weekly rifapentine and isoniazid compared with other standard treatment regimens for latent tuberculosis infection: a decision analysis study.

Background: Latent tuberculosis infection (LTBI) is a critical driver of the global burden of active TB, and therefore LTBI treatment is key for TB elimination. Treatment regimens for LTBI include self-administered daily isoniazid for 6 (6H) or 9 (9H) months, self-administered daily rifampicin plus isoniazid for 3 months (3RH), self-administered daily rifampicin for 4 months (4R) and weekly rifapentine plus isoniazid for 3 months self-administered (3HP-SAT) or administered by a healthcare worker as directly observed therapy (3HP-DOT). Data on the relative cost-effectiveness of these regimens are needed to assist policymakers and clinicians in selecting an LTBI regimen. Objectives: To evaluate the cost-effectiveness of all regimens for treating LTBI. Methods: We developed a Markov model to investigate the cost-effectiveness of 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H for LTBI treatment in a cohort of 10000 adults with LTBI. Cost-effectiveness was evaluated from a health system perspective over a 20 year time horizon. Results: Compared with no preventive treatment, 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H prevented 496, 470, 442, 418, 370 and 276 additional cases of active TB per 10000 patients, respectively. All regimens reduced costs and increased QALYs compared with no preventive treatment. 3HP was more cost-effective under DOT than under SAT at a cost of US$27948 per QALY gained. Conclusions: Three months of weekly rifapentine plus isoniazid is more cost-effective than other regimens. Greater recognition of the benefits of short-course regimens can contribute to the scale-up of prevention and achieving the 'End TB' targets.

Methods used in the spatial analysis of tuberculosis epidemiology: a systematic review.

BACKGROUND: Tuberculosis (TB) transmission often occurs within a household or community, leading to heterogeneous spatial patterns. However, apparent spatial clustering of TB could reflect ongoing transmission or co-location of risk factors and can vary considerably depending on the type of data available, the analysis methods employed and the dynamics of the underlying population. Thus, we aimed to review methodological approaches used in the spatial analysis of TB burden. METHODS: We conducted a systematic literature search of spatial studies of TB published in English using Medline, Embase, PsycInfo, Scopus and Web of Science databases with no date restriction from inception to 15 February 2017. The protocol for this systematic review was prospectively registered with PROSPERO ( CRD42016036655 ). RESULTS: We identified 168 eligible studies with spatial methods used to describe the spatial distribution (n = 154), spatial clusters (n = 73), predictors of spatial patterns (n = 64), the role of congregate settings (n = 3) and the household (n = 2) on TB transmission. Molecular techniques combined with geospatial methods were used by 25 studies to compare the role of transmission to reactivation as a driver of TB spatial distribution, finding that geospatial hotspots are not necessarily areas of recent transmission. Almost all studies used notification data for spatial analysis (161 of 168), although none accounted for undetected cases. The most common data visualisation technique was notification rate mapping, and the use of smoothing techniques was uncommon. Spatial clusters were identified using a range of methods, with the most commonly employed being Kulldorff's spatial scan statistic followed by local Moran's I and Getis and Ord's local Gi(d) tests. In the 11 papers that compared two such methods using a single dataset, the clustering patterns identified were often inconsistent. Classical regression models that did not account for spatial dependence were commonly used to predict spatial TB risk. In all included studies, TB showed a heterogeneous spatial pattern at each geographic resolution level examined. CONCLUSIONS: A range of spatial analysis methodologies has been employed in divergent contexts, with all studies demonstrating significant heterogeneity in spatial TB distribution. Future studies are needed to define the optimal method for each context and should account for unreported cases when using notification data where possible. Future studies combining genotypic and geospatial techniques with epidemiologically linked cases have the potential to provide further insights and improve TB control.

Modular programming for tuberculosis control, the "AuTuMN" platform.

BACKGROUND: Tuberculosis (TB) is now the world's leading infectious killer and major programmatic advances will be needed if we are to meet the ambitious new End TB Targets. Although mathematical models are powerful tools for TB control, such models must be flexible enough to capture the complexity and heterogeneity of the global TB epidemic. This includes simulating a disease that affects age groups and other risk groups differently, has varying levels of infectiousness depending upon the organ involved and varying outcomes from treatment depending on the drug resistance pattern of the infecting strain. RESULTS: We adopted sound basic principles of software engineering to develop a modular software platform for simulation of TB control interventions ("AuTuMN"). These included object-oriented programming, logical linkage between modules and consistency of code syntax and variable naming. The underlying transmission dynamic model incorporates optional stratification by age, risk group, strain and organ involvement, while our approach to simulating time-variant programmatic parameters better captures the historical progression of the epidemic. An economic model is overlaid upon this epidemiological model which facilitates comparison between new and existing technologies. A "Model runner" module allows for predictions of future disease burden trajectories under alternative scenario situations, as well as uncertainty, automatic calibration, cost-effectiveness and optimisation. The model has now been used to guide TB control strategies across a range of settings and countries, with our modular approach enabling repeated application of the tool without the need for extensive modification for each application. CONCLUSIONS: The modular construction of the platform minimises errors, enhances readability and collaboration between multiple programmers and enables rapid adaptation to answer questions in a broad range of contexts without the need for extensive re-programming. Such features are particularly important in simulating an epidemic as complex and diverse as TB.

A user-friendly mathematical modelling web interface to assist local decision making in the fight against drug-resistant tuberculosis.

Multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) represent an important challenge for global tuberculosis (TB) control. The high rates of MDR/RR-TB observed among re-treatment cases can arise from diverse pathways: de novo amplification during initial treatment, inappropriate treatment of undiagnosed MDR/RR-TB, relapse despite appropriate treatment, or reinfection with MDR/RR-TB. Mathematical modelling allows quantification of the contribution made by these pathways in different settings. This information provides valuable insights for TB policy-makers, allowing better contextualised solutions. However, mathematical modelling outputs need to consider local data and be easily accessible to decision makers in order to improve their usefulness. We present a user-friendly web-based modelling interface, which can be used by people without technical knowledge. Users can input their own parameter values and produce estimates for their specific setting. This innovative tool provides easy access to mathematical modelling outputs that are highly relevant to national TB control programs. In future, the same approach could be applied to a variety of modelling applications, enhancing local decision making.

High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from?

BACKGROUND: Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment. METHODS: We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB. RESULTS: At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions. CONCLUSIONS: Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.

Scenario Analysis for Programmatic Tuberculosis Control in Western Province, Papua New Guinea.

Tuberculosis (TB) and multidrug-resistant TB (MDR-TB) are major health problems in Western Province, Papua New Guinea. While comprehensive expansion of TB control programs is desirable, logistical challenges are considerable, and there is substantial uncertainty regarding the true disease burden. We parameterized our previously described mathematical model of Mycobacterium tuberculosis dynamics in Western Province, following an epidemiologic assessment. Five hypothetical scenarios representing alternative programmatic approaches during the period from 2013 to 2023 were developed with local staff. Bayesian uncertainty analyses were undertaken to explicitly acknowledge the uncertainty around key epidemiologic parameters, and an economic evaluation was performed. With continuation of existing programmatic strategies, overall TB incidence remained stable at 555 cases per 100,000 population per year (95% simulation interval (SI): 420, 807), but the proportion of incident cases attributable to MDR-TB increased from 16% to 35%. Comprehensive, provincewide strengthening of existing programs reduced incidence to 353 cases per 100,000 population per year (95% SI: 246, 558), with 46% being cases of MDR-TB, while incorporating programmatic management of MDR-TB into these programs reduced incidence to 233 cases per 100,000 population per year (95% SI: 198, 269) with 14% MDR-TB. Most economic costs were due to hospitalization during the intensive treatment phase. Broad scale-up of TB control activities in Western Province with incorporation of programmatic management of MDR-TB is vital if control is to be achieved. Community-based treatment approaches are important to reduce the associated economic costs.

Replicating superspreader dynamics with compartmental models.

Infectious disease outbreaks often exhibit superspreader dynamics, where most infected people generate no, or few secondary cases, and only a small fraction of individuals are responsible for a large proportion of transmission. Although capturing this heterogeneity is critical for estimating outbreak risk and the effectiveness of group-specific interventions, it is typically neglected in compartmental models of infectious disease transmission-which constitute the most common transmission dynamic modeling framework. In this study we propose different classes of compartmental epidemic models that incorporate transmission heterogeneity, fit them to a number of real outbreak datasets, and benchmark their performance against the canonical superspreader model (i.e., the negative binomial branching process model). We find that properly constructed compartmental models can capably reproduce observed superspreader dynamics and we provide the pathogen-specific parameter settings required to do so. As a consequence, we also show that compartmental models parameterized according to a binary clinical classification have limited support.

Finding and treating both tuberculosis disease and latent infection during population-wide active case finding for tuberculosis elimination.

In recognition of the high rates of undetected tuberculosis in the community, the World Health Organization (WHO) encourages targeted active case finding (ACF) among "high-risk" populations. While this strategy has led to increased case detection in these populations, the epidemic impact of these interventions has not been demonstrated. Historical data suggest that population-wide (untargeted) ACF can interrupt transmission in high-incidence settings, but implementation remains lacking, despite recent advances in screening tools. The reservoir of latent infection-affecting up to a quarter of the global population -complicates elimination efforts by acting as a pool from which future tuberculosis cases may emerge, even after all active cases have been treated. A holistic case finding strategy that addresses both active disease and latent infection is likely to be the optimal approach for rapidly achieving sustainable progress toward TB elimination in a durable way, but safety and cost effectiveness have not been demonstrated. Sensitive, symptom-agnostic community screening, combined with effective tuberculosis treatment and prevention, should eliminate all infectious cases in the community, whilst identifying and treating people with latent infection will also eliminate tomorrow's tuberculosis cases. If real strides toward global tuberculosis elimination are to be made, bold strategies are required using the best available tools and a long horizon for cost-benefit assessment.

Estimating the long-term effects of mass screening for latent and active tuberculosis in the Marshall Islands.

BACKGROUND: Ambitious population-based screening programmes for latent and active tuberculosis (TB) were implemented in the Republic of the Marshall Islands in 2017 and 2018. METHODS: We used a transmission dynamic model of TB informed by local data to capture the Marshall Islands epidemic's historical dynamics. We then used the model to project the future epidemic trajectory following the active screening interventions, as well as considering a counterfactual scenario with no intervention. We also simulated future scenarios including periodic interventions similar to those previously implemented, to assess their ability to reach the End TB Strategy targets and TB pre-elimination in the Marshall Islands. RESULTS: The screening activities conducted in 2017 and 2018 were estimated to have reduced TB incidence and mortality by around one-third in 2020, and are predicted to achieve the End TB Strategy milestone of 50% incidence reduction by 2025 compared with 2015. Screening interventions had a considerably greater impact when latent TB screening and treatment were included, compared with active case finding alone. Such combined programmes implemented at the national level could achieve TB pre-elimination around 2040 if repeated every 2 years. CONCLUSIONS: Our model suggests that it would be possible to achieve TB pre-elimination by 2040 in the Marshall Islands through frequent repetition of the same interventions as those already implemented in the country. It also highlights the importance of including latent infection testing in active screening activities.

Understanding how Victoria, Australia gained control of its second COVID-19 wave.

During 2020, Victoria was the Australian state hardest hit by COVID-19, but was successful in controlling its second wave through aggressive policy interventions. We calibrated a detailed compartmental model of Victoria's second wave to multiple geographically-structured epidemic time-series indicators. We achieved a good fit overall and for individual health services through a combination of time-varying processes, including case detection, population mobility, school closures, physical distancing and face covering usage. Estimates of the risk of death in those aged ≥75 and of hospitalisation were higher than international estimates, reflecting concentration of cases in high-risk settings. We estimated significant effects for each of the calibrated time-varying processes, with estimates for the individual-level effect of physical distancing of 37.4% (95%CrI 7.2-56.4%) and of face coverings of 45.9% (95%CrI 32.9-55.6%). That the multi-faceted interventions led to the dramatic reversal in the epidemic trajectory is supported by our results, with face coverings likely particularly important.

Tuberculosis in the Western Pacific Region: Estimating the burden of disease and return on investment 2020-2030 in four countries.

BACKGROUND: We aimed to estimate the disease burden of Tuberculosis (TB) and return on investment of TB care in selected high-burden countries of the Western Pacific Region (WPR) until 2030. METHODS: We projected the TB epidemic in Viet Nam and Lao People's Democratic Republic (PDR) 2020-2030 using a mathematical model under various scenarios: counterfactual (no TB care); baseline (TB care continues at current levels); and 12 different diagnosis and treatment interventions. We retrieved previous modeling results for China and the Philippines. We pooled the new and existing information on incidence and deaths in the four countries, covering >80% of the TB burden in WPR. We estimated the return on investment of TB care and interventions in Viet Nam and Lao PDR using a Solow model. FINDINGS: In the baseline scenario, TB incidence in the four countries decreased from 97•0/100,000/year (2019) to 90•1/100,000/year (2030), and TB deaths from 83,300/year (2019) to 71,100/year (2030). Active case finding (ACF) strategies (screening people not seeking care for respiratory symptoms) were the most effective single interventions. Return on investment (2020-2030) for TB care in Viet Nam and Lao PDR ranged US$4-US$49/dollar spent; additional interventions brought up to US$2•7/dollar spent. INTERPRETATION: In the modeled countries, TB incidence will only modestly decrease without additional interventions. Interventions that include ACF can reduce TB burden but achieving the End TB incidence and mortality targets will be difficult without new transformational tools (e.g. vaccine, new diagnostic tools, shorter treatment). However, TB care, even at its current level, can bring a multiple-fold return on investment. FUNDING: World Health Organization Western Pacific Regional Office; Swiss National Science Foundation Grant 163878.