Associations Between Alcohol Use, Antiretroviral Therapy Use, and Viral Load Suppression Among People Living with HIV in Rural Central Uganda.

Alcohol use among people living with HIV (PWH) is common and may negatively affect engagement in HIV care. We evaluated the relationships between alcohol use, ART use, and viral suppression among PWH in Uganda. PATH/Ekkubo was a trial evaluating a linkage to HIV care intervention in four Ugandan districts, Nov 2015-Sept 2021. Our analytical sample included: (1) baseline data from individuals not enrolled in the intervention trial (previously diagnosed HIV+); and 12-month follow-up data from the control group (newly diagnosed or previously diagnosed, but not in care). Level of alcohol use was categorized using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C): none (AUDIT-C = 0), low (women = 1-2, men = 1-3), medium (women = 3-5, men = 4-5), high/very high (6-12). Multivariable logistic regression models evaluated associations between alcohol use, ART use and viral suppression (a viral load of < 20); we also stratified by gender. Among 931 PWH, medium (OR: 0.43 [95% CI 0.25-0.72]) and high/very high (OR: 0.22 [95% CI 0.11-0.42]) levels of alcohol use were associated with lower odds of being on ART. In a sub-sample of 664, medium use (OR: 0.63 [95% CI 0.41-0.97]) was associated with lower odds of viral suppression. However, this association was not statistically significant when restricting to those on ART, suggesting the relationship between alcohol use and viral suppression is explained by ART use. Among men, high/very high, and among women, medium alcohol use levels were associated with lower odds of being on ART and being virally suppressed. Interventions for PWH who use higher levels of alcohol may be needed to optimize the benefits of Uganda's Universal Test and Treat strategy.

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Predictors of unsuccessful tuberculosis treatment outcomes in Brazil: an analysis of 259,484 patient records.

INTRODUCTION: Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil. METHODS: We obtained data on individuals treated for TB between 2015 and 2018 from Brazil's National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment. RESULTS: Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62-3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25-1.32], vs. female sex), Black race (aOR 1.23 [1.19-1.28], vs. White race), no education (aOR 2.03 [1.91-2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63-2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88-2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41-1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16-1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95-3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11-1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14-2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29-2.41], vs. receiving DOT). CONCLUSION: The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.

The Full Value of Vaccine Assessments Concept-Current Opportunities and Recommendations.

For vaccine development and adoption decisions, the 'Full Value of Vaccine Assessment' (FVVA) framework has been proposed by the WHO to expand the range of evidence available to support the prioritization of candidate vaccines for investment and eventual uptake by low- and middle-income countries. Recent applications of the FVVA framework have already shown benefits. Building on the success of these applications, we see important new opportunities to maximize the future utility of FVVAs to country and global stakeholders and provide a proof-of-concept for analyses in other areas of disease control and prevention. These opportunities include the following: (1) FVVA producers should aim to create evidence that explicitly meets the needs of multiple key FVVA consumers, (2) the WHO and other key stakeholders should develop standardized methodologies for FVVAs, as well as guidance for how different stakeholders can explicitly reflect their values within the FVVA framework, and (3) the WHO should convene experts to further develop and prioritize the research agenda for outcomes and benefits relevant to the FVVA and elucidate methodological approaches and opportunities for standardization not only for less well-established benefits, but also for any relevant research gaps. We encourage FVVA stakeholders to engage with these opportunities.

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis.

Background: Globally, over one-third of pulmonary tuberculosis (TB) disease diagnoses are made based on clinical criteria after a negative diagnostic test result. Understanding factors associated with clinicians' decisions to initiate treatment for individuals with negative test results is critical for predicting the potential impact of new diagnostics. Methods: We performed a systematic review and individual patient data meta-analysis using studies conducted between January/2010 and December/2022 (PROSPERO: CRD42022287613). We included trials or cohort studies that enrolled individuals evaluated for TB in routine settings. In these studies participants were evaluated based on clinical examination and routinely-used diagnostics, and were followed for ≥1 week after the initial test result. We used hierarchical Bayesian logistic regression to identify factors associated with treatment initiation following a negative result on an initial bacteriological test (e.g., sputum smear microscopy, Xpert MTB/RIF). Findings: Multiple factors were positively associated with treatment initiation: male sex [adjusted Odds Ratio (aOR) 1.61 (1.31-1.95)], history of prior TB [aOR 1.36 (1.06-1.73)], reported cough [aOR 4.62 (3.42-6.27)], reported night sweats [aOR 1.50 (1.21-1.90)], and having HIV infection but not on ART [aOR 1.68 (1.23-2.32)]. Treatment initiation was substantially less likely for individuals testing negative with Xpert [aOR 0.77 (0.62-0.96)] compared to smear microscopy and declined in more recent years. Interpretation: Multiple factors influenced decisions to initiate TB treatment despite negative test results. Clinicians were substantially less likely to treat in the absence of a positive test result when using more sensitive, PCR-based diagnostics.

Targeting strategies of antenatal balanced energy and protein supplementation in Addis Ababa, Ethiopia: study protocol for a randomized effectiveness study.

BACKGROUND: Antenatal balanced energy and protein (BEP) supplements have well-documented benefits for pregnancy outcomes. However, considerable practical gaps remain in the effective and cost-effective delivery of antenatal BEP supplements at scale in low- and middle-income countries. METHODS: A randomized effectiveness study will be conducted in two sub-cities of Addis Ababa, Ethiopia, to evaluate the effectiveness, cost-effectiveness, and implementation of different targeting strategies of antenatal BEP supplements. Pregnant women aged 18 to 49, with a gestational age of 24 weeks or less, and attending antenatal visits in one of the nine study health facilities are eligible for enrollment. In six of the health facilities, participants will be randomized to one of three study arms: control (Arm 1), targeted BEP provision based on baseline nutritional status (Arm 2), and targeted BEP supplementation based on baseline nutritional status and monthly gestational weight gain (GWG) monitoring (Arm 3). In the remaining three facilities, participants will be assigned to universal BEP provision (Arm 4). Participants in Arms 2 and 3 will receive BEP supplements if they have undernutrition at enrollment, as defined by a baseline body mass index less than 18.5 kg/m2 or mid-upper arm circumference less than 23 cm. In Arm 3, in addition to targeting based on baseline undernutrition, regular weight measurements will be used to identify insufficient GWG and inform the initiation of additional BEP supplements. Participants in Arm 4 will receive BEP supplements until the end of pregnancy, regardless of baseline nutritional status or GWG. All participants will receive standard antenatal care, including iron and folic acid supplementation. A total of 5400 pregnant women will be enrolled, with 1350 participants in each arm. Participants will be followed up monthly during their visits to the antenatal facilities until delivery. Maternal and infant health status will be evaluated within 72 h after delivery and at 6 weeks postpartum. The effectiveness and cost-effectiveness of the different BEP targeting strategies in preventing adverse pregnancy outcomes will be compared across arms. Qualitative data will be analyzed to assess the feasibility, acceptability, and implementation of different supplementation strategies. DISCUSSION: This study will inform global recommendations and operational guidelines for the effective and cost-effective delivery of antenatal BEP supplements. The targeted approaches have the potential for broader scale-up in Ethiopia and other low-resource settings with a high burden of undernutrition among pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT06125860. Registered November 9, 2023.

Health impact and cost-effectiveness of expanding routine immunization coverage in India through Intensified Mission Indradhanush.

Many children do not receive a full schedule of childhood vaccines, yet there is limited evidence on the cost-effectiveness of strategies for improving vaccination coverage. Evidence is even scarcer on the cost-effectiveness of strategies for reaching "zero-dose children," who have not received any routine vaccines. We evaluated the cost-effectiveness of periodic intensification of routine immunization (PIRI), a widely applied strategy for increasing vaccination coverage. We focused on Intensified Mission Indradhanush (IMI), a large-scale PIRI intervention implemented in India in 2017-2018. In 40 sampled districts, we measured the incremental economic cost of IMI using primary data, and used controlled interrupted time-series regression to estimate incremental vaccination doses delivered. We estimated deaths and disability-adjusted life years (DALYs) averted using the Lives Saved Tool and reported cost-effectiveness from immunization program and societal perspectives. We found that, in sampled districts, IMI had an estimated incremental cost of 2021US$13.7 (95% uncertainty interval: 10.6 to 17.4) million from an immunization program perspective and increased vaccine delivery by an estimated 2.2 (-0.5 to 4.8) million doses over a 12-month period, averting an estimated 1,413 (-350 to 3,129) deaths. The incremental cost from a program perspective was $6.21 per dose ($2.80 to dominated), $82.99 per zero-dose child reached ($39.85 to dominated), $327.63 ($147.65 to dominated) per DALY averted, $360.72 ($162.56 to dominated) per life-year saved, and $9,701.35 ($4,372.01 to dominated) per under-five death averted. At a cost-effectiveness threshold of 1x per-capita GDP per DALY averted, IMI was estimated to be cost-effective with 90% probability. This evidence suggests IMI was both impactful and cost-effective for improving vaccination coverage, though there is a high degree of uncertainty in the results. As vaccination programs expand coverage, unit costs may increase due to the higher costs of reaching currently unvaccinated children.

Disparities in Tuberculosis Incidence by Race and Ethnicity Among the U.S.-Born Population in the United States, 2011 to 2021 : An Analysis of National Disease Registry Data.

BACKGROUND: Elevated tuberculosis (TB) incidence rates have recently been reported for racial/ethnic minority populations in the United States. Tracking such disparities is important for assessing progress toward national health equity goals and implementing change. OBJECTIVE: To quantify trends in racial/ethnic disparities in TB incidence among U.S.-born persons. DESIGN: Time-series analysis of national TB registry data for 2011 to 2021. SETTING: United States. PARTICIPANTS: U.S.-born persons stratified by race/ethnicity. MEASUREMENTS: TB incidence rates, incidence rate differences, and incidence rate ratios compared with non-Hispanic White persons; excess TB cases (calculated from incidence rate differences); and the index of disparity. Analyses were stratified by sex and by attribution of TB disease to recent transmission and were adjusted for age, year, and state of residence. RESULTS: In analyses of TB incidence rates for each racial/ethnic population compared with non-Hispanic White persons, incidence rate ratios were as high as 14.2 (95% CI, 13.0 to 15.5) among American Indian or Alaska Native (AI/AN) females. Relative disparities were greater for females, younger persons, and TB attributed to recent transmission. Absolute disparities were greater for males. Excess TB cases in 2011 to 2021 represented 69% (CI, 66% to 71%) and 62% (CI, 60% to 64%) of total cases for females and males, respectively. No evidence was found to indicate that incidence rate ratios decreased over time, and most relative disparity measures showed small, statistically nonsignificant increases. LIMITATION: Analyses assumed complete TB case diagnosis and self-report of race/ethnicity and were not adjusted for medical comorbidities or social determinants of health. CONCLUSION: There are persistent disparities in TB incidence by race/ethnicity. Relative disparities were greater for AI/AN persons, females, and younger persons, and absolute disparities were greater for males. Eliminating these disparities could reduce overall TB incidence by more than 60% among the U.S.-born population. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Quantifying gaps in the tuberculosis care cascade in Brazil: A mathematical model study using national program data.

BACKGROUND: In Brazil, many individuals with tuberculosis (TB) do not receive appropriate care due to delayed or missed diagnosis, ineffective treatment regimens, or loss-to-follow-up. This study aimed to estimate the health losses and TB program costs attributable to each gap in the care cascade for TB disease in Brazil. METHODS AND FINDINGS: We constructed a Markov model simulating the TB care cascade and lifetime health outcomes (e.g., death, cure, postinfectious sequelae) for individuals developing TB disease in Brazil. We stratified the model by age, human immunodeficiency virus (HIV) status, drug resistance, state of residence, and disease severity, and developed a parallel model for individuals without TB that receive a false-positive TB diagnosis. Models were fit to data (adult and pediatric) from Brazil's Notifiable Diseases Information System (SINAN) and Mortality Information System (SIM) for 2018. Using these models, we assessed current program performance and simulated hypothetical scenarios that eliminated specific gaps in the care cascade, in order to quantify incremental health losses and TB diagnosis and treatment costs along the care cascade. TB-attributable disability-adjusted life years (DALYs) were calculated by comparing changes in survival and nonfatal disability to a no-TB counterfactual scenario. We estimated that 90.0% (95% uncertainty interval [UI]: 85.2 to 93.4) of individuals with TB disease initiated treatment and 10.0% (95% UI: 7.6 to 12.5) died with TB. The average number of TB-attributable DALYs per incident TB case varied across Brazil, ranging from 2.9 (95% UI: 2.3 to 3.6) DALYs in Acre to 4.0 (95% UI: 3.3 to 4.7) DALYs in Rio Grande do Sul (national average 3.5 [95% UI: 2.8 to 4.1]). Delayed diagnosis contributed the largest health losses along the care cascade, followed by post-TB sequelae and loss to follow up from TB treatment, with TB DALYs reduced by 71% (95% UI: 65 to 76), 41% (95% UI: 36 to 49), and 10% (95% UI: 7 to 16), respectively, when these factors were eliminated. Total health system costs were largely unaffected by improvements in the care cascade, with elimination of treatment failure reducing attributable costs by 3.1% (95% UI: 1.5 to 5.4). TB diagnosis and treatment of false-positive individuals accounted for 10.2% (95% UI: 3.9 to 21.7) of total programmatic costs but contributed minimally to health losses. Several assumptions were required to interpret programmatic data for the analysis, and we were unable to estimate the contribution of social factors to care cascade outcomes. CONCLUSIONS: In this study, we observed that delays to diagnosis, post-disease sequelae and treatment loss to follow-up were primary contributors to the TB burden of disease in Brazil. Reducing delays to diagnosis, improving healthcare after TB cure, and reducing treatment loss to follow-up should be prioritized to improve the burden of TB disease in Brazil.

Modelling the health and economic impacts ofM72/AS01E vaccination and BCG-revaccination: Estimates for South Africa.

BACKGROUND: Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact of these vaccines is unknown. METHODS: We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS: M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION: Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING: This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).

Racial and ethnic disparities in diagnosis and treatment outcomes among US-born people diagnosed with tuberculosis, 2003-19: an analysis of national surveillance data.

BACKGROUND: Persistent racial and ethnic disparities in tuberculosis incidence exist in the USA, however, less is known about disparities along the tuberculosis continuum of care. This study aimed to describe how race and ethnicity are associated with tuberculosis diagnosis and treatment outcomes. METHODS: In this analysis of national surveillance data, we extracted data from the US National Tuberculosis Surveillance System on US-born patients with tuberculosis during 2003-19. To estimate the association between race and ethnicity and tuberculosis diagnosis (diagnosis after death, cavitation, and sputum smear positivity) and treatment outcomes (treatment for more than 12 months, treatment discontinuation, and death during treatment), we fitted log-binomial regression models adjusting for calendar year, sex, age category, and regional division. Race and ethnicity were defined based on US Census Bureau classification as White, Black, Hispanic, Asian, American Indian or Alaska Native, Native Hawaiian or Pacific Islander, and people of other ethnicities. We quantified racial and ethnic disparities as adjusted relative risks (aRRs) using non-Hispanic White people as the reference group. We also calculated the Index of Disparity as a summary measure that quantifies the dispersion in a given outcome across all racial and ethnic groups, relative to the population mean. We estimated time trends in each outcome to evaluate whether disparities were closing or widening. FINDINGS: From 2003 to 2019, there were 72 809 US-born individuals diagnosed with tuberculosis disease of whom 72 369 (35·7% women and 64·3% men) could be included in analyses. We observed an overall higher risk of any adverse outcome (defined as diagnosis after death, treatment discontinuation, or death during treatment) for non-Hispanic Black people (aRR 1·27, 95% CI 1·22-1·32), Hispanic people (1·20, 1·14-1·27), and American Indian or Alaska Native people (1·24, 1·12-1·37), relative to non-Hispanic White people. The Index of Disparity for this summary outcome remained unchanged over the study period. INTERPRETATION: This study, based on national surveillance data, indicates racial and ethnic disparaties among US-born tuberculosis patients along the tuberculosis continuum of care. Initiatives are needed to reduce diagnostic delays and improve treatment outcomes for US-born racially marginalised people in the USA. FUNDING: US Centers for Disease Control and Prevention.

Estimated rates of progression to tuberculosis disease for persons infected with Mycobacterium tuberculosis in the United States.

BACKGROUND: In the United States, over 80% of tuberculosis (TB) disease cases are estimated to result from reactivation of latent TB infection (LTBI) acquired more than 2 years previously ("reactivation TB"). We estimated reactivation TB rates for the US population with LTBI, overall, by age, sex, race-ethnicity, and US-born status, and for selected comorbidities (diabetes, end-stage renal disease, and HIV). METHODS: We collated nationally representative data for 2011-2012. Reactivation TB incidence was based on TB cases reported to the National TB Surveillance System that were attributed to LTBI reactivation. Person-years at risk of reactivation TB were calculated using interferon-gamma release assay (IGRA) positivity from the National Health and Nutrition Examination Survey, published values for interferon-gamma release assay sensitivity and specificity, and population estimates from the American Community Survey. RESULTS: For persons aged ≥6 years with LTBI, the overall reactivation rate was estimated as 0.072 (95% uncertainty interval: 0.047, 0.12) per 100 person-years. Estimated reactivation rates declined with age. Compared to the overall population, estimated reactivation rates were higher for persons with diabetes (adjusted rate ratio [aRR] = 1.6 [1.5, 1.7]), end-stage renal disease (aRR = 9.8 [5.4, 19]), and HIV (aRR = 12 [10, 13]). CONCLUSIONS: In our study, individuals with LTBI faced small, non-negligible risks of reactivation TB. Risks were elevated for individuals with medical comorbidities that weaken immune function.

In-kind nutritional supplementation for household contacts of persons with tuberculosis would be cost-effective for reducing tuberculosis incidence and mortality in India: a modeling study.

Background: Undernutrition is the leading cause of tuberculosis (TB) globally, but nutritional interventions are often considered cost prohibitive. The RATIONS study demonstrated that nutritional support provided to household contacts of persons with TB can reduce TB incidence. However, the long-term cost-effectiveness of this intervention is unclear. Methods: We assessed the cost-effectiveness of a RATIONS-style intervention (daily 750 kcal dietary supplementation and multi-micronutrient tablet). Using a Markov state transition model we simulated TB incidence, treatment, and TB-attributable mortality among household contacts receiving the RATIONS intervention, as compared to no nutritional support. We calculated health outcomes (TB cases, TB deaths, and disability-adjusted life years [DALYs]) over the lifetime of intervention recipients and assessed costs from government and societal perspectives. We tested the robustness of results to parameter changes via deterministic and probabilistic sensitivity analysis. Findings: Over two years, household contacts receiving the RATIONS intervention would experience 39% (95% uncertainty interval (UI): 23-52) fewer TB cases and 59% (95% UI: 44-69) fewer TB deaths. The intervention was estimated to avert 13,775 (95% UI: 9036-20,199) TB DALYs over the lifetime of the study cohort comprising 100,000 household contacts and was cost-effective from both government (incremental cost-effectiveness ratio: $229 per DALY averted [95% UI: 133-387]) and societal perspectives ($184 per DALY averted [95% UI: 83-344]). The results were most sensitive to the cost of the nutritional supplement. Interpretation: Prompt nutritional support for household contacts of persons with TB disease would be cost-effective in reducing TB incidence and mortality in India. Summary: Undernutrition is the leading cause of tuberculosis in India. Using a Markov state-transition model, we found that food baskets for household contacts of persons with tuberculosis would be cost-effective in reducing tuberculosis incidence and mortality in India. Research in context: Evidence before this study: Undernutrition is the leading risk factor for TB worldwide. Recently, the RATIONS study demonstrated a roughly 40% reduction in incident TB among household contacts who received in-kind macronutrient and micronutrient supplementation. Added value of this study: Although the RATIONS study demonstrated a dramatic reduction in incident TB, it is unclear if nutritional interventions to prevent TB are cost-effective. Previously, only one cost-effectiveness analysis of nutritional interventions for household contacts has been published. Due to lack of published data, that study had to make assumptions regarding the impact of nutritional interventions on TB incidence and mortality. In this study, we conducted an economic evaluation of a RATIONS-style intervention to reduce incident TB and mortality in India using observed data. Implications of all the available evidence: In-kind nutritional supplementation for household contacts of individuals with TB disease would be cost-effective in reducing incident TB and TB mortality, particularly if TB programs leverage economies of scale to bring down the cost of the nutritional intervention.

Predictive power of wastewater for nowcasting infectious disease transmission: A retrospective case study of five sewershed areas in Louisville, Kentucky.

BACKGROUND: Epidemiological nowcasting traditionally relies on count surveillance data. The availability and quality of such count data may vary over time, limiting representation of true infections. Wastewater data correlates with traditional surveillance data and may provide additional value for nowcasting disease trends. METHODS: We obtained SARS-CoV-2 case, death, wastewater, and serosurvey data for Jefferson County, Kentucky (USA), between August 2020 and March 2021, and parameterized an existing nowcasting model using combinations of these data. We assessed the predictive performance and variability at the sewershed level and compared the effects of adding or replacing wastewater data to case and death reports. FINDINGS: Adding wastewater data minimally improved the predictive performance of nowcasts compared to a model fitted to case and death data (Weighted Interval Score (WIS) 0.208 versus 0.223), and reduced the predictive performance compared to a model fitted to deaths data (WIS 0.517 versus 0.500). Adding wastewater data to deaths data improved the nowcasts agreement to estimates from models using cases and deaths data. These findings were consistent across individual sewersheds as well as for models fit to the aggregated total data of 5 sewersheds. Retrospective reconstructions of epidemiological dynamics created using different combinations of data were in general agreement (coverage >75%). INTERPRETATION: These findings show wastewater data may be valuable for infectious disease nowcasting when clinical surveillance data are absent, such as early in a pandemic or in low-resource settings where systematic collection of epidemiologic data is difficult.

Impact of 1,7-malaria reactive community-based testing and response (1,7-mRCTR) approach on malaria prevalence in Tanzania.

BACKGROUND: Progress in malaria control has stalled in recent years and innovative surveillance and response approaches are needed to accelerate malaria control and elimination efforts in endemic areas of Africa. Building on a previous China-UK-Tanzania pilot study on malaria control, this study aimed to assess the impact of the 1,7-malaria Reactive Community-Based Testing and Response (1,7-mRCTR) approach implemented over two years in three districts of Tanzania. METHODS: The 1,7-mRCTR approach provides community-based malaria testing via rapid diagnostic tests and treatment in villages with the highest burden of malaria incidence based on surveillance data from health facilities. We used a difference-in-differences quasi-experimental design with linear probability models and two waves of cross-sectional household surveys to assess the impact of 1,7-mRCTR on malaria prevalence. We conducted sensitivity analyses to assess the robustness of our results, examined how intervention effects varied in subgroups, and explored alternative explanations for the observed results. RESULTS: Between October 2019 and September 2021, 244,771 community-based malaria rapid tests were completed in intervention areas, and each intervention village received an average of 3.85 rounds of 1-7mRCTR. Malaria prevalence declined from 27.4% at baseline to 11.7% at endline in the intervention areas and from 26.0% to 16.0% in the control areas. 1,7-mRCTR was associated with a 4.5-percentage-point decrease in malaria prevalence (95% confidence interval: - 0.067, - 0.023), equivalent to a 17% reduction from the baseline. In Rufiji, a district characterized by lower prevalence and where larviciding was additionally provided, 1,7-mRCTR was associated with a 63.9% decline in malaria prevalence. CONCLUSIONS: The 1,7-mRCTR approach reduced malaria prevalence. Despite implementation interruptions due to the COVID-19 pandemic and supply chain challenges, the study provided novel evidence on the effectiveness of community-based reactive approaches in moderate- to high-endemicity areas and demonstrated the potential of South-South cooperation in tackling global health challenges.

Spatially-targeted tuberculosis screening has limited impact beyond household contact tracing in Lima, Peru: A model-based analysis.

Mathematical models have suggested that spatially-targeted screening interventions for tuberculosis may efficiently accelerate disease control, but empirical data supporting these findings are limited. Previous models demonstrating substantial impacts of these interventions have typically simulated large-scale screening efforts and have not attempted to capture the spatial distribution of tuberculosis in households and communities at a high resolution. Here, we calibrate an individual-based model to the locations of case notifications in one district of Lima, Peru. We estimate the incremental efficiency and impact of a spatially-targeted interventions used in combination with household contact tracing (HHCT). Our analysis reveals that HHCT is relatively efficient with a median of 40 (Interquartile Range: 31.7 to 49.9) household contacts required to be screened to detect a single case of active tuberculosis. However, HHCT has limited population impact, producing a median incidence reduction of only 3.7% (Interquartile Range: 5.8% to 1.9%) over 5 years. In comparison, spatially targeted screening (which we modeled as active case finding within high tuberculosis prevalence areas 100 m2 grid cell) is far less efficient, requiring evaluation of ≈12 times the number of individuals as HHCT to find a single individual with active tuberculosis. Furthermore, the addition of the spatially targeted screening effort produced only modest additional reductions in tuberculosis incidence over the 5 year period (≈1.3%) in tuberculosis incidence. In summary, we found that HHCT is an efficient approach for tuberculosis case finding, but has limited population impact. Other screening approaches which target areas of high tuberculosis prevalence are less efficient, and may have limited impact unless very large numbers of individuals can be screened.

The potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study.

Background: India has the largest tuberculosis burden globally, but this burden varies nationwide. All-age tuberculosis prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. Previous modelling has demonstrated the benefits and costs of introducing novel tuberculosis vaccines in India overall. However, no studies have compared the potential impact of tuberculosis vaccines in regions within India with differing tuberculosis disease and infection prevalence. We used mathematical modelling to investigate how the health and economic impact of two potential tuberculosis vaccines, M72/AS01E and BCG-revaccination, could differ in Delhi and Gujarat under varying delivery strategies. Methods: We applied a compartmental tuberculosis model separately for Delhi (higher disease and infection prevalence) and Gujarat (lower disease and infection prevalence), and projected epidemiological trends to 2050 assuming no new vaccine introduction. We simulated M72/AS01E and BCG-revaccination scenarios varying target ages and vaccine characteristics. We estimated cumulative cases, deaths, and disability-adjusted life years averted between 2025-2050 compared to the no-new-vaccine scenario and compared incremental cost-effectiveness ratios to three cost-effectiveness thresholds. Results: M72/AS01E averted a higher proportion of tuberculosis cases than BCG-revaccination in both regions (Delhi: 16.0% vs 8.3%, Gujarat: 8.5% vs 5.1%) and had higher vaccination costs (Delhi: USD$118 million vs USD$27 million, Gujarat: US$366 million vs US$97 million). M72/AS01E in Delhi could be cost-effective, or even cost-saving, for all modelled vaccine characteristics. M72/AS01E could be cost-effective in Gujarat, unless efficacy was assumed only for those with current infection at vaccination. BCG-revaccination could be cost-effective, or cost-saving, in both regions for all modelled vaccine scenarios. Discussion: M72/AS01E and BCG-revaccination could be impactful and cost-effective in Delhi and Gujarat. Differences in impact, costs, and cost-effectiveness between vaccines and regions, were determined partly by differences in disease and infection prevalence, and demography. Age-specific regional estimates of infection prevalence could help to inform delivery strategies for vaccines that may only be effective in people with a particular infection status. Evidence on the mechanism of effect of M72/AS01E and its effectiveness in uninfected individuals, which were important drivers of impact and cost-effectiveness, particularly in Gujarat, are also key to improve estimates of population-level impact.

Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.

In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

Costs incurred by people receiving tuberculosis treatment in low-income and middle-income countries: a meta-regression analysis.

BACKGROUND: People accessing and completing treatment for tuberculosis can face large economic costs, even when treatment is provided free of charge. The WHO End TB Strategy targets the elimination of catastrophic costs among tuberculosis-affected households. While low-income and middle-income countries (LMICs) represent 99% of global tuberculosis cases, only 29 of 135 LMICs had conducted national surveys of costs for patients with tuberculosis by December, 2022. We estimated costs for patients with tuberculosis in countries that have not conducted a national survey, to provide evidence on the economic burden of tuberculosis in these settings and inform estimates of global economic burden. METHODS: We extracted data from 22 national surveys of costs faced by patients with tuberculosis that were completed across 2015-22 and met inclusion criteria. Using a Bayesian meta-regression approach, we used these data and covariate data for all 135 LMICs to estimate per-patient costs (2021 US$) by cost category (ie, direct medical, direct non-medical, and indirect), country, drug resistance, and household income quintile. We also estimated the proportion of households experiencing catastrophic total costs (defined as >20% of annual household income) as a result of tuberculosis disease. FINDINGS: Across LMICs, mean direct medical costs incurred by patients with tuberculosis were estimated as US$211 (95% uncertainty interval 154-302), direct non-medical costs were $512 (428-620), and indirect costs were $530 (423-663) per episode of tuberculosis. Overall, per-patient costs were $1253 (1127-1417). Estimated proportions of tuberculosis-affected households experiencing catastrophic total costs ranged from 75·2% (70·3-80·0) in the poorest quintile to 42·5% (34·3-51·5) in the richest quintile, compared with 54·9% (47·0-63·2) overall. INTERPRETATION: Tuberculosis diagnosis and treatment impose substantial costs on affected households. Eliminating these economic losses is crucial for removing barriers to accessing tuberculosis diagnosis and completing treatment among affected households and achieving the targets set in WHO's End TB Strategy. FUNDING: World Health Organization.

New tuberculosis vaccines in India: modelling the potential health and economic impacts of adolescent/adult vaccination with M72/AS01E and BCG-revaccination.

BACKGROUND: India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. METHODS: We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025-2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to the no-new-vaccine baseline, as well as costs and cost-effectiveness from health-system and societal perspectives. RESULTS: M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. CONCLUSIONS: M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given the unknowns surrounding the mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.