An Opportunity to END TB: Using the Sustainable Development Goals for Action on Socio-Economic Determinants of TB in High Burden Countries in WHO South-East Asia and the Western Pacific Regions

The progress towards ending tuberculosis (TB) by 2035 is less than expected in 11 high TB burden countries in the World Health Organization South-East Asia and Western Pacific regions. Along with enhancing measures aimed at achieving universal access to quality-assured diagnosis, treatment and prevention services, massive efforts are needed to mitigate the prevalence of health-related risk factors, preferably through broader actions on the determinants of the “exposure-infection-disease-adverse outcome” spectrum. The aim of this manuscript is to describe the major socio-economic determinants of TB and to discuss how there are opportunities to address these determinants in an englobing manner under the United Nations Sustainable Development Goals (SDGs) framework. The national TB programs must identify stakeholders working on the other SDGs, develop mechanisms to collaborate with them and facilitate action on social-economic determinants in high TB burden geographical areas. Research (to determine the optimal mechanisms and impact of such collaborations) must be an integral part of this effort. We call upon stakeholders involved in achieving the SDGs and End TB targets to recognize that all goals are highly interlinked, and they need to combine and complement each other’s efforts to end TB and the determinants behind this disease.


Introduction
Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis (Mtb), is one of the top 10 leading causes of death world-wide and the leading cause of death from a single infectious agent [1]. Mtb spreads from person to person through airborne droplet nuclei. When a person with active TB of the lungs or throat, coughs or sneezes, droplets containing Mtb are expelled into the air and inhalation of this contaminated air may cause TB infection [2]. Once infected, about 5-15% of the people develop

End TB Strategy
In 2014, to rid mankind of the enormous burden of TB, the 67th World Health Assembly adopted a resolution to make the world free of TB by the year 2035. WHO's "End TB Strategy" provides a holistic overview of this resolution and has four principles and three pillars [8]. The three high-level target indicators of the End TB Strategy are reductions in TB deaths by 95%, reductions in the TB incidence rate by 90% and the percentage of TB patients and their households experiencing catastrophic costs being maintained at zero. These indicators and targets are relevant to all countries, with interim milestones to be achieved by 2020, 2025 and 2030.

Progress towards the 2020 Milestones of the End TB Strategy
By the end of 2019, at the global level, most of the WHO regions and many high TB burden countries were not on track to reach the End TB Strategy's 2020 milestones (20% reduction in TB incidence rate, 35% reduction in the number of TB deaths and reduction in the households experiencing catastrophic costs to 0%). The reduction in the cumulative global TB incidence rate between 2015 and 2018 was only 6.3%, and the reduction in the total number of TB deaths between 2015 and 2018 was 11% [6]. Table 2 shows the reduction in the TB incidence rate, TB mortality, and catastrophic costs in the 11 high TB burden countries in the Asia Pacific region (which comprises South-East Asia and the Western Pacific). However, with this rate of decline in incidence and mortality, and with the data on catastrophic costs unavailable, it is unlikely that any of the countries in the Asia Pacific region will be able to reach all the End TB Strategy's 2020 milestones.

Factors Influencing the Risk of Exposure to Mycobacterium tuberculosis (Mtb), Infection, the Progression from Infection to Disease and Adverse Treatment Outcomes
There are two important aspects to understanding the TB epidemiology. First, Mtb infection in humans results in a spectrum of clinical presentations. As mentioned earlier, most infections are subclinical and asymptomatic, with Mtb replication contained by the host immunity-a condition called latent TB infection (LTBI)-and only a small subset of infected individuals presenting with symptomatic, active TB disease. Even within and between these two states, there is a wide ranging spectrum of Mtb bacterial load, immune responses, pathologies and clinical presentations [9]. Second, like all other infectious diseases, the risk of infection and disease is dependent on the characteristics and interaction of the bacteria, the human host and the environment [7]. A good understanding of these factors and their unique complex interactions-at both the population level and the individual level-is crucial for designing the intervention strategies to mitigate the TB burden.
The factors that influence the risk of exposure to Mtb, infection, the progression of infection to disease, and adverse treatment outcomes (such as death) are shown in Box 1 [10,11]. The factor that is essential for TB infection and disease is close contact with a person with a person with infectious TB disease; the greater the closeness, bacterial load and duration of contact, the higher the chances of infection. Other factors such as age, sex, tobacco use, alcohol use, malnutrition, human immunodeficiency virus (HIV) infection, diabetes mellitus and silicosis increase the risk of infection, the progression from infection to disease and adverse TB treatment outcomes, and are therefore called major health-related risk factors. Factors such as poverty, socio-economic and/or gender inequality, food and/or job insecurity and weak health systems affect not only all aspects of the "exposure-infection-disease-adverse outcome" spectrum, but also several aspects of the health of populations in general, and are therefore called the critical underlying 'determinants' or the 'root causes' of TB. While age and sex are not modifiable, all the other factors listed in Box 1 can be modified by human interventions. Table 3 shows the health-related risk factors and the corresponding lifetime increase in the risk of TB disease and the 'population attributable fraction (PAF)' of these factors [12][13][14][15][16][17][18]. * Source: Global TB report 2019 [6]); ** these are approximates and vary widely across countries; *** PAF indicates the proportion of all cases of a particular disease in a population that is attributable to a specific exposure and is estimated based on the relative risk and the prevalence of the risk factor in the population [18].

Box 1.
Factors influencing the "exposure-infection-disease-adverse outcome" spectrum of TB.

The essential factor for TB infection and TB disease
•

Close contact with a person with infectious TB disease
Major health-related risk factors (factors that increase the chances of infection, disease, adverse TB treatment outcomes) • Age, sex, tobacco use, alcohol abuse, malnutrition, HIV infection, diabetes mellitus, exposure to indoor air pollution, silicosis, intake of immunosuppressive drugs/medications (e.g., tumor necrosis factor-alpha (TNF) antagonists, corticosteroids)

Major underlying determinants
• Poverty, socio-economic and gender inequality, overcrowding, food and job insecurity, weak health systems

Relationship between Various Health-Related Risk factors and Major Underlying Socio-Economic Determinants of TB
In the past, the trends in TB incidence rates in high-income countries clearly show that efforts towards improving the socio-economic status, living conditions and nutritional status (as was seen before and soon after the world wars) resulted in the rapid decline in the TB burden, and, deterioration in these conditions (during times of war) increased the TB incidence rates. Both in high and low-income countries, TB predominantly affects people of lower socio-economic status [19,20].
Most of the risk factors for TB are associated with poverty, socio-economic and gender inequalities, and living conditions [21]. Malnutrition, poor housing/living conditions, and overcrowding are direct markers of poverty [22]. People from lower socio-economic groups are more likely to live and/or work in overcrowded settings, experience greater food insecurity, have lower levels of awareness about healthy behavior, and are less likely to have access to quality health care services [23]. They are also more likely to come into contact with people with active TB disease. The prevalence of tobacco use, alcohol use, HIV, and diabetes mellitus is relatively higher in people of low socio-economic status groups in various settings [24][25][26][27][28].
The Multisectoral Accountability Framework to accelerate progress to end TB (MAF-TB) by 2035 developed by the WHO in 2019 [29] urges governments to address a wide range of socio-economic 5 of 19 determinants through collaborations and partnerships. Although the primary responsibility to pursue public health in all policies rests with different ministries within governments, the national TB programs, as champions and implementers of the TB care and prevention services in the countries, should take the lead in developing partnerships and support the implementation of the multisectoral accountability framework, both through advocacy and by helping to address the social conditions of patients and their families.

Need for Action on Risk Factors and Major Determinants of TB
TB (as described earlier) is a multifactorial disease, and the achievement of the End TB Strategy milestones requires universal access to quality-assured diagnosis, treatment, and prevention services promptly. For this, it is necessary to strengthen the national TB programs, by ensuring adequate resources for deploying latest WHO-endorsed rapid TB diagnostics and drug susceptibility testing (DST) facilities, the provision of appropriate treatment services for drug-susceptible and drug-resistant TB, preventive treatment for high risk individuals (people living with HIV and household and other close contacts of TB patients), and the implementation of infection control measures in all health facilities. While these are necessary, it is being increasingly recognized that End TB targets are ambitious and unlikely to be achieved by these measures alone [10,11,30]. Massive efforts are needed to mitigate the prevalence of health-related risk factors, preferably through broader actions on the determinants of the "exposure-infection-disease-adverse outcome" spectrum, such as health system strengthening, poverty alleviation, addressing socio-economic and gender inequality, limiting job loss and food insecurity, improving housing quality and reducing overcrowding. An increase in the health-related risk factors of TB or the worsening of the determinants of TB (as is currently happening due to the socio-economic consequences of the SARS-CoV-2 pandemic [31]) can harm the global progress made towards ending TB.

Framework for Action on Social Determinants of Tuberculosis: Sustainable Development Goals
The sustainable development goals (SDGs) [32]

3.
Good Health and Well-being 4.
Clean Water and Sanitation 7.
Affordable and Clean Energy 8.  [33]. These goals necessitate collaboration and the alignment of all actions to secure a fair, healthy, and prosperous future for everyone on this planet-Earth. These SDGs provide a framework for action on the determinants of TB disease. Action on the determinants of TB through the SDGs framework will also mean endorsing the socio-ecological model of health which outlines that disease prevention and its mitigation may require action at five levels: individual, interpersonal, organisational, community and public policy [34] and addressing every TB determinant may require actions at these five levels. As discussed above, poverty is a significant determinant of several aspects of health including TB [22,35]. Globally, more than 90% of TB cases and deaths occur in low and middle income countries [36]. There is an inverse correlation between a country's gross domestic product (GDP) per capita and TB incidence rates [21]. Therefore, efforts to reduce poverty will have a substantial impact on the TB burden. Despite great progress made globally in reducing poverty levels, some countries in the WHO South-East Asia and Western Pacific Regions, such as India (~21%) and Papua New Guinea (38%), have high reported levels of people living below the international poverty line (SDG Indicator 1.1.1 in Table (SDG Indicator 2.1.1 in Table 4).

SDG Goal 2: Zero Hunger
Hunger leads to undernutrition, which is one of the significant determinants of TB [37]. It is estimated that in India (the highest TB burden country in the world), where the prevalence of undernutrition is high, nearly 50% of TB cases are attributable to undernutrition [38,39]. Undernutrition is also ubiquitous in all high TB burden countries in Asia and the Pacific region (SDG Indicator 2.1.1 in Table 4). Therefore, ending hunger and improving the nutritional status of populations can dramatically reduce the burden of TB.

SDG Goal 3: Good Health and Well Being
One of the key targets of this goal (Target 8) is to achieve universal health coverage (UHC) by 2030 [40]. UHC means that everyone can access and receive sufficient and quality health services that they need without suffering financial hardship. There are two key indicators to monitor progress. They are: a) UHC service coverage index (SCI)-SDG Indicator 3.8.1 (Table 5), and b) the percentage of the population experiencing expenditures on health care that are relatively large in relation to the household expenditures or income-SDG Indicator 3.8.2 ( Table 5). The achievement of UHC and improved patient-centered TB care will have a direct effect on the reach and delivery of quality TB services and on catastrophic costs incurred by TB patients and their families [40]. Apart from this, the SDG goal also has indicators for dramatically reducing the prevalence of HIV, tobacco and alcohol use, and diabetes mellitus, all of which will have a considerable impact on reducing the TB burden.

SDG Goal 4: Quality Education
Quality education typically leads to better and secure jobs, more money and higher purchasing power, resulting in better access to quality health care (including for TB) [41]. Higher earnings also allow people to afford homes in safer neighbor hoods, as well as consume healthier diets. Incorporating health within the ambit of 'quality education' builds knowledge, skills, and positive attitudes about health and all other determinants of health, which can directly or indirectly have a considerable impact on efforts to End TB [42]. Education also improves the ability to identify the symptoms suggestive of TB and seek timely care for diagnosis and treatment of TB [43], thus, limiting the delays in the diagnosis of TB and the community spread of the disease.

SDG Goal 5: Gender Equality
TB can affect either gender. In almost all countries, the notification rates of TB are higher in males than in females. Although more men than women develop TB disease and die from it, TB is nevertheless a leading infectious cause of death among women. Higher tuberculosis notification rates in men partly reflect epidemiological and biological differences in exposure, risk of infection, and progression from infection to disease [44]. Despite this, in several countries, gender inequality, socio-economic, and cultural factors act as barriers to accessing health care among women. These may lead to the under-detection and under-notification of TB in women. The stigma and discrimination associated with TB and certain co-morbidities, such as HIV infection, adversely affect women more than men, often leaving them in a more vulnerable position [45,46]. It is also widely believed that the medical care-seeking behavior of men and women with TB is mostly determined by how they and those around them perceive the symptoms, regard the diagnosis, accept the treatment, and complete it. Gender may influence each of these components and affect the early detection of the disease and its outcome [47]. Studies that have assessed gender differences have shown that, on average, women are either undiagnosed, or diagnosed late in the course of TB disease when compared to men [48,49]. Promoting gender equality in all spheres of life helps to mitigate some of these issues and contribute towards ending TB.

SDG Goal 6: Clean Water and Sanitation
Access to clean water and sanitation is essential to reduce illness, malnutrition, poor physical and cognitive development, and death due to water-borne diseases [50]. In countries of the Asia-Pacific region, the proportion with access to clean water ranges from 16.7% in rural Cambodia to 92.3% in urban China. The proportion with access to safe sanitation ranges from 5.1% in rural Democratic People's Republic of Korea to 83.7% in urban China. The provision of clean water and sanitation can affect the TB burden by reducing infections and improving nutritional status.

SDG Goal 7: Affordable and Clean Energy
There is evidence of an association between indoor air pollution (such as that caused by the burning of solid fuels for cooking at homes), outdoor ambient air pollution and TB infection and TB disease [51][52][53][54]. Depending on the prevalence of indoor air pollution, the fraction of TB cases attributable to indoor air pollution varies across countries. The proportion of the population using clean fuels in the South-East Asia and Western Pacific regions ranges from 11% in DPR Korea to 74% in Thailand (Table 4; indicator 7.1.2). Interventions such as clean cook stoves to reduce the adverse effects of indoor air pollution merit rigorous evaluation [50], particularly in high TB burden countries in Asia and the Pacific, where the prevalence of both indoor air pollution and TB is high. Clean energy is also expected to reduce outdoor air pollution and improve ambient air quality, which can reduce the risk of TB [55].

SDG Goal 8: Decent Work and Economic Growth
TB predominantly affects people in the economically productive age-groups [56]. Apart from providing stable and regular job opportunities for the economically productive age groups, provision for early diagnosis and treatment of TB at workplaces, making workplaces safe by reducing the chances of airborne transmission of infections, adopting favorable policies towards social/job security in case of diseases and reducing occupational diseases like silicosis, will help in reducing the TB burden and improving the economic productivity of the workforce [57]. Stable/formal employment also increases access to employer-sponsored social health insurance programs and paid sick leaves, both of which are known to be associated with the reduced risk of occupational diseases and all-cause mortality [58][59][60].

SDG Goal 10: Reduced Inequalities
Empowering and promoting social, economic and political inclusion of all, irrespective of age, sex, sexual orientation, disability, race, ethnicity, origin, religion or economic or another status will help in mitigating the effects of socio-economic disparities-disparities that are key drivers of all the risk factors of TB [61].

SDG Goal 11: Sustainable Cities and Communities
Rapid industrialization, urbanization, and migration-dominant occurrences in most developing countries in the Asia Pacific region-can create ideal conditions for infectious diseases (including TB) to flourish [62,63], unless accompanied by proper urban planning, social reforms, environmental protection, adequate housing, transportation, and a well-coordinated and robust health system.

SDG Goal 13: Climate Action
Climate change that manifests itself in the form of higher variations in temperatures and rainfall is known to have a substantial effect on several aspects of human health and behaviour (such as crowding, migration, changes in food habits), either directly or through several intermediaries, resulting in an increase in the burden of infectious diseases including TB [64,65].
The linkages between the various SDGs and TB are pictorially depicted in Figure 1. also increases access to employer-sponsored social health insurance programs and paid sick leaves, both of which are known to be associated with the reduced risk of occupational diseases and all-cause mortality [58][59][60].

SDG Goal 10: Reduced Inequalities
Empowering and promoting social, economic and political inclusion of all, irrespective of age, sex, sexual orientation, disability, race, ethnicity, origin, religion or economic or another status will help in mitigating the effects of socio-economic disparities-disparities that are key drivers of all the risk factors of TB [61].

SDG Goal 11: Sustainable Cities and Communities
Rapid industrialization, urbanization, and migration-dominant occurrences in most developing countries in the Asia Pacific region-can create ideal conditions for infectious diseases (including TB) to flourish [62,63], unless accompanied by proper urban planning, social reforms, environmental protection, adequate housing, transportation, and a well-coordinated and robust health system.

SDG Goal 13: Climate Action
Climate change that manifests itself in the form of higher variations in temperatures and rainfall is known to have a substantial effect on several aspects of human health and behaviour (such as crowding, migration, changes in food habits), either directly or through several intermediaries, resulting in an increase in the burden of infectious diseases including TB [64,65].
The linkages between the various SDGs and TB are pictorially depicted in Figure 1.

Role of National TB Programs in Accelerating the Progress towards Achieving SDGs
Together, TB and poverty form a vicious cycle: TB decreases people's capacity to work and adds to treatment expenses. This, in turn, exacerbates their poverty. Poor people also go hungry and live in close, unhygienic quarters, where TB and its risk factors flourish. Progress in ending TB will accelerate the progress on SDG goal 1, and through it, progress on other related SDGs [36].
According to the WHO's "A Multisectoral Accountability Framework to accelerate progress to end Tuberculosis by 2030 (MAF-TB)" [29], the following are recommended actions for national TB programs: • Development of national (and local) strategic and operational plans to end (or eliminate) TB, with a multisectoral perspective involving government and partners, consistent with the End TB Strategy. • Development and use of a national MAF-TB. • Establishment, strengthening or maintenance of a national multisectoral mechanism (e.g., inter-ministerial commission), tasked with providing oversight, coordination and a periodic review of the national tuberculosis response. • Implementation of multisectoral actions on the social determinants of tuberculosis.

•
Revisions to plans and policies, and associated activities, based on monitoring, reporting, and recommendations from reviews.
WHO has identified the following fourteen SDG indicators as relevant to TB. These include The levels of these seven within SDG-3 indicators at the end of 2018 is in the 11 high TB burden countries in WHO South-East Asia, and Western Pacific Regions is given in Table 5.
National TB programs, Ministries of Health and Governments in the 11 high TB burden countries must realize that interventions beyond diagnosis and treatment of TB and LTBI are needed to reduce the risk factors and determinants of TB. TB programs must take a lead and list the stakeholders in their countries who are working on the other SDGs and equip themselves with resources and the necessary skillsets to engage with them. Since TB is not homogenously distributed within the country, there will be geographical areas/communities with high TB burdens. As a first step, TB programs should share details/information of high TB burden geographical areas, assess the socio-economic determinants that are locally relevant/prevalent, and facilitate concentrated action on those socio-economic determinants as a priority in these areas wherever possible. The list of sample interventions that can be undertaken to reduce the prevalence of the socio-economic determinants of TB (based on needs assessment) are given in Table 6. (In this table, using India as an example, we have highlighted public programs [69][70][71][72][73][74][75][76][77][78][79][80][81][82] that can be galvanized to address the determinants at the local level.) The stakeholders/partners who can be involved in carrying out the interventions could be respective government departments (who have the mandate and jurisdiction to perform the intervention), non-governmental/community based organizations, private sector, developmental partners etc., who may share the common vision of improving the lives of the people. Identifying suitable partners will help the national TB programs, in facilitating their interventions in such geographic high TB burden areas. This holistic approach may contribute towards ending TB in such communities or geographic areas in a sustainable manner. Demonstration projects on how to operationalize intersectoral coordination and build partnerships (at the local level) are urgently needed to generate evidence and to show that the impact of such initiatives goes beyond the simple sum of its immediate returns. Research-to find out the optimal mechanisms for collaboration and to measure the impact of such collaborations-must also be undertaken, so that the lessons learnt are disseminated widely. Apart from this, national TB programs must also find themselves represented in all in-country developmental committees and agendas of the government, so that ending TB is seen, not just as a responsibility of the health sector, but seen as a necessity for human development in all spheres of life. International technical and funding agencies/organizations, like WHO, the Global Fund, etc., should advocate for progress on broader SDGs and provide technical and financial assistance on this aspect to TB programs. Table 6. Sample policies/interventions that can be implemented at the community level in high TB burden geographical areas within a country by the National TB program and its partners to address determinants of tuberculosis.  • Provision of improved cookstoves, cleaner and drier fuels which aim to burn fuel more efficiently and therefore produce fewer harmful combustion products; • Improving natural and artificial ventilation, to avoid air pollution inside the household; •

Determinant of TB
Changing cooking behavior and patterns, to reduce the amount of time an individual spends in proximity to a fire or stove; • Altering regulatory or financial policies, with intent to improve access to advanced cookstoves or fuels and provide incentives for changes within communities or towards community development. Reduced inequalities (SDG-10) • Local programs aimed at financial inclusion and social security or linkages to existing social security schemes • Jan Dhan-Aadhaar-Mobile programs (For Financial Inclusion to ensure access to financial services, namely banking savings and deposit accounts, remittance, credit, insurance and pension in an affordable manner and to prevent leakage of government subsidies) [73] Sustainable cities and communities (SDG-11) • Local implementation of slum development schemes/ slums upgrading programs which includes improvements in housing conditions, water supply and sanitation, roads, ground stabilization, storm water drainage etc., • Jawaharlal Nehru National Urban Renewal Mission (a city-modernization scheme) [74] Climate action (SDG-13) • Efforts to reduce carbon emissions through increased generation of power using renewable sources of energy • Increase additional forest and tree cover • National Solar mission [83] • National Afforestation Program [84]

Conclusions
Achieving End TB targets with the current pace of progress is highly challenging and un-realistic if the thrust is mainly medical and focusing only on 'diagnosis and treatment' of TB and LTBI, without addressing the underlying determinants of TB. While the strengthening of national TB programs under the framework of universal health coverage is quintessential for accelerating the progress towards End TB targets, the SDG framework provides an excellent opportunity for acting on several determinants and risk factors of TB. All stakeholders, be it government ministries, non-governmental organizations or private sectors involved in achieving SDGs and the End TB targets must recognize that most of their goals are strongly interlinked. Failure to acknowledge this fact may result in ineffective and inappropriate actions and a delay in the achievement of both SDG goals and End TB targets.