Economic implications of novel regimens for tuberculosis treatment in three high-burden countries: a modelling analysis.

BACKGROUND: With numerous trials investigating novel drug combinations to treat tuberculosis, we aimed to evaluate the extent to which future improvements in tuberculosis treatment regimens could offset potential increases in drug costs. METHODS: In this modelling analysis, we used an ingredients-based approach to estimate prices at which novel regimens for rifampin-susceptible and rifampin-resistant tuberculosis treatment would be cost-neutral or cost-effective compared with standards of care in India, the Philippines, and South Africa. We modelled regimens meeting targets set in the WHO's 2023 Target Regimen Profiles (TRPs). Our decision-analytical model tracked cohorts of adults initiating rifampin-susceptible or rifampin-resistant tuberculosis treatment, simulating their health outcomes and costs accumulated during and following treatment under standard-of-care and novel regimen scenarios. Price thresholds included short-term cost-neutrality (considering only savings accrued during treatment), medium-term cost-neutrality (additionally considering savings from averted retreatments and secondary cases), and cost-effectiveness (incorporating willingness-to-pay for improved health outcomes). FINDINGS: Total medium-term costs per person treated using standard-of-care regimens were estimated at US$450 (95% uncertainty interval 310-630) in India, $560 (350-860) in the Philippines, and $730 (530-1090) in South Africa for rifampin-susceptible tuberculosis (current drug costs $46) and $2100 (1590-2810) in India, $2610 (2090-3280) in the Philippines, and $3790 (3090-4630) in South Africa for rifampin-resistant tuberculosis (current drug costs $432). A rifampin-susceptible tuberculosis regimen meeting the optimal targets defined in the TRPs could be cost-neutral in the short term at drug costs of $140 (90-210) per full course in India, $230 (130-380) in the Philippines, and $280 (180-460) in South Africa. For rifampin-resistant tuberculosis, short-term cost-neutral thresholds were higher with $930 (720-1230) in India, $1180 (980-1430) in the Philippines, and $1480 (1230-1780) in South Africa. Medium-term cost-neutral prices were approximately $50-100 higher than short-term cost-neutral prices for rifampin-susceptible tuberculosis and $250-550 higher for rifampin-resistant tuberculosis. Health system cost-neutral prices that excluded patient-borne costs were 45-70% lower (rifampin-susceptible regimens) and 15-50% lower (rifampin-resistant regimens) than the cost-neutral prices that included patient costs. Cost-effective prices were substantially higher. Shorter duration was the most important driver of medium-term savings with novel regimens, followed by ease of adherence. INTERPRETATION: Improved tuberculosis regimens, particularly shorter regimens or those that facilitate better adherence, could reduce overall costs, potentially offsetting higher prices. FUNDING: WHO.

Cost-effectiveness and public health impact of typhoid conjugate vaccine introduction strategies in Bangladesh.

PURPOSE: Typhoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear. METHODS: We extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons. RESULTS: We projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9-12 months of age with a single catch-up campaign for children ages 1-15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 - 5.18), 11.31 thousand deaths (95 % CrI: 3.77 - 23.60), and save $172.35 million (95 % CrI: -14.29 - 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds. CONCLUSIONS: We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.

Impact and cost-effectiveness of short-course tuberculosis preventive treatment for household contacts and people with HIV in 29 high-incidence countries: a modelling analysis.

BACKGROUND: Guidelines and implementation of tuberculosis preventive treatment (TPT) vary by age and HIV status. Specifically, TPT is strongly recommended for people living with HIV/AIDS (PLWHA) and household contacts younger than 5 years but only conditionally recommended for older contacts. Cost remains a major barrier to implementation. The aim of this study was to evaluate the cost-effectiveness of TPT for household contacts and PLWHA. METHODS: We developed a state-transition model to simulate short-course TPT for household contacts and PLWHA in 29 high-incidence countries based on data from previous studies and public databases. Our primary outcome was the incremental cost-effectiveness ratio, expressed as incremental discounted costs (2020 US$, including contact investigation costs) per incremental discounted disability-adjusted life year (DALY) averted, compared with a scenario without any TPT or contact investigation. We propagated uncertainty in all model parameters using probabilistic sensitivity analysis and also evaluated the sensitivity of results to the screening algorithm used to rule out active disease, the choice of TPT regimen, the modelling time horizon, assumptions about TPT coverage, antiretroviral therapy discontinuation, and secondary transmission. FINDINGS: Between 2023 and 2035, scaling up TPT prevented 0·9 (95% uncertainty interval 0·4-1·6) people from developing tuberculosis and 0·13 (0·05-0·27) tuberculosis deaths per 100 PLWHA, at an incremental cost of $15 (9-21) per PLWHA. For household contacts, TPT (with contact investigation) averted 1·1 (0·5-2·0) cases and 0·7 (0·4-1·0) deaths per 100 contacts, at a cost of $21 (17-25) per contact. Cost-effectiveness was most favourable for household contacts younger than 5 years ($22 per DALY averted) and contacts aged 5-14 years ($104 per DALY averted) but also fell within conservative cost-effectiveness thresholds in many countries for PLWHA ($722 per DALY averted) and adult contacts ($309 per DALY averted). Costs per DALY averted tended to be lower when compared with a scenario with contact investigation but no TPT. The cost-effectiveness of TPT was not substantially altered in sensitivity analyses, except that TPT was more favourable in analysis that considered a longer time horizon or included secondary transmission benefits. INTERPRETATION: In many high-incidence countries, short-course TPT is likely to be cost-effective for PLWHA and household contacts of all ages, regardless of whether contact investigation is already in place. Failing to implement tuberculosis contact investigation and TPT will incur a large burden of avertable illness and mortality in the next decade. FUNDING: Unitaid.

Comparison of model predictions of typhoid conjugate vaccine public health impact and cost-effectiveness.

Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence model-predicted outcomes. To provide robust estimates for the potential public health impact of TCVs that account for structural model differences, we compared four dynamic and one static mathematical model of typhoid transmission and vaccine impact. All models were fitted to a common dataset of age-specific typhoid fever cases in Kolkata, India. We evaluated three TCV strategies: no vaccination, routine vaccination at 9 months of age, and routine vaccination at 9 months with a one-time catch-up campaign (ages 9 months to 15 years). The primary outcome was the predicted percent reduction in symptomatic typhoid cases over 10 years after vaccine introduction. For three models with economic analyses (Models A-C), we also compared the incremental cost-effectiveness ratios (ICERs), calculated as the incremental cost (US$) per disability-adjusted life-year (DALY) averted. Routine vaccination was predicted to reduce symptomatic cases by 10-46 % over a 10-year time horizon under an optimistic scenario (95 % initial vaccine efficacy and 19-year mean duration of protection), and by 2-16 % under a pessimistic scenario (82 % initial efficacy and 6-year mean protection). Adding a catch-up campaign predicted a reduction in incidence of 36-90 % and 6-35 % in the optimistic and pessimistic scenarios, respectively. Vaccine impact was predicted to decrease as the relative contribution of chronic carriers to transmission increased. Models A-C all predicted routine vaccination with or without a catch-up campaign to be cost-effective compared to no vaccination, with ICERs varying from $95-789 per DALY averted; two models predicted the ICER of routine vaccination alone to be greater than with the addition of catch-up campaign. Despite differences in model-predicted vaccine impact and cost-effectiveness, routine vaccination plus a catch-up campaign is likely to be impactful and cost-effective in high incidence settings such as Kolkata.

Ending tuberculosis in a post-COVID-19 world: a person-centred, equity-oriented approach.

The COVID-19 pandemic has disrupted systems of care for infectious diseases-including tuberculosis-and has exposed pervasive inequities that have long marred efforts to combat these diseases. The resulting health disparities often intersect at the individual and community levels in ways that heighten vulnerability to tuberculosis. Effective responses to tuberculosis (and other infectious diseases) must respond to these realities. Unfortunately, current tuberculosis programmes are generally not designed from the perspectives of affected individuals and fail to address structural determinants of health disparities. We describe a person-centred, equity-oriented response that would identify and focus on communities affected by disparities, tailor interventions to the mechanisms by which disparities worsen tuberculosis, and address upstream determinants of those disparities. We detail four key elements of the approach (data collection, programme design, implementation, and sustainability). We then illustrate how organisations at multiple levels might partner and adapt current practices to incorporate these elements. Such an approach could generate more substantial, sustainable, and equitable reductions in tuberculosis burden at the community level, highlighting the urgency of restructuring post-COVID-19 health systems in a more person-centred, equity-oriented way.

A subnational affordability assessment of nutritious foods for complementary feeding in Kenya.

Complementary feeding among children aged 6-23 months is a key determinant of micronutrient deficiencies and childhood stunting, the burdens of which remain high in Kenya. This study examines the affordability of complementary foods to increase young children's nutrient consumption across eight provinces in Kenya. We combined data from household surveys, food composition tables and published sources to estimate the cost of portion sizes that could meet half of the children's daily iron, vitamin A, calcium, zinc, folate, vitamin B12 and protein requirements from complementary feeding. These costs were compared to current household food expenditures. The selection of foods and price and expenditure data were stratified by province. Our analysis indicates that vitamin A, vitamin B12 and folate are affordable to most households in Kenya via liver, beans and in some provinces, orange-fleshed fruits and vegetables, avocado and small dried fish. Calcium, animal-source protein, zinc and iron were less affordable and there was more provincial variation. In some provinces, small dried fish were an affordable source of calcium, protein and zinc. In others (North Eastern, Central, Eastern, parts of Rift Valley and Coast), small dried fish were not commonly consumed and other foods were less affordable. Future research should consider interventions aimed at reducing prices, increasing availability and changing behaviours related to these foods. Solutions such as supplementation and fortification may be needed for iron and zinc in some locations. Food affordability presented the greatest barriers in North Eastern province, which had lower dietary diversity and may require additional targeted interventions.

Affordability of nutritious foods for complementary feeding in Eastern and Southern Africa.

Low intake of diverse complementary foods causes critical nutrient gaps in the diets of young children. Inadequate nutrient intake in the first 2 years of life can lead to poor health, educational, and economic outcomes. In this study, the extent to which food affordability is a barrier to consumption of several nutrients critical for child growth and development was examined in Ethiopia, Mozambique, South Africa, Tanzania, Uganda, and Zambia. Drawing upon data from nutrient gap assessments, household surveys, and food composition tables, current consumption levels were assessed, the cost of purchasing key nutritious foods that could fill likely nutrient gaps was calculated, and these costs were compared with current household food expenditure. Vitamin A is affordable for most households (via dark leafy greens, orange-fleshed vegetables, and liver) but only a few foods (fish, legumes, dairy, dark leafy greens, liver) are affordable sources of iron, animal-source protein, or calcium, and only in some countries. Zinc is ubiquitously unaffordable. For unaffordable nutrients, approaches to reduce prices, enhance household production, or increase household resources for nutritious foods are needed.

Affordability of nutritious foods for complementary feeding in South Asia.

The high prevalence of stunting and micronutrient deficiencies among children in South Asia has lifelong health, educational, and economic consequences. For children aged 6-23 months, undernutrition is influenced by inadequate intake of complementary foods containing nutrients critical for growth and development. The affordability of nutrients lacking in young children's diets in Bangladesh, India, and Pakistan was assessed in this study. Using data from nutrient gap assessments and household surveys, household food expenditures were compared with the cost of purchasing foods that could fill nutrient gaps. In all 3 countries, there are multiple affordable sources of vitamin A (orange-fleshed vegetables, dark leafy greens, liver), vitamin B12 (liver, fish, milk), and folate (dark leafy greens, liver, legumes, okra); few affordable sources of iron and calcium (dark leafy greens); and no affordable sources of zinc. Affordability of animal-source protein varies, with several options in Pakistan (fish, chicken, eggs, beef) and India (fish, eggs, milk) but few in Bangladesh (eggs). Approaches to reduce prices, enhance household production, or increase incomes are needed to improve affordability.

Comparison of Strategies for Typhoid Conjugate Vaccine Introduction in India: A Cost-Effectiveness Modeling Study.

BACKGROUND: Typhoid fever causes substantial global mortality, with almost half occurring in India. New typhoid vaccines are highly effective and recommended by the World Health Organization for high-burden settings. There is a need to determine whether and which typhoid vaccine strategies should be implemented in India. METHODS: We assessed typhoid vaccination using a dynamic compartmental model, parameterized by and calibrated to disease and costing data from a recent multisite surveillance study in India. We modeled routine and 1-time campaign strategies that target different ages and settings. The primary outcome was cost-effectiveness, measured by incremental cost-effectiveness ratios (ICERs) benchmarked against India's gross national income per capita (US$2130). RESULTS: Both routine and campaign vaccination strategies were cost-saving compared to the status quo, due to averted costs of illness. The preferred strategy was a nationwide community-based catchup campaign targeting children aged 1-15 years alongside routine vaccination, with an ICER of $929 per disability-adjusted life-year averted. Over the first 10 years of implementation, vaccination could avert 21-39 million cases and save $1.6-$2.2 billion. These findings were broadly consistent across willingness-to-pay thresholds, epidemiologic settings, and model input distributions. CONCLUSIONS: Despite high initial costs, routine and campaign typhoid vaccination in India could substantially reduce mortality and was highly cost-effective.

Methods for Model Calibration under High Uncertainty: Modeling Cholera in Bangladesh.

Background. Published data on a disease do not always correspond directly to the parameters needed to simulate natural history. Several calibration methods have been applied to computer-based disease models to extract needed parameters that make a model's output consistent with available data. Objective. To assess 3 calibration methods and evaluate their performance in a real-world application. Methods. We calibrated a model of cholera natural history in Bangladesh, where a lack of active surveillance biases available data. We built a cohort state-transition cholera natural history model that includes case hospitalization to reflect the passive surveillance data-generating process. We applied 3 calibration techniques: incremental mixture importance sampling, sampling importance resampling, and random search with rejection sampling. We adapted these techniques to the context of wide prior uncertainty and many degrees of freedom. We evaluated the resulting posterior parameter distributions using a range of metrics and compared predicted cholera burden estimates. Results. All 3 calibration techniques produced posterior distributions with a higher likelihood and better fit to calibration targets as compared with prior distributions. Incremental mixture importance sampling resulted in the highest likelihood and largest number of unique parameter sets to better inform joint parameter uncertainty. Compared with naïve uncalibrated parameter sets, calibrated models of cholera in Bangladesh project substantially more cases, many of which are not detected by passive surveillance, and fewer deaths. Limitations. Calibration cannot completely overcome poor data quality, which can leave some parameters less well informed than others. Calibration techniques may perform differently under different circumstances. Conclusions. Incremental mixture importance sampling, when adapted to the context of high uncertainty, performs well. By accounting for biases in data, calibration can improve model projections of disease burden.

Gavi's Transition Policy: Moving From Development Assistance To Domestic Financing Of Immunization Programs.

Gavi, the Vaccine Alliance, was created in 2000 to accelerate the introduction of new and underused vaccines in lower-income countries. The period 2000-15 was marked by the rapid uptake of new vaccines in more than seventy countries eligible for Gavi support. To stay focused on the poorest countries, Gavi's support phases out after countries' gross national income per capita surpasses a set threshold, which requires governments to assume responsibility for the continued financing of vaccines introduced with Gavi support. Gavi's funding will end in the period 2016-20 for nineteen countries that have exceeded the eligibility threshold. To avoid disrupting lifesaving immunization programs and to ensure the long-term sustainable impact of Gavi's investments, it is vital that governments succeed in transitioning from development assistance to domestic financing of immunization programs. This article discusses some of the challenges facing countries currently transitioning out of Gavi support, how Gavi's policies have evolved to help manage the risks involved in this process, and the lessons learned from this experience.

Funding AIDS programmes in the era of shared responsibility: an analysis of domestic spending in 12 low-income and middle-income countries.

BACKGROUND: As the incomes of many AIDS-burdened countries grow and donors' budgets for helping to fight the disease tighten, national governments and external funding partners increasingly face the following question: what is the capacity of countries that are highly affected by AIDS to finance their responses from domestic sources, and how might this affect the level of donor support? In this study, we attempt to answer this question. METHODS: We propose metrics to estimate domestic AIDS financing, using methods related to national prioritisation of health spending, disease burden, and economic growth. We apply these metrics to 12 countries in sub-Saharan Africa with a high prevalence of HIV/AIDS, generating scenarios of possible future domestic expenditure. We compare the results with total AIDS financing requirements to calculate the size of the resulting funding gaps and implications for donors. FINDINGS: Nearly all 12 countries studied fall short of the proposed expenditure benchmarks. If they met these benchmarks fully, domestic spending on AIDS would increase by 2·5 times, from US$2·1 billion to $5·1 billion annually, covering 64% of estimated future funding requirements and leaving a gap of around a third of the total $7·9 billion needed. Although upper-middle-income countries, such as Botswana, Namibia, and South Africa, would become financially self-reliant, lower-income countries, such as Mozambique and Ethiopia, would remain heavily dependent on donor funds. INTERPRETATION: The proposed metrics could be useful to stimulate further analysis and discussion around domestic spending on AIDS and corresponding donor contributions, and to structure financial agreements between recipient country governments and donors. Coupled with improved resource tracking, such metrics could enhance transparency and accountability for efficient use of money and maximise the effect of available funding to prevent HIV infections and save lives. FUNDING: US Centers for Disease Control and Prevention.

Overcoming challenges to sustainable immunization financing: early experiences from GAVI graduating countries.

Over the 5-year period ending in 2018, 16 countries with a combined birth cohort of over 6 million infants requiring life-saving immunizations are scheduled to transition (graduate) from outside financial and technical support for a number of their essential vaccines. This support has been provided over the past decade by the GAVI Alliance. Will these 16 countries be able to continue to sustain these vaccination efforts? To address this issue, GAVI and its partners are supporting transition planning, entailing country assessments of readiness to graduate and intensive dialogue with national officials to ensure a smooth transition process. This approach was piloted in Bhutan, Republic of Congo, Georgia, Moldova and Mongolia in 2012. The pilot showed that graduating countries are highly heterogeneous in their capacity to assume responsibility for their immunization programmes. Although all possess certain strengths, each country displayed weaknesses in some of the following areas: budgeting for vaccine purchase, national procurement practices, performance of national regulatory agencies, and technical capacity for vaccine planning and advocacy. The 2012 pilot experience further demonstrated the value of transition planning processes and tools. As a result, GAVI has decided to continue with transition planning in 2013 and beyond. As the graduation process advances, GAVI and graduating countries should continue to contribute to global collective thinking about how developing countries can successfully end their dependence on donor aid and achieve self-sufficiency.