Search

Background: A pan-tuberculosis regimen that could be initiated without knowledge of drug susceptibility has been proposed as an objective of tuberculosis regimen development. We modelled the health and economic benefits of such a regimen and analysed which of its features contribute most to impact and savings., Methods: We constructed a mathematical model of tuberculosis treatment parameterised with data from the published literature specific to three countries with a high tuberculosis burden (India, the Philippines, and South Africa). Our model simulated cohorts of newly diagnosed tuberculosis patients, including drug susceptibility testing if performed, regimen assignment, discontinuation, adherence, costs, and resulting outcomes of durable cure (microbiological cure without relapse), need for retreatment, or death. We compared a pan-tuberculosis regimen meeting the WHO 2023 target regimen profile against the standard of care of separate rifampicin-susceptible and rifampicin-resistant regimens. We estimated incremental cures; averted deaths, secondary cases, and costs; and prices below which a pan-tuberculosis regimen would be cost saving. We also assessed scenarios intended to describe which mechanisms of benefit from a pan-tuberculosis regimen (including improved characteristics compared with the current rifampicin-susceptible and rifampicin-resistant regimens and improved regimen assignment and retention in care for patients with rifampicin-resistant tuberculosis) would be most impactful. Results are presented as a range of means across countries with the most extreme 95% uncertainty intervals (UIs) from the three UI ranges., Findings: Compared with the standard of care, a pan-tuberculosis regimen could increase the proportion of patients durably cured after an initial treatment attempt from 69-71% (95% UI 57-80) to 75-76% (68-83), preventing 30-32% of the deaths (20-43) and 17-20% of the transmission (9-29) that occur after initial tuberculosis diagnosis. Considering savings to the health system and patients during and after the initial treatment attempt, the regimen could reduce non-drug costs by 32-42% (22-49) and would be cost saving at prices below US$170-340 (130-510). A rifamycin-containing regimen that otherwise met pan-tuberculosis targets yielded only slightly less impact, indicating that most of the benefits from a pan-tuberculosis regimen resulted from its improvements upon the rifampicin-susceptible standard of care. Eliminating non-adherence and treatment discontinuation, for example via a long-acting injectable regimen, increased health impact and savings., Interpretation: In countries with a high tuberculosis burden, a shorter, highly efficacious, safe, and tolerable regimen to treat all tuberculosis could yield substantial health improvements and savings., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests TSR reports funding for work outside of this study from WHO. CFM was funded for work outside of this study by the Bill & Melinda Gates Foundation (TB MAC OPP1135288) and Unitaid (20193-3-ASCENT). All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals who were formerly incarcerated have high tuberculosis incidence, but are generally not considered among the risk groups eligible for tuberculosis prevention. We investigated the potential health impact and cost-effectiveness of Mycobacterium tuberculosis infection screening and tuberculosis preventive treatment (TPT) for individuals who were formerly incarcerated in Brazil., Methods: Using published evidence for Brazil, we constructed a Markov state transition model estimating tuberculosis-related health outcomes and costs among individuals who were formerly incarcerated, by simulating transitions between health states over time. The analysis compared tuberculosis infection screening and TPT, to no screening, considering a combination of M tuberculosis infection tests and TPT regimens. We quantified health effects as reductions in tuberculosis cases, tuberculosis deaths, and disability-adjusted life-years (DALYs). We assessed costs from a tuberculosis programme perspective. We report intervention cost-effectiveness as the incremental costs per DALY averted, and tested how results changed across subgroups of the target population., Findings: Compared with no intervention, an intervention incorporating tuberculin skin testing and treatment with 3 months of isoniazid and rifapentine would avert 31 (95% uncertainty interval 14-56) lifetime tuberculosis cases and 4·1 (1·4-5·8) lifetime tuberculosis deaths per 1000 individuals, and cost US$242 per DALY averted. All test and regimen combinations were cost-effective compared with no screening. Younger age, longer incarceration, and more recent prison release were each associated with significantly greater health benefits and more favourable cost-effectiveness ratios, although the intervention was cost-effective for all subgroups examined., Interpretation: M tuberculosis infection screening and TPT for individuals who were formerly incarcerated appears cost-effective, and would provide valuable health gains., Funding: National Institutes of Health., Translation: For the Portuguese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of interests TY, PN, NN, KF, and IGB are employees of WHO. AP and NAM declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: Tuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios., Methods: We calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy., Findings: The base-case scenario would prevent 44·0 million (95% uncertainty range 37·2-51·6) tuberculosis cases and 5·0 million (4·6-5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6-76·0) cases and 7·9 million (7·3-8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6-10·1) cases and 1·1 million (0·9-1·2) deaths before 2050, relative to baseline., Interpretation: Our results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction-at a pace similar to that seen for COVID-19 vaccines-would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up., Funding: WHO (2020/985800-0)., Translations: For the French, Spanish, Italian and Dutch translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SM reports employment by the International AIDS Vaccine Initiative, a non-profit product development partnership supporting the access-oriented development of vaccines for several disease areas, including tuberculosis, and grant funding from WHO. MJ is funded by the Bill & Melinda Gates Foundation, Gavi the Vaccine Alliance, the UK Research Institute, the National Institute for Health Research, the European Commission, and the Wellcome Trust, and reports leadership or fiduciary roles in the board, society, committee, or advocacy groups for WHO and Gavi. RCH reports employment by Sanofi Pasteur, unrelated to tuberculosis and outside the submitted work. NAM received consulting fees from The Global Fund to Fight AIDS, Tuberculosis and Malaria and WHO, and reports funding to their institution from the US Centers for Disease Control and Prevention, the Gates Foundation, the National Institute of Health, and the US Council of State and Territorial Epidemiologists. RGW is funded for other work by the Wellcome Trust (218261/Z/19/Z), the National Institute of Health (1R01AI147321–01), EDCTP (RIA208D-2505B), the UK's Medical Research Council (CCF17–7779 via SET Bloomsbury), the Economic and Social Research Council (ES/P008011/1), the Gates Foundation (OPP1084276, OPP1135288, and INV-001754), and WHO. All other authors declare no competing interests., (Copyright © 2023 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Isoniazid preventive therapy (IPT) can prevent tuberculosis among people receiving antiretroviral therapy (ART). HIV programmes are now initiating patients on ART with higher average CD4 cell counts and lower tuberculosis risks under test-and-treat guidelines. We aimed to investigate how this change has affected the health impact and cost-effectiveness of IPT., Methods: We constructed a tuberculosis-HIV microsimulation model parameterised using data from a large HIV treatment programme in Dar es Salaam, Tanzania. We simulated long-term health and cost outcomes for the 211 748 individuals initiating ART between Jan 1, 2014, and Dec 31, 2020, under three scenarios: no IPT access; observed levels of IPT access (75%) and completion (71%); and full (100%) IPT access and completion. We stratified results by ART initiation year and starting CD4 cell count., Findings: Observed levels of IPT access were estimated to have averted 12 800 (95% uncertainty interval 7300 to 21 600) disability-adjusted life-years (DALYs) and saved US$23 000 (-2 268 000 to 1 388 000). Full IPT access would have averted 24 500 (15 100 to 38 300) DALYs and cost $825 000 (-1 594 000 to 4 751 000), equivalent to $23·4 per DALY averted. Lifetime health benefits of IPT were estimated to be greater for more recent ART cohorts, while lifetime costs were stable. In subgroup analyses, a higher CD4 cell count at ART initiation was associated with greater health gains from IPT (15 900 [10 300 to 22 500] DALYs averted by full IPT per 100 000 patients for CD4 count >500 cells per μL at ART initiation, versus 7400 [4500 to 11 600] for CD4 count <100 cells per μL) and lower incremental lifetime costs., Interpretation: IPT remains highly cost-effective or cost-saving for recent ART cohorts. The health impact and cost-effectiveness of IPT are estimated to improve as patients initiate ART earlier in the course of infection., Funding: US National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2019, tuberculosis incidence and mortality in Brazil were 46 and 3·3 per 100 000 population, respectively, and the country has reported rising tuberculosis case rates since 2016, following an economic crisis beginning in mid-2014. We aimed to estimate the number of excess tuberculosis cases and deaths during the recession period, and assessed potential causes., Methods: In this multi-level regression modelling study, we extracted tuberculosis case notifications from Brazil's National Notifiable Disease Information System (known as SINAN), and tuberculosis deaths from the Mortality Information System (known as SIM), for all ages. We fitted mixed-effects regression models estimating trends in these outcomes-stratified by sex, age group, and state-during the pre-recession period (Jan 1, 2010-Dec 31, 2014). We calculated excess cases and deaths between Jan 1, 2015, and Dec 31, 2019 (the recession period) as the difference between reported values and a counterfactual of continued pre-recession trends. We examined the relationship between excess cases and possible explanatory factors using ordinary least squares regression. We tested the robustness of our findings to alternative model specifications related to the pre-recession period and criteria for defining tuberculosis deaths., Findings: We estimated 22 900 excess tuberculosis cases (95% uncertainty interval 18 100-27 500) during 2015-19. By 2019, reported cases were 12% (10-13) higher than predicted by historical trends. 54% (44-66) of excess cases occurred among 20-29-year-old men. In this group, reported cases in 2019 were 30% (25-36) higher than predicted. Excess cases were positively associated with an increasing fraction of cases among incarcerated individuals (p=0·001) and higher unemployment (p=0·04) at the state level. Estimated excess deaths for 2015-19 were not statistically significant from 0 (-600 [-2100 to 1000]). These results were robust to alternative definitions of the pre-recession period and criteria for defining tuberculosis deaths., Interpretation: Tuberculosis cases in Brazil rose substantially in 2015-19 during the recession, largely affecting young men. This increase seems to be linked to increasing tuberculosis transmission among incarcerated populations. Rising tuberculosis case rates threaten tuberculosis control in Brazil, and highlight the threat posed by prison-based tuberculosis transmission., Funding: US National Institutes of Health., Translation: For the Portuguese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Many children who develop tuberculosis are thought to be missed by diagnostic and reporting systems. We aimed to estimate paediatric tuberculosis incidence and underreporting between 2013 and 2019 in countries representing more than 99% of the global tuberculosis burden., Methods: We developed a mathematical model of paediatric tuberculosis natural history, accounting for key mechanisms and risk factors for infectious exposure (HIV, malnutrition, and BCG non-vaccination), the probability of infection given exposure, and progression to disease among infected individuals. We extracted paediatric population estimates from UN Population Division data, and we used WHO estimates for adult tuberculosis incidence rates. We parameterised this model for 185 countries and calibrated it using data from countries with stronger case detection and reporting systems. Using this model, we estimated trends in paediatric incidence, and the proportion of these cases that are diagnosed and reported (case detection ratio [CDR]) for each country, age group, and year., Findings: For 2019, we estimated 997 500 (95% credible interval [CrI] 868 700-1 163 100) incident tuberculosis cases among children, with 481 000 cases (398 400-587 400) among those aged 0-4 years and 516 500 cases (442 900-608 000) among those aged 5-14 years. The paediatric CDR was estimated to be lower in children aged 0-4 years (41%, 95% CrI 34-50) than in those aged 5-14 years (63%, 53-75) and varied widely between countries. Estimated CDRs increased substantially over the study period, from 18% (15-20) in 2013 to 53% (45-60) in 2019, with improvements concentrated in the Eastern Mediterranean, South-East Asia, and Western Pacific regions. Over the study period, global incidence was estimated to have declined slowly at an average annual rate of 1·52% (1·42-1·66)., Interpretation: Paediatric tuberculosis causes substantial morbidity and mortality, and these data indicate that cases (and, thus, probably associated mortality) are currently substantially underreported. These findings reinforce the need to ensure prompt diagnosis and care for children developing tuberculosis, strengthen reporting systems, and invest in research to develop more accurate and easy-to-use diagnostics for paediatric tuberculosis in high-burden settings., Funding: National Institutes of Health., Competing Interests: Declaration of interests TC reports grants from the National Institutes of Health (NIH), Bill & Melinda Gates Foundation, USAID, and the US Centers for Disease Control and Prevention (CDC) and financial support for attending meetings from the Bill & Melinda Gates Foundation, all to his institution. NAM reports grants from NIH, Bill & Melinda Gates Foundation, WHO, US Council of State and Territorial Epidemiologists, CDC, and Facebook, all to his institution; consulting fees from the Global Fund to Fight AIDS, Tuberculosis and Malaria; and advisory board membership for NIH and Tufts University. RA reports grants from the National Institute for Health Research, Union for International Cancer Control, Novo Nordisk, and Sloan Memorial Kettering Hospital; and payments from Merck, Novartis, and F Hoffmann–La Roche, outside the submitted study. SY declares no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, the impact of post-tuberculosis sequelae is generally omitted from policy analyses and disease burden estimates. We therefore estimated the global burden of tuberculosis, inclusive of post-tuberculosis morbidity and mortality., Methods: We constructed a hypothetical cohort of individuals developing tuberculosis in 2019, including pulmonary and extrapulmonary disease. We simulated lifetime health outcomes for this cohort, stratified by country, age, sex, HIV status, and treatment status. We used disability-adjusted life-years (DALYs) to summarise fatal and non-fatal health losses attributable to tuberculosis, during the disease episode and afterwards. We estimated post-tuberculosis mortality and morbidity based on the decreased lung function caused by pulmonary tuberculosis disease., Findings: Globally, we estimated 122 (95% uncertainty interval [UI] 98-151) million DALYs due to incident tuberculosis disease in 2019, with 58 (38-83) million DALYs attributed to post-tuberculosis sequelae, representing 47% (95% UI 37-57) of the total burden estimate. The increase in burden from post-tuberculosis varied substantially across countries and regions, driven largely by differences in estimated case fatality for the disease episode. We estimated 12·1 DALYs (95% UI 10·0-14·9) per incident tuberculosis case, of which 6·3 DALYs (5·6-7·0) were from the disease episode and 5·8 DALYs (3·8-8·3) were from post-tuberculosis. Per-case post-tuberculosis burden estimates were greater for younger individuals, and in countries with high incidence rates. The burden of post-tuberculosis was spread over the remaining lifetime of tuberculosis survivors, with almost a third of total DALYs (28%, 95% UI 23-34) accruing 15 or more years after incident tuberculosis., Interpretation: Post-tuberculosis sequelae add substantially to the overall disease burden caused by tuberculosis. This hitherto unquantified burden has been omitted from most previous policy analyses. Future policy analyses and burden estimates should take better account of post-tuberculosis, to avoid the potential misallocation of funding, political attention, and research effort resulting from continued neglect of this issue., Funding: National Institutes of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In settings of high tuberculosis incidence, previously treated individuals remain at high risk of recurrent tuberculosis and contribute substantially to overall disease burden. Whether tuberculosis case finding and preventive interventions among previously treated people are cost-effective has not been established. We aimed to estimate costs and health benefits of annual post-treatment follow-up examinations and secondary preventive therapy for tuberculosis in a tuberculosis-endemic setting., Methods: We developed a transmission-dynamic mathematical model and calibrated it to data from two high-incidence communities of approximately 40 000 people in suburban Cape Town, South Africa. We used the model to estimate overall cost and disability-adjusted life-years (DALYs) associated with annual follow-up examinations and secondary isoniazid preventive therapy (IPT), alone and in combination, among individuals completing tuberculosis treatment. We investigated scenarios under which these interventions were restricted to the first year after treatment completion, or extended indefinitely. For each intervention scenario, we projected health system costs and DALYs averted with respect to the current status quo of tuberculosis control. All estimates represent mean values derived from 1000 epidemic trajectories simulated over a 10-year period (2019-28), with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values., Findings: We estimated that a single follow-up examination at the end of the first year after treatment completion combined with 12 months of secondary IPT would avert 2472 DALYs (95% UI -888 to 7801) over a 10-year period and is expected to be cost-saving compared with current control efforts. Sustained annual follow-up and continuous secondary IPT beyond the first year after treatment would avert an additional 1179 DALYs (-1769 to 4377) over 10 years at an expected additional cost of US$18·2 per DALY averted. Strategies of follow-up without secondary IPT were dominated (ie, expected to result in lower health impact at higher costs) by strategies that included secondary IPT., Interpretation: In this high-incidence setting, post-treatment follow-up and secondary preventive therapy can accelerate declines in tuberculosis incidence and potentially save resources for tuberculosis control. Empirical trials to assess the feasibility of these interventions in settings most severely affected by tuberculosis are needed., Funding: National Institutes of Health, Günther Labes Foundation, Oskar Helene Heim Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In high-incidence settings, recurrent disease among previously treated individuals contributes substantially to the burden of incident and prevalent tuberculosis. The extent to which interventions targeted to this high-risk group can improve tuberculosis control has not been established. We aimed to project the population-level effect of control interventions targeted to individuals with a history of previous tuberculosis treatment in a high-incidence setting., Methods: We developed a transmission-dynamic model of tuberculosis and HIV in a high-incidence setting with a population of roughly 40 000 people in suburban Cape Town, South Africa. The model was calibrated to data describing local demography, TB and HIV prevalence, TB case notifications and treatment outcomes using a Bayesian calibration approach. We projected the effect of annual targeted active case finding in all individuals who had previously completed tuberculosis treatment and targeted active case finding combined with lifelong secondary isoniazid preventive therapy. We estimated the effect of these targeted interventions on local tuberculosis incidence, prevalence, and mortality over a 10 year period (2016-25)., Findings: We projected that, under current control efforts in this setting, the tuberculosis epidemic will remain in slow decline for at least the next decade. Additional interventions targeted to previously treated people could greatly accelerate these declines. We projected that annual targeted active case finding combined with secondary isoniazid preventive therapy in those who previously completed tuberculosis treatment would avert 40% (95% uncertainty interval [UI] 21-56) of incident tuberculosis cases and 41% (16-55) of tuberculosis deaths occurring between 2016 and 2025., Interpretation: In this high-incidence setting, the use of targeted active case finding in combination with secondary isoniazid preventive therapy in previously treated individuals could accelerate decreases in tuberculosis morbidity and mortality. Studies to measure cost and resource implications are needed to establish the feasibility of this type of targeted approach for improving tuberculosis control in settings with high tuberculosis and HIV prevalence., Funding: National Institutes of Health, German Research Foundation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The economic burden on households affected by tuberculosis through costs to patients can be catastrophic. WHO's End TB Strategy recognises and aims to eliminate these potentially devastating economic effects. We assessed whether aggressive expansion of tuberculosis services might reduce catastrophic costs., Methods: We estimated the reduction in tuberculosis-related catastrophic costs with an aggressive expansion of tuberculosis services in India and South Africa from 2016 to 2035, in line with the End TB Strategy. Using modelled incidence and mortality for tuberculosis and patient-incurred cost estimates, we investigated three intervention scenarios: improved treatment of drug-sensitive tuberculosis; improved treatment of multidrug-resistant tuberculosis; and expansion of access to tuberculosis care through intensified case finding (South Africa only). We defined tuberculosis-related catastrophic costs as the sum of direct medical, direct non-medical, and indirect costs to patients exceeding 20% of total annual household income. Intervention effects were quantified as changes in the number of households incurring catastrophic costs and were assessed by quintiles of household income., Findings: In India and South Africa, improvements in treatment for drug-sensitive and multidrug-resistant tuberculosis could reduce the number of households incurring tuberculosis-related catastrophic costs by 6-19%. The benefits would be greatest for the poorest households. In South Africa, expanded access to care could decrease household tuberculosis-related catastrophic costs by 5-20%, but gains would be seen largely after 5-10 years., Interpretation: Aggressive expansion of tuberculosis services in India and South Africa could lessen, although not eliminate, the catastrophic financial burden on affected households., Funding: Bill & Melinda Gates Foundation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements., Methods: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy., Findings: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis., Interpretation: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level., Funding: Bill and Melinda Gates Foundation., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: The post-2015 End TB Strategy sets global targets of reducing tuberculosis incidence by 50% and mortality by 75% by 2025. We aimed to assess resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa., Methods: We examined intervention scenarios developed in consultation with country stakeholders, which scaled up existing interventions to high but feasible coverage by 2025. Nine independent modelling groups collaborated to estimate policy outcomes, and we estimated the cost of each scenario by synthesising service use estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health effects (ie, disability-adjusted life-years averted) and resource implications for 2016-35, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios with a base case representing continued current practice., Findings: Incremental tuberculosis service costs differed by scenario and country, and in some cases they more than doubled existing funding needs. In general, expansion of tuberculosis services substantially reduced patient-incurred costs and, in India and China, produced net cost savings for most interventions under a societal perspective. In all three countries, expansion of access to care produced substantial health gains. Compared with current practice and conventional cost-effectiveness thresholds, most intervention approaches seemed highly cost-effective., Interpretation: Expansion of tuberculosis services seems cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, although substantial new funding would be required. Further work to determine the optimal intervention mix for each country is necessary., Funding: Bill & Melinda Gates Foundation., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage., Methods: We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the country's 2012 per-head gross domestic product (GDP; South Africa: $8040; Zambia: $1425; India: $1489; Vietnam: $1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP., Findings: In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from $237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to $749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost effective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to $241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost effective., Interpretation: Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost effective in low-income and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets., Funding: Bill & Melinda Gates Foundation, WHO., (Copyright © 2014 Eaton et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by .. All rights reserved.)

Background: WHO's 2013 revisions to its Consolidated Guidelines on antiretroviral drugs recommend routine viral load monitoring, rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most cost-effective use of resources in view of other competing priorities such as expansion of antiretroviral therapy coverage. We assessed the cost-effectiveness of alternative patient monitoring strategies., Methods: We evaluated a range of monitoring strategies, including clinical, CD4 cell count, and viral load monitoring, alone and together, at different frequencies and with different criteria for switching to second-line therapies. We used three independently constructed and validated models simultaneously. We estimated costs on the basis of resource use projected in the models and associated unit costs; we quantified impact as disability-adjusted life years (DALYs) averted. We compared alternatives using incremental cost-effectiveness analysis., Findings: All models show that clinical monitoring delivers significant benefit compared with a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefit over clinical monitoring alone, at an incremental cost that makes it affordable in more settings than viral load monitoring, which is currently more expensive. Viral load monitoring without CD4 cell count every 6-12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing antiretroviral therapy coverage or expanding antiretroviral therapy eligibility., Interpretation: The priority for HIV programmes should be to expand antiretroviral therapy coverage, firstly at CD4 cell count lower than 350 cells per μL, and then at a CD4 cell count lower than 500 cells per μL, using lower-cost clinical or CD4 monitoring. At current costs, viral load monitoring should be considered only after high antiretroviral therapy coverage has been achieved. Point-of-care technologies and other factors reducing costs might make viral load monitoring more affordable in future., Funding: Bill & Melinda Gates Foundation, WHO., (Copyright © 2014 Keebler et al. Open Access article distributed under the terms CC BY-NC-ND. Published by .. All rights reserved.)

Background: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly., Methods: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the $/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and 'cost-effective' if $/DALY was less than three times per capita GDP., Findings: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective., Interpretation: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets., Funding: The Bill and Melinda Gates Foundation and World Health Organization.