Chagas Disease and the London Declaration on Neglected Tropical Diseases

Fil: Tarleton, Rick L.. University of Georgia; Estados Unidos. Chagas Disease Foundation; Estados Unidos


What Is Chagas Disease?
American trypanosomiasis is a chronic parasitosis caused by the kinetoplastid parasite Trypanosoma cruzi and is highly prevalent among a large variety of marsupial and placental mammals autochthonous to the American continent. The infection is naturally transmitted by blood-feeding Reduviid insects, but transmission by oral contamination, transplacentally, or by blood transfusion or issue transplantation is also common. The human disease is known as ''Chagas disease'' for the Brazilian physician who described it over a century ago. The human invasion of natural ecotopes as well as the establishment of the vectors in human dwellings associated with poor socioeconomic conditions makes Chagas disease a major public health hazard from the United States to Argentina. As such, the disease is a zoonosis that has afflicted humanity since its earliest presence in the New World and is still the largest parasitic disease burden on the American continent [1,2]. Recently, increased international migrations have spread the infection to nonendemic areas, including Western Europe, Australia, and Japan, where transmission is restricted to congenital and transfusion or solid organ transplant. In most infected individuals, a highly effective immune response controls the initial infection but fails to eradicate it. The consequential lifelong infection and associated inflammatory response result in symptomatic cardiac and digestive disease, significant morbidity, and eventually death in 30%-40% of patients.

Successes and Advances
Among the successes in the control and prevention of Chagas disease is the reduction of vector-based transmission in some countries in the Southern Cone of South America using a combination of widespread and recurrent domestic application of pyrethroid insecticides and screening of blood donations to prevent transfusion-related transmission. Chagas disease also benefits from having two nitro-heterocyclic drugs (benznidazole and nifurtimox) that have proven to be partially effective in use for .40 years in humans. The fact that T. cruzi infects many different mammal species is both a curse and blessing, as this parasite will never be eradicated and thus there will always be a risk of infection to humans. However, the wide host range of T. cruzi provides multiple excellent and highly relevant host models to evaluate immune responses and test specific treatments. This latter advantage is rare among neglected diseases. Furthermore, nonhuman host species that serve as links in the transmission to humans are being identified and can be targeted for control of transmission. The imminent completion of clinical trials to assess the benefit of treatment with benznidazole during chronic infection in humans should address a long-standing question regarding the clinical benefit of treating patients with long-established chronic T. cruzi infections [3][4][5]. In addition, human clinical trials of several new therapies are advancing or have been recently completed [5][6][7].
In addition to these operational advances, research developments over the last 20 or more years provide baseline information for improving detection, prevention, and control of T. cruzi infection. In contrast to long-held views on the autoimmune origin of the pathology of the chronic stage of Chagas disease, multiple lines of investigation confirm that the persistence of parasites is the key factor underlying the sustained inflammatory responses that lead to such manifestations [8,9]. Thus, the condition should be treated as an infectious, not an autoimmune, disease, and specific treatment should be offered to all seropositive patients, perhaps with the exception of those with terminal disease [2,10]. The challenges for sensitive serodiagnosis of T. cruzi infection and Chagas disease remain to be solved. The use of multiple, partially informative tests that ignore ''discordant'' samples (i.e., those positive on one but not all serologic tests) is not a sustainable and effective way to identify all those who need treatment. The mechanisms of action of existing treatments are only beginning to be understood [2,11], and this provides hope that we can ultimately understand why treatment sometimes fails. Novel treatment regimens and combination therapies with currently available drugs, as well as drug candidates with novel mechanisms of action, are being preclinically [12][13][14] and clinically evaluated [5][6][7]15]. Studies of the immune response to T. cruzi are identifying ways in which we may enhance parasite-specific immune responses [16] but are also raising questions about the potential for developing effective vaccines in the foreseeable future.
What Are the 2020 London Declaration Goals for Chagas Disease? eliminate or control ten neglected diseases by 2020-six years from now. Chagas disease is among these. The effort was launched in January 2012, spearheaded by the WHO and the Bill and Melinda Gates Foundation (BMGF) and including in the collaboration many of the world's leading pharmaceutical companies. To set specific goals and monitor achievement of those goals, the principals behind the London Declaration have established milestones for each disease (Table 1) and plan a yearly review and issuance of a ''scorecard'' of progress. For Chagas disease, the initial milestones were established primarily by WHO with rather limited input from the research community, at-risk communities, patient associations, or healthcare services within endemic countries. The purpose of the present document is to (1) assess these milestones and address if they can be achieved and if so, how; (2) propose additional milestones when appropriate and document other achievements to date towards these goals, and (3) identify the tools, infrastructure, and resources that are needed to achieve the overall goal of effective control of T. cruzi infection by the targeted 2020 date. Additional input on the London Declaration milestones (as well as a quick view of the current scorecard) can also be logged at https://sites.google.com/site/chagasddc/ home/chagas-disease-milestones.

Current Status of Chagas Disease
1. The full magnitude of the problem is only a guess because screening for infection is inconsistently applied, especially in endemic, resource-constrained rural areas in which infection prevalence has been historically high-''seek, and ye shall find.'' 2. Current diagnostics probably identify the majority but certainly not all infected individuals, even when the standard two or three distinct testing platforms are used. 3. Vector transmission of T. cruzi has been interrupted only in some countries or regions of the Southern Cone. The sustainability of that achievement and its extension to other endemic areas is compromised by, among other factors, persisting infestations after routine insecticide spraying, abundance of other vector species, limited resources, lack of sustained political will, decentralization of disease control programs, dwindling numbers of trained personnel in charge of vector control operations, and the ever-increasing expansion of dengue outbreaks [17][18][19]. Recent documentation in northern Argentina and Bolivia of increasing numbers of foci of vector species highly resistant to the frontline pyrethroids may make current vector control protocols useless in some of the regions of highest transmission [20][21][22]. New and better insecticides are not in the pipeline. Little is known about the impact of the dramatic changes in the demographic and ecological landscape of Latin America on the extent and modes of T. cruzi transmission to humans. It is also becoming increasingly clear that transmission of T. cruzi is not limited to rural communities; urban and periurban vector-mediated transmission has been documented in Peru, Bolivia, Argentina, Mexico, and Venezuela, among others [23,24]. 4. Although reports of T. cruzi transmission unrelated to ''conventional'' vector infestation of houses, including via contaminated food or drink, congenital transmission, and by blood transfusion and tissue transplantation, have increased in recent decades [25,26], and the extent and impact of these transmission modes has not been fully assessed in all affected countries. 5. Although treatment of the infection using currently available drugs can be effective, this is not always the case [2,27]. Treatment, when offered, is generally restricted to only certain age groups in urban settings, and it has recently been estimated that less than 1% of those currently living with T. cruzi infections have received treatment [28]. Rural populations display the highest levels of infection prevalence and the lowest treatment coverage rates-the quintessence of neglect and inequity. The lack of screening programs to identify those who are infected and the inaccessibility of drugs due to cost or inadequate supply greatly limit the number of infected individuals receiving treatment. However, perhaps the biggest bottleneck in getting treatment to affected individuals is the lack of knowledge among atrisk populations and health and healthcare personnel and thus a failure to seek or prescribe treatment because of lack of understanding of its benefits. Many of these issues are surmountable using resources and knowledge already available-e.g., the capacity to produce affordable drugs is relatively high, and adverse reactions to treatment can be managed so that most can complete treatment. Unfortunately, when treatment failures occur, they are difficult to detect due to the lack of validated biomarkers for infection control or parasitological cure [29][30][31]. The organizations leading the initiative have a natural vested interest in declaring, for example, that elimination of transmission has been achieved in every county, department, state, or country. The information used for certifying the interruption of transmission is provided by the same health authorities in charge of disease control programs, who are also eager to claim they have achieved elimination because of the political value it affords. Moreover, current methods and procedures used to assess transmission indices have severe limitations [33]. The pressure to claim success is enormous, and there is very little expertise and independence to actually determine that disease transmission has been interrupted anywhere. 4. As a result, there is very little trust that the certification of met milestones will be believable or can endure the ''curse of success'' and prevent disease resurgence in the foreseeable future. The milestones also do not consider or recommend the information systems needed to be able to verify and validate information. Where there is a persistent problem, as in El Salvador, there is no mention. Some control programs have been shut down, as in Ecuador; others have been downscaled, as in Colombia; and disease control efforts are passive and rudimentary in countries such as Mexico. Much of the data in official documents have not been independently verified to justify or back up strategies, conclusions, and recommendations. 5. Perhaps most importantly, the milestones are based on the assumption that the programs, tools, and resources to achieve them are already in place. They are not. Where are the diagnostics, access to or a system for distribution of treatments, measurement of vector infestation, and the integrated bug control programs that are going to be needed to achieve these milestones? Expansion of treatment with benznidazole is moving very, very slowly in the most affected areas of the Southern Cone countries and much less so elsewhere, and it is not always a question of drug availability but rather lack of procurement procedures or political priority and social equity. Furthermore, the long-standing, widespread foci of T. infestans highly resistant to pyrethroids must be suppressed immediately, their fate monitored closely, and the results of these efforts made public. More than a decade after its discovery, there is no further information regarding this unique situation even though the opportunity for spread of these resistant vector populations is high. 6. Previous policy initiatives and documentation of successes in control or elimination of transmission in the regions are neither appropriately focused nor consistent with scientific data. For example, there has been a push to issue statements of elimination of native triatomine species that thrive in the wild and invade houses often, some of them infected, but that only occasionally transmit T. cruzi to humans [33]. Such initiatives allow declarations of so called ''success'' but have minimal impact on overall transmission.
In short, by underestimating the magnitude of the actual problem, overestimating what has been achieved or is in place and effective, and failing to identify the actual challenges, the London Declaration and Scorecard continues to build the case that ''we're moving fast and easily towards Chagas elimination by the year 2020.'' The majority opinion in the scientific, medical, and public health communities is that this is not the case. The status of Chagas disease control is highly heterogeneous between and within regions and countries and even within a given province, department, or county.
What Needs to Be Done to Reach the Goal of Control of Chagas Disease by 2020?

Proposed Milestones for 2014-2015
The milestones for the short term need to focus on obtaining accurate information, developing sound policies, and assuring that insecticides, diagnostics, and drugs are readily available. Appropriate investments and political commitment can translate into actions that will reduce the impact of Chagas disease significantly by 2020. As outlined above, this will require a combination of more efficient healthcare systems, information systems, infrastructure (for diagnostic screening, vector control, drug production and distribution, etc.), improved tools (e.g., diagnostic assays, methods to monitor treatment efficacy, etc.), and broader knowledge and a better dialogue with communities and their acceptance of and collaboration with these projects. Without these developments, it is virtually impossible that any of the proposed 2020 milestones for Chagas disease in the London Declaration can be met. Establishing these milestones without a plan to develop appropriate resources is a recipe for failure.
In addition to the resources needed to reduce the impact of Chagas disease by 2020 as described above, concurrently there have to be additional investments in research if Chagas disease is to be eliminated as a human health problem, including in the following areas: 1. Drug discovery and testing. There is currently substantial interest and ongoing efforts in drug discovery for Chagas disease. Unfortunately, many of these efforts are poorly organized, disconnected, and woefully underfunded. Drug discovery is often divorced from parasite biology and pharmacological and infection parameters, promising leads are not vigorously pursued, and existing drugs and clinical candidates are not rigorously tested using the best possible model systems. As a result, compounds are going to clinical trials with insufficient data-and then failing in those trials-and the pipeline for new clinical candidates is nearly empty.
Virtually nothing is known about the mode of action of current drugs, and efforts to optimize dosing strategies for monotherapies and combination therapies are nearly nonexistent. This is all happening in a landscape of incredibly good animal models for testing, including many nonhuman primate species with naturally acquired infections. T. cruzi infection can be treated and cured at any stage of the infection/ disease. It is inexcusable that more people are not treated and that more effective treatments are not being effectively pursued. 2. Vector ecology and strategies for their control. The insecticidal spraying of houses to control vector species has done more than any other method to reduce the impact of Chagas disease. However, a more integrated approach is necessary for sustainable prevention.
There are a number of excellent complementary interventions required for transmission control (e.g., use of insecticide-treated bednets or netting, preventing bugs from feeding on animal reservoirs by use of insecticidetreated dog collars, and/or vaccination of potential reservoirs to reduce their ability to transmit) [34,35]. Extensively testing these methods individually or in combination is likely to lead to improved, lower cost and more sustainable vector control protocols. Investment in this area of research has to be made if we expect to significantly and permanently reduce the incidence of human infection with T. cruzi. 3. Vaccine development. Prophylactic vaccines are the most cost-effective means to prevent many human infections. It is yet to be proven that T. cruzi infection is vaccine preventable in any host species. Nevertheless, efforts in this area need to continue if for no other reason than to determine if vaccines are likely to be part of the long-term strategy for prevention of T. cruzi infection or if we will have to rely on other transmission control tools and treatment when these controls fail.
In addition to these research needs, it is also essential to incorporate at-risk and clinically affected populations into Chagas disease public health and clinical care program design and implementation. Civil society should be an integral consultant or collaborator in any public or private initiative, and it is important to analyze governance issues related to integration of an effective Chagas disease program within existing healthcare systems.

Final Thoughts
We believe that Chagas disease is a solvable problem. The London Declaration on Neglected Tropical Diseases initiative provides an enormous opportunity to implement solutions. This opportunity should not be squandered by having weakly vetted and ill-defined goals. We hope that the current document can serve as a blueprint that all the communities involved in and affected by Chagas disease can contribute to and rally around. We welcome comments and additional suggestions at https://sites. google.com/site/chagasddc/home/chagasdisease-milestones.