Can Economic Analysis Contribute to Disease Elimination and Eradication? A Systematic Review

Background Infectious diseases elimination and eradication have become important areas of focus for global health and countries. Due to the substantial up-front investments required to eliminate and eradicate, and the overall shortage of resources for health, economic analysis can inform decision making on whether elimination/eradication makes economic sense and on the costs and benefits of alternative strategies. In order to draw lessons for current and future initiatives, we review the economic literature that has addressed questions related to the elimination and eradication of infectious diseases focusing on: why, how and for whom? Methods A systematic review was performed by searching economic literature (cost-benefit, cost-effectiveness and economic impact analyses) on elimination/eradication of infectious diseases published from 1980 to 2013 from three large bibliographic databases: one general (SCOPUS), one bio-medical (MEDLINE/PUBMED) and one economic (IDEAS/REPEC). Results A total of 690 non-duplicate papers were identified from which only 43 met the inclusion criteria. In addition, only one paper focusing on equity issues, the “for whom?” question, was found. The literature relating to “why?” is the largest, much of it focusing on how much it would cost. A more limited literature estimates the benefits in terms of impact on economic growth with mixed results. The question of how to eradicate or eliminate was informed by an economic literature highlighting that there will be opportunities for individuals and countries to free-ride and that forms of incentives and/or disincentives will be needed. This requires government involvement at country level and global coordination. While there is little doubt that eliminating infectious diseases will eventually improve equity, it will only happen if active steps to promote equity are followed on the path to elimination and eradication. Conclusion The largest part of the literature has focused on costs and economic benefits of elimination/eradication. To a lesser extent, challenges associated with achieving elimination/eradication and ensuring equity have also been explored. Although elimination and eradication are, for some diseases, good investments compared with control, countries’ incentives to eliminate do not always align with the global good and the most efficient elimination strategies may not prioritize the poorest populations. For any infectious disease, policy-makers will need to consider realigning contrasting incentives between the individual countries and the global community and to assure that the process towards elimination/eradication considers equity.

A total of 690 non-duplicate papers were identified from which only 43 met the inclusion criteria. In addition, only one paper focusing on equity issues, the "for whom?" question, was found. The literature relating to "why?" is the largest, much of it focusing on how much it would cost. A more limited literature estimates the benefits in terms of impact on economic growth with mixed results. The question of how to eradicate or eliminate was informed by an economic literature highlighting that there will be opportunities for individuals and countries to free-ride and that forms of incentives and/or disincentives will be needed. This requires government involvement at country level and global coordination. While there is little doubt that eliminating infectious diseases will eventually improve equity, it will only happen if active steps to promote equity are followed on the path to elimination and eradication.

Introduction
The major global health achievements of the last century were possible due to improvements in health technologies and services consequent to advances in knowledge, science and technology, building on improvements in socio-economic conditions [1,2]. The links between health improvements and socio-economic development are well established and the relationship is complex and bi-directional. For example, increasing incomes, education and other forms of social development improve living conditions and reduce risks to health. They allow people to take more responsibility for, and invest in their own health. On the other hand, improved health also allows people to earn more and improve their own living standards [3][4][5][6][7]. There is no doubt, however, that increased coverage of many types of health interventions-vaccines, safe childbirth delivery, treatment for tuberculosis, malaria and HIV/AIDS and prevention of cardiovascular disease to name a few-have also contributed to worldwide health improvements.
Economic analysis has facilitated a better understanding of the relationship between economic growth and health, but has also helped to make the case that investments in health produce excellent returns not just in terms of improved morbidity and mortality but also through their impact on the economic wellbeing. Economic analysis has now been extended to questions surrounding one of the most pressing global health challenges: should countries press for the elimination and eradication of infectious diseases and if so, how? Partly because of the heavy initial investments required, there are a number of areas in which economics can inform these important decisions.
We, therefore, undertook a systematic review of the literature to explore how economic analysis has to date contributed to inform the debate about the elimination/eradication of different infectious diseases. We focus particularly on whether there are common strands across diseases in the way this analysis has sought to answer three questions: why eliminate, how, and for whom? [8].
reduction to zero of the global incidence [12]. Interventions are needed after elimination to prevent the reestablishment of transmission but, in principle, no longer needed after eradication.
Elimination and eradication are biologically feasible when there are safe and effective tools able to interrupt transmission; no animal or environmental reservoirs; adequate public health and health system infrastructures, sufficient funding and sustained political/societal will are also required [13].
The investments needed in the early years of elimination/eradication are generally much larger than those involved in running a routine control programme so economics, a science of choice in the face of limited resources, can contribute to inform decisions.
Polio eradication is close to being achieved and a plan for the eradication of measles and rubella is under development [14,15]. Malaria is another disease where eradication has reemerged as a global goal [16]. The vision of eliminating and eradicating selected neglected tropical diseases (NTDs) has also gathered momentum over recent years. In 2011, the WHO Strategic and Technical Advisory Group for Neglected Tropical Diseases and its partners adopted a roadmap for the elimination and eradication of 12 NTDs by 2020-rabies, blinding trachoma, endemic treponematoses, leprosy, chagas disease, human african trypanosomiasis, visceral leishmaniasis, dracunculiasis, lymphatic filariasis, onchocerciasis, schistosomiasis, and dengue [17].
The results of the literature review were organized by the three key questions described earlier: why, how and for whom to eliminate or eradicate? [8]. The studies dealing with the "why" question compare costs with benefits. The "how" question assesses which intervention/s or strategy/ies should be adopted using economic criteria; how to generate incentives for each country to eliminate; how many resources would be required; and how these resources could be mobilized. The "for whom" question assesses who would benefit from eradication, and the likely impact on equity and fairness.
We also classified the papers according to the type of economic issues that were considered: • Impact of elimination/eradication on GDP growth or on its determinants-social and human capital accumulation • Theoretical analyses using game theory • Financial and economic costs of elimination/eradication • Cost-benefit or cost-effectiveness analyses.
The articles aimed at assessing the impact of disease elimination/eradication on economic growth/development were analysed tabulating the following aspects: • Main hypothesis tested/research question The articles classified as costing studies, cost-benefit and cost-effectiveness analyses were analysed tabulating the following aspects: • Hypothesis tested Articles exploring the question "how to eliminate/eradicate" were analysed tabulating two main aspects: role of incentives and financial issues associated with elimination/eradication.
Review or opinion articles that we found during the literature search were not tabulated but we draw on them in the introduction and discussion sections of this manuscript.

Why eliminate or eradicate?
Elimination and eradication are associated with high risks of failure in terms of disease reemergence and require substantially higher investments than routine control activities at least initially. The health and economic benefits therefore need to be higher to justify the higher costs in the context of scarce resources and competing health problems [18]. There is considerable uncertainty about the time path, costs and outcomes of elimination and eradication strategies, so a number of studies have developed cost estimates for a number of different scenarios [19]. The various authors have also used varying methodologies in estimating costs and benefits, such as the extent to which they have discounted future benefits which accrue in perpetuity, and in the treatment of intangible costs and benefits such as anxiety or pain associated with an elimination program and the benefit of the security when a health risk no longer exists [20,21].
To take a complete economic view of elimination/eradication would require a cost-benefit or cost-effectiveness analysis [22], but many of the studies reviewed did not undertake a complete assessment (Table 1). For example, many considered only the costs of elimination-as in the case of lymphatic filariasis either in specific countries or globally [23][24][25]; HIV in South Africa [26]; schistosomiasis from the Guangxi region in China [27]; visceral leishmaniasis in Bangladesh, India and Nepal [28]; and leprosy globally [29]. For malaria, Sabot et al. presented the first attempt to model costs and benefits of elimination campaigns using data from eight case studies. The probability that elimination would be cost-saving compared to control ranged from 0% to 42% [22]. This does not mean that elimination should be rejected as an option because it would bring many health benefits to the affected populations, but only that it will not be "self-financing" in the long run.
Several economic evaluations of global measles eradication or elimination indicate that the strategies are either cost-effective or cost-beneficial compared to routine immunization and mortality reduction campaigns [30][31][32][33]. These studies found that the benefit consequent to measles elimination or eradication applied to high and middle income (particularly Latin American) countries as well as to low income countries. For the former, the benefit consisted in not having to manage responses to imported measles cases; for the latter the benefit consisted in ending the need to conduct resource-intensive mortality reduction campaigns after eradication. Bishai et al. disputed the idea that measles eradication and elimination were costeffective for low-and middle-income countries if they acted by themselves. An important reason why the global benefits of elimination and eradication outweigh the costs is because they prevent the high costs currently associated with identifying and treating imported cases of measles in high-income countries. An economic analysis from the perspective of the lower income countries themselves is less clear cut [34]. The implication is that globally it would make economic sense to eradicate measles, but low and middle income countries may have limited incentive to do so by themselves because an important part of the returns to their investments would accrue to high income countries.
The eradication of dracunculiasis has been estimated to have a high return on investment (29%) [35], and elimination of visceral leishmaniasis in Nepal was estimated to have an even higher return (35%) [36]. The benefit-cost ratio of the elimination of varicella in Germany was estimated to be 4.12 (estimates above 1 imply the investment is worthwhile on economic grounds) [37]. Elimination and eradication of lymphatic filariasis (LF) was found to be less cost-effective than control in the short term [33] although the lifetime economic benefits of reduced treatment in the first eight years of a Global Programme to Eliminate LF were estimated to be US$ 21.8 billion [24].
The studies reported here were based on models of what would happen if a disease was eliminated or eradicated. Few diseases have been eliminated or eradicated in practice, so we could find only one economic study, dated 1986, of actual elimination (of malaria from Sardinia). The same study also examined the past attempts to eliminate malaria in Sri-Lanka [38].
As we stated earlier, the reductions in treatment costs that would result from elimination or eradication are only one part of the potential economic benefits. Few studies tried to estimate the impact of elimination or eradication on economic growth through the effects on human capital accumulation (Table 2). In most of these studies elimination programmes are retrospectively used as quasi-natural experiments with the aim of identifying the causal relationship between health improvements and subsequent economic growth [39][40][41][42][43][44]. Where studies looked at the impact of past malaria or hookworm elimination campaigns on the incomes of individuals or households as opposed to economies as a whole, the results are conflicting, sometimes suggesting higher earnings and literacy rates or years of schooling in adults born after malaria elimination campaigns and sometimes results show no significant effects. Some studies suggest a possible dilemma resulting from eradication/elimination. If life expectancy increases, GDP per capita could fall unless the increase in GDP associated with a larger labour force was sufficient to offset the increase in population [39]. However, focusing on the impact of the size of the labour force on GDP through the effect of elimination/eradication on life expectancy may not always be appropriate [6]. Some health improvements may not lead to a longer life but may improve quality of life and hence the productivity of people who work. Hookworm infection is a case in point. Eliminating hookworm disease has been shown to make children learn quicker in school and increase their incomes later in life [43]. However, it does not increase life expectancy. Nevertheless, improving health without affecting life expectancy may still provide a large economic pay-off and a focus on life expectancy may miss this. When studying the impact of a malaria eradication campaign in Colombia, Bleakey noted that the elimination of Plasmodium vivax malaria led to more significant gains in human capital and income than the elimination of Plasmodium falciparum, even though falciparum causes more deaths than vivax [42].
The effects of malaria elimination campaigns on selected non-health drivers of economic growth have also been studied. The effect on tourism was estimated for Mauritius and the Dominican Republic. At the national level, and after accounting for several possible confounding factors, the impact was small and not significant [45]. From a macro-economic point of view it has been argued that there was little impact of malaria elimination on GDP growth and that other factors, such as technological change and human capital accumulation, were the major drivers of the escape from poverty in the South of Europe in the fifties [46].
How to eliminate and eradicate?
Regional elimination and global eradication imply collective decision making, where several stakeholders have to decide on issues of collective interest in a context of different preferences and endowments. As part of the broad economic analysis, social choice theory is the study of collective decision processes and outcomes and game theory studies the strategic interdependence of individual choices and the design of collective choice rules to implement socially optimal decisions [47]. These approaches could be used to assess the success probabilities, or the impact, of different elimination or eradication strategies, to better inform a global or regional decision-e.g. should the strategy start by focusing on areas of the most intense transmission before moving to other areas? Our search did not reveal any examples of this type of analysis. However, there has been some theoretical work focused on how to encourage all of the affected countries to move towards eradication or elimination (Table 3) [19,[48][49][50][51]. These studies recognize that most infectious diseases are cross-border issues and that once a disease is eradicated, all countries benefit independently from their individual contributions (the public good concept). However, in order to achieve eradication (or regional elimination) all affected countries need to take actions. For countries that share borders the success of elimination depends also on the decision of the neighbors to eliminate.
Starting from a rationality assumption where stakeholders take decisions aimed at maximizing their net benefits, there are four possible outcomes: a. The net benefits of eradication for the whole world or for the countries involved in regional elimination may be negative, making control the chosen option for everyone; b. The net benefits of elimination may be so high that every country chooses to eliminate a disease unilaterally, making eradication or regional elimination the universal choice; c. It may not be worthwhile for any country to eliminate the disease unilaterally given that others have not eliminated the disease. It may also not be worthwhile for any country to eliminate the disease once all others have done so. In this case, eradication or regional elimination is a "coordination" game. There are two possible outcomes: in one, no country eliminates; in the other, every country eliminates the disease and eradication is achieved. To tip the balance towards eradication, each country would need to be convinced that all other countries will eliminate and not try to free ride on the efforts of others; d. It may not be worthwhile for the last country to eliminate a disease after all others have done so, and yet the net benefits of eradication may be positive to the world as a whole. In this case, incentives or disincentives aimed at the recalcitrant country would need to be developed.
Given that options c) and d) are the most likely, researchers are exploring if forms of global governance or international regulation within the field of international law might be appropriate [52]. The other option is that the richer countries will need to pay for the elimination efforts in poorer countries or in countries that do not choose to do it voluntarily, as happened for smallpox eradication [49].
Within country borders, the elimination of an infectious disease implies increasing the demand for preventative measures, such as vaccines. In this case, incentives are needed to raise immunization coverage that allows blocking transmission of the infection. Bahram et al. Table 3. How to eliminate/eradicate: the role of incentives and financial issues.

Study and year
Type of study and content Incentives Financial issues Barrett, 2004 [48] Policy paper/review As benefit can be much higher than costs, the incentives for countries to participate in an eradication initiative can be strong. Based on the smallpox experience, poor countries that may trying to eliminate might fail due to lack of expertise. Thus, eradication may require international cooperation on top of coordination. In some cases, the incentive to eliminate may depend on each country being assured that all other countries would eliminate. For this, eradication may require third party enforcement.
If poor countries are either unable or they lack the incentive to eliminate a disease on their own or as part of a coordinated effort, rich countries might have an incentive to finance the global eradication program. This way, rich countries would earn a return on their investment, making poor countries also better off. Barrett, 2006 [49] Policy paper on smallpox eradication According to costs and benefits of eradication, the rich countries had an incentive to eliminate smallpox unilaterally. Many poor countries, such as India, also had an incentive to eliminate unilaterally, but lacked the capability to do so.
International assistance was needed.
The weakest link nature of eradication, and the very high benefit-cost ratio (over 400:1), translate into developed country financing of elimination in developing countries. This could be achieved by coordination. Barrett, 2007 [50] Theoretical paper where a general epidemiology model is linked with the optimization model (constraint maximization of a socially efficient vaccination program) A full global cost-benefit analysis is needed to determine whether eradication is a good deal overall. Being eradication an extreme goal, the analysis of an eradication program needs to begin from the perspective of where the program will end, thus from the "last mile".
NA Barrett, 2011 [51] Theoretical paper on polio, modelling the cessation of vaccination after eradication linking a epidemiology, a risk of reemergence and an economic model evaluated a randomized experiment showing that cash incentives paid to mothers increased vaccination coverage to 95% in rural Nicaragua [53]. Theoretical work by Geoffard and Philipson analyzed the difficulties of achieving disease eradication through vaccination using various types of incentives, highlighting that increased coverage levels reduce the incentive of those not yet vaccinated because they are less at risk of contracting the disease [54]. Chesson et al. found that greater amounts of state-level funding for syphilis elimination had a notable impact in lowering syphilis rates in subsequent years within the context of a national elimination plan in the US [55].
For whom to eradicate?
In principle, elimination and eradication should resolve the equity/efficiency trade-off inherent in the scale-up of health interventions, in which efficiency implies quickly providing access to the easy-to-reach groups (e.g. more affluent groups in urban areas) and equity implies specifically targeting resources to poor and vulnerable groups who might be harder and more costly to reach [56]. All infectious diseases that are targeted for elimination are concentrated among the poor, so elimination/eradication would improve the health of the poor disproportionally. Disease elimination thus, interpreted through the lens of the social-choice theory described earlier, can be seen as the realization of an egalitarian policy: policies should aim either at compensating for unequal endowments for which the affected individuals are not responsible or at equalising certain "capabilities" essential for the preservation of life and the ability to freely choose one's own way of life [57,58]. In this respect, health is both an endowment for which individuals are at birth not responsible and a crucial constituent of human capabilities. The literature applying these concepts to disease elimination and eradication is, however, limited apart from concerns that the process leading to disease elimination may lead to greater inequity in the short term. This may occur if countries choose to begin expensive elimination programs in less challenging areas which are usually low transmission areas where people are more affluent and healthier. The implications for equity may be even higher if elimination fails so control ends up being more effective in the areas that were relatively affluent initially, a concern that has been expressed for example with malaria elimination programmes [59]. These concerns seem to be supported by apparent small improvements in equity that have been observed with the scale up of coverage of certain malaria interventions to date, suggesting that the least affluent and most needy have proved more difficult to cover [60,61].

Discussion
We have examined the contribution that economic analysis has made to the question of the elimination/eradication of infectious diseases. Elimination/eradication is particularly interesting because it will require substantial initial investments, more than running routine control programs. It is also linked to the concept of public good; it will not happen unless all affected countries take a conscious decision to do it, while at the same time countries have an incentive to let others pay.
The economic literature relating to "why eliminate/eradicate" is the largest, much of it suggesting that the eventual financial returns could be high-in the long run there might be substantial savings from not having to treat people or run routine control programs. In some cases, however, this does not look likely but then there are other economic benefits in terms of increased economic productivity. A problem in this case is that these additional benefits do not necessarily accrue to the people who pay for the elimination efforts in the first place, which make financing elimination/eradication challenging.
Despite the belief of some public health experts that the economic benefits of investing in health should not be relevant to public decision-making, which should focus only on human rights to the highest attainable level of health, we suggest that national governments, global health policy makers, and donors always need to know how much a proposed course of action will cost, and what the benefits will be in terms of health and economic wellbeing. We acknowledge the importance of human rights, but it does not help to ignore the fact that resources are always limited.
Economics has contributed to addressing the question of how to invest in eradication or elimination by highlighting that there will be incentives for individuals and for countries to free-ride and that forms of incentives and/or disincentives for this behaviour will need to be developed. This requires government involvement at country level and global coordination and cooperation. It will not happen if left to the market or to individual endemic countries to act alone. While equity should be a key factor to guide the implementation of any health intervention, we found only one article analysing the impact on equity of disease elimination campaigns. However, when complemented with other evidence on the trade-offs between equity and efficiency in healthcare delivery more generally, this was sufficient to trigger a series of reflections. While there is little doubt that eliminating infectious diseases will eventually improve equity, it is not clear that equity will be improved on the path to elimination and/or eradication in the short run. Countries will have an incentive to begin with easier-to-reach areas which will often be those with higher incomes and levels of health, so specific equity strategies would need to be applied early. An interesting twist to the equity story is currently being provided by measles where the refusal to have children vaccinated among affluent people in the richest countries is proving a stumbling block to the final efforts towards eradication. The strategies adopted on the path to elimination are, therefore, particularly important and must be based not simply on considerations of cost and cost-effectiveness.
Though this was not the focus of our review, disease eradication/elimination initiatives clearly need to take into account the broad health system impacts as well which are often difficult to incorporate into an economic analysis [62,63]. This is an added dimension that policymakers always consider in addition to cost and impacts, and equity.
We found few articles on this aspect, and few eligible articles for this review of the economic literature in general. No article integrated the different components of costs, benefits, public good and equity issues. We found, instead, that articles published in public health journals were more focused on costs and benefits in terms of reduced treatment costs (direct benefits) while articles published in economic journals concentrated on the impact on household or national incomes (indirect benefits). None of these strands of literature included equity issues. Despite this, the literature reviewed provides some evidence of the costs of various elimination/ eradication strategies, the possible impact in terms of treatment costs and sometimes incomes, and allowed us to draw some important policy conclusions. The most important one involves the need to understand and realign contrasting incentives between the motivation of individual countries and the global community if elimination/eradication is to happen. It is also critical to consider equity on the path to elimination/eradication rather than just at the end.
Supporting Information S1