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REGIONAL APPROACHES TO NEGLECTED TROPICAL DISEASES CONTROL IN LATIN AMERICA AND THE CARIBBEAN

Steven Kenyon Ault and Mirta Roses Periago

Pan American Health Organization

Neglected [tropical] diseases impose a huge burden on developing countries, constituting a serious obstacle for socioeconomic development and quality of life … Thus, taking decisive action to eliminate them as a public health problem in the Region, which is an achievable dream—provided the necessary political commitment and resources are in place—for which we are working in PAHO, would also be a clear reassertion of our countries’ deep commitment with human rights as enshrined in international treaties and standards.


—Mirta Roses Periago, Director, Pan American Health Organization (Director’s Blog, April 8, 2008, http://66.101.212.220/mirtaroses/index.php?id=69)

Background

In the Latin America and Caribbean region (LAC) at least 180 million people live below the poverty line. These impoverished and marginalized populations are often heavily burdened with neglected tropical diseases (NTDs) and other infectious diseases of poverty. This group of diseases continues to take a measur-



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A Contributed Manuscripts A1 REGIONAL APPROACHES TO NEGLECTED TROPICAL DISEASES CONTROL IN LATIN AMERICA AND THE CARIBBEAN Steven Kenyon Ault and Mirta Roses Periago Pan American Health Organization Neglected [tropical] diseases impose a huge burden on developing countries, constituting a serious obstacle for socioeconomic development and quality of life . . . Thus, taking decisive action to eliminate them as a public health problem in the Region, which is an achievable dream—provided the necessary political commitment and resources are in place—for which we are working in PAHO, would also be a clear reassertion of our countries’ deep commitment with human rights as enshrined in international treaties and standards. —Mirta Roses Periago, Director, Pan American Health Organization (Director’s Blog, April 8, 2008, http://66.101.212.220/mirtaroses/index.php?id=69) Background In the Latin America and Caribbean region (LAC) at least 180 million people live below the poverty line. These impoverished and marginalized populations are often heavily burdened with neglected tropical diseases (NTDs) and other infectious diseases of poverty. This group of diseases continues to take a measur- 115

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116 NEGLECTED TROPICAL AND ZOONOTIC DISEASES able toll, not only on families and communities but also on the socioeconomic development of nations. NTDs and Their Impact The NTDs largely comprise infectious and parasitic tropical diseases. Today, NTDs can be usefully considered as a group because they are concentrated al - most exclusively among impoverished populations living in marginalized areas whether rural or peri-urban. These incapacitating diseases, such as lymphatic filariasis, onchocerciasis or river blindness, schistosomiasis (including bilhar- zia), soil-transmitted helminthiasis (ascariasis, trichuriasis, and hookworm infec - tion), Chagas disease, leishmaniasis, leprosy or Hansen’s disease, and trachoma continue to perpetuate poverty, generate prejudice, or inflict severe incapacity (lymphatic filariasis), disability (e.g., leprosy/Hansen’s, onchocerciasis), and sometimes premature death (e.g., Chagas disease and schistosomiasis) in LAC and other regions of the world. Children with heavy intestinal worm burdens may become stunted or anemic, or they may suffer from maldigestion, malabsorption, and poor physical and cognitive development. These worms can reduce school attendance, attention span in class, and test scores. Infection with NTDs reduces income-earning capacity, and this in turn often creates a loss of the ability to care for a family. Social Determinants Although biologically and medically diverse, NTDs share features that allow them to persist in conditions of poverty where they frequently overlap (Brooker et al., 2006). These conditions of poverty include unsafe water, poor sanitation, and refuse disposal, which sustain transmission cycles and favor the prolifera - tion of vectors that transmit disease. Other conditions, such as a lack of access to health services, low levels of literacy, inadequate nutrition and poor personal hygiene all help to increase vulnerability to infection and work against prevention efforts. Addressing these social determinants of poverty complements the use of existing tools to combat and eliminate NTDs. Specific technical opportunities to control and eliminate NTDs in LAC through intersectoral and multidisease approaches while addressing social determinants were recently reviewed (Ault, 2008; Ehrenberg and Ault, 2005; Holveck et al., 2007; Hotez et al., 2008), and provide background for this paper. Legacy of Slavery Interestingly, some of the NTDs—for example lymphatic filariasis (LF), onchocerciasis, and schistosomiasis—are parasitic diseases that were imported to the Western Hemisphere through the European slave trade, which targeted

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117 APPENDIX A Africa. Today, a little more than 200 years after the end of that colonial slave trade, they still cause substantial morbidity and are particularly attractive targets of elimination. As noted by Lammie et al. (2007), “the elimination of diseases that are a consequence of this trade will represent a tangible contribution to the health and well being of people and communities who, arguably, still suffer from the residual affects of slavery.” Tools and Mandate to Combat Tools exist today to effectively combat the NTDs, including safe and inex- pensive antihelminthics, dose poles, quantitative and rapid mapping methods, and rapid test kits for several parasites, and having these tools in hand makes it an ethical imperative to work toward the control and elimination of NTDs. Since 2007, the Pan-American Health Organization (PAHO) also made headway in the scientific and political debate that guided the development of an elimina - tion agenda and made it possible to subsequently mobilize the necessary will and resources. In 2009, PAHO received a mandate in the form of a resolution (CD49-R19) from its Directing Council (composed of the Ministers of Health of the region) to support the countries in the region in eliminating or significantly reducing the burden of a group of 12 neglected diseases and other poverty-related infections. This chapter discusses this mandate and the region’s plans to tackle and eliminate several NTDs over the next five years. Elimination Agenda Working together, the LAC countries and PAHO have had significant suc- cess in eliminating several infectious diseases in the region in the recent decades: smallpox (1977), poliomyelitis (1994, wild poliovirus), and measles (2002). As well, at the end of 2010, onchocerciasis transmission has been apparently elimi - nated in 8 of 13 foci among six endemic countries in the region. The number of human cases of rabies transmitted by dogs in Latin America dropped signifi - cantly, by nearly 90 percent, between 1990 and 2007 (PAHO, 2009). A significant reduction in the transmission of Chagas disease by two im - portant domestic vectors (Rhodnius prolixus and Triatoma infestans) in the 21 endemic countries has been achieved since 1990 principally as a result of sys - tematic indoor spraying with residual pyrethroid insecticides of houses in rural endemic areas, infection and mortality have declined as has the population at risk (Table A1-1). As of 2010, 10 countries have eliminated these vectors and 3 others have eliminated them in parts of their national territories. A reduction in blood transfusion–origin Chagas disease has also been achieved in the region, as endemic countries began universal screening of blood donors at blood banks using a rapid Enzyme-linked immunosorbent assay (ELISA) test.

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118 NEGLECTED TROPICAL AND ZOONOTIC DISEASES TABLE A1-1 Evolution of Change in Epidemiological Parameters of Chagas Disease in LAC Changas Disease Epidemiological Parameters 1990 2006 Annual deaths >45,000 12,500 Human cases of infection 30 million 15 million New cases per year 700,000 41,200 At-risk population 100 million 28 million SOURCE: PAHO (2009). What Is Feasible? There is broad technical consensus that there are available tools and strate - gies to combat several neglected tropical diseases that have been included in the World Health Organization’s (WHO’s) 2008–2015 Global Plan to Combat Neglected Tropical Diseases (WHO, 2007). Beginning in 2007, PAHO began to review the data to determine which of these NTDs and other infectious diseases of poverty we can eliminate or significantly reduce transmission of in the entire region by 2015, such as onchocerciasis, LF, and trachoma. PAHO reviewed others that can be eliminated in certain subregions or in a particular country, as in the cases of plague in Peru and Ecuador, schistosomiasis in St. Lucia and Suriname, and malaria in the Caribbean and Central America. The agency focused on identi- fying successful strategies for control and elimination, collecting epidemiological data on the presence and prevalence of these diseases in the region, and prepar- ing maps down to the first administrative level of where the diseases overlapped geographically. With these data and information in hand, PAHO published its epidemiological profiles of 10 neglected diseases in 14 countries in early 2009 (PAHO, 2009). Next, a regional elimination strategy was developed during 2009 by the agency’s communicable diseases project for 10 neglected diseases of poverty with input from PAHO technical staff, managers and external experts, and the draft strategy was vetted with the Ministers of Health and approved by the Direct- ing Council in October 2009 as Resolution CD49-R19. In approving the resolu - tion, the Member States of the region have committed to an objective by 2015 to eliminate or reduce neglected diseases and other infections related to poverty for which tools exist, to levels such that these diseases are no longer considered public health problems. This effort requires long-term political and financial commitment and the preparation and implementation of integrated national plans of action (POAs). In 2010, several countries in the region have now established national committees with the objective to develop their POAs for the integrated control and elimination of NTDs. The PAHO strategy uses two definitions for elimination, depending on the

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119 APPENDIX A disease. The elimination of a disease is a reduction to zero of the incidence of a given disease in a defined geographic area as a result of deliberate efforts, with continued intervention measures being required (WHO, 1998). Elimination of a disease as a public health problem occurs by drastically reducing the disease’s burden to a level that is acceptable given the current tools available and the region’s health situation. At this level, the prevalence of the disease does not constrain social productivity and community development. Achievable goals have been established for each disease. In this chapter, both definitions are used to select the diseases targeted for elimination, according to previous global and regional mandates for elimination. PAHO considered the following criteria in selecting the diseases that could feasibly be eliminated or drastically reduced in the region: (a) the “unfinished agenda”—diseases that already had been priority targets for elimination by PAHO or WHO and for which, despite progress made, some areas lagged behind; (b) technical feasibility—including the availability of knowledge and tools for structuring interventions to interrupt or reduce transmission; (c) regional evi - dence of achievable elimination—existence of successful regional experiences in accomplishing elimination at country or subnational levels; (d) economic criteria—including relatively low unit cost of interventions and demonstrated cost-effectiveness; (e) unequal burden of disease—wherein the more vulnerable populations (such as indigenous and Afro-descendant populations, women, and children who have been historically excluded) suffer from a higher prevalence and social consequences of these diseases, thus perpetuating the cycle of pov - erty; (f) political relevance—the diseases must be recognized as being of public health importance with a broad international appeal, which could be expressed through existing resolutions approved by the World Health Assembly or PAHO’s Directing Council; and (g) best practices, including those utilized in primary health care, well-accepted interventions such as mass preventive chemotherapy and high-coverage vaccination campaigns, integrated approaches for vector-borne diseases, and local projects with community participation to improve health through intersectoral action. These examples of best practices have already been developed in the region and will provide the basis for the scale-up of local and national proposals for disease elimination. The selected diseases were classified into two groups, those with greater potential for being eliminated, and those that can be drastically reduced with available tools. Group 1 diseases are those that have a greater potential for being eliminated: Chagas disease (vector-borne and transfusional transmission, both as a public health problem); congenital syphilis (as a public health problem); LF (as a public health problem); onchocerciasis; rabies transmitted by dogs; neona - tal tetanus (as a public health problem); trachoma (as a public health problem); leprosy (as a public health problem at the national and first subnational level); malaria (elimination in Haiti and the Dominican Republic and in México and Central America); and plague (as a public health problem). Cost-effective strate -

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120 NEGLECTED TROPICAL AND ZOONOTIC DISEASES gies and tools exist for elimination, there is evidence of feasibility of elimination in other countries or areas in LAC, or there are global or regional mandates to reach elimination. Next, we highlight two of the Group 1 diseases, onchocerciasis and lymphatic filariasis. Onchocerciasis is endemic in parts of Africa and in 13 foci in six countries of the Americas where it was introduced through the slave trade. It is estimated that more than half a million people live in areas of México, Guatemala, Colombia, Ecuador, Venezuela, and Brazil where documented transmission of onchocer- ciasis occurs or has been documented in the recent past. The basic strategy for achieving elimination in this Region is mass drug administration (MDA) using a form of ivermectin (Mectizan®, a donated medicine) given twice a year to at least 85 percent of all eligible population, accompanied by health education and promotion of community participation for at least 10 consecutive years. The minimum required coverage in all the 13 foci in the Region was achieved in 2002 and has been maintained since. New cases of onchocercal blindness were eliminated since 2007. However, some cases of ocular morbidity still occur in a few foci, mainly in the Amazon region of Southern Venezuela and Northern Brazil inhabited by the Yanomami Amerindians. As of January 2011 onchocer- ciasis transmission has been interrupted in 8 of the 13 foci, with those currently being in the post-treatment surveillance phase. Transmission is suspected to be suppressed in two other foci: South Chiapas in México and the Central focus in Guatemala. Onchocerciasis transmission persists in the three foci (Northeastern focus of Venezuela, and the southern focus of Venezuela and northern focus of Brazil, which share the Yanomami area (epidemiologically, it constitutes one shared focus). The Yanomami area represents the greatest challenge to the re - gional elimination efforts. Lymphatic filariasis, another NTD imported to LAC by the trans-Atlantic slave trade, was common in port cities, some Caribbean islands, and coastal areas in the Region until the last century when advances in sanitation began to reduce and then interrupt transmission by its Culex mosquito vector. In the past few decades three countries (Costa Rica, Suriname, and Trinidad and Tobago) have presented evidence of interruption of transmission, together with two cities in Brazil (Belém, Pará state and Maceió, Alagoas state). Today more than 9 million people are considered at risk for lymphatic filariasis in four endemic countries in the Region (one focus in metro Recife, Brazil, and Guyana, Dominican Republic and Haiti), with the highest proportion living in Haiti. People at risk benefit from more than 10 years of effort to eliminate transmission by MDA with the drugs diethlycarbamazine and albendazole. In 2009 about 3.4 million were treated via MDA. The January 2010 earthquake in Haiti and the Dominican Republic complicated the timely delivery of medicines. A meeting convened by PAHO in February 2010 with international partners created solidarity in support of Haiti to continue the work and reach the elimination goal, which helped enable the Haitian Ministry of Health and Population’s MDA program to pick up and con -

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121 APPENDIX A tinue in 2010. Ministries of Health are intensifying their efforts to eliminate the remaining foci in Brazil, Dominican Republic, and Guyana. Group 2 diseases are those whose burden can be drastically reduced with available tools: schistosomiasis and soil-transmitted helminthiasis (STH), for which there exist safe and very effective drugs and a record of success in greatly reducing intensity of infection though MDA in a strategy of preventive chemo - therapy. In LAC, the parasites targeted are Schistosoma mansoni (the only human schistosome in the region) and the three common types of STHs (Ascaris lumbri- coides, Trichuris trichura, and the human hookworms Ancylostoma duodenale and Necator americanus). They persist in some areas (poor rural communities or peri-urban shantytowns), sometimes with a very high prevalence (more than 50 percent) in vulnerable populations like children; however in many countries there is very limited or no recent epidemiological data about their distribution, prevalence, and burden, hampering awareness and adequate interventions. Soil-transmitted helminthiasis is considered to be present in all the LAC Region’s countries, with prevalence varying. PAHO estimates conservatively that 13 million preschool-age children and 33 million school-age children are at risk of STH infections in the Region, where transmission is closely associated with a lack of access to basic sanitation and safe water. A handful of countries have established national deworming programs, principally for school-age children, while in other countries various international nongovernmental organizations (NGOs) contribute to deworming efforts through their community-targeted in - terventions. Epidemiological information on STH is sparse, as these infections are not reportable; however, in PAHO’s review of published prevalence rates some surveys have indicted prevalence higher than 50 percent in some groups of school-age children and indigenous populations, and intensity of infection varies but has been seen high enough to be associated with adverse health effects like anemia. The Region’s high-risk countries are being encouraged and supported to scale-up deworming efforts to reach all vulnerable populations. In LAC, PAHO estimates that approximately 1.8 million persons are in- fected, and up to 25 million are at risk of schistosomiasis. Schistosomiasis infection occurs in humans in contact with infested freshwater reservoirs when the cercarial stage of the parasitic fluke leaves the intermediate host snail and penetrates the person’s skin and enters the bloodstream. The drug praziquantel is the recommended treatment, which can be provided by MDA or individual treatment. MDA with praziquantel can interrupt transmission. Today the disease is limited to four countries in LAC: parts of Brazil (principally the northeast of the country), St. Lucia, and parts of Suriname and Venezuela. Morbidity appears low, and reported deaths (from Brazil) are few. Brazil’s national schistosomia - sis control program has, over the decades, significantly reduced morbidity and mortality, while the other countries treat cases as encountered; Suriname and St. Lucia are taking steps to eliminate the disease while Venezuela is evaluating its epidemiological situation.

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122 NEGLECTED TROPICAL AND ZOONOTIC DISEASES For other infectious diseases, such as leishmaniasis and leptospirosis, the burden of the disease needs to be further assessed, better tools need to be devel - oped for diagnosis (e.g., leishmaniasis), and methods and strategies for achieving cost-effective and sustainable prevention and control need to be established (e.g., leptospirosis, cysticercosis/taeniasis). For these diseases and for others that have epidemiological relevance to some of the region’s countries, more operational research needs to be conducted, new tools need to be assessed, and surveillance systems need to be improved. Framework for Elimination The public health strategies and interventions that are used to eliminate or re- duce infectious diseases to acceptable levels go beyond routine control measures. In order to strengthen the efforts against diseases related to poverty as a group, endemic countries can develop integrated POAs under the same framework, while considering the following: • Available plans at the global, regional, or country level to eliminate or control these diseases. • Available guidelines for the selected diseases to support the countries in achieving the goals of elimination or control. • Available tools such as drugs and diagnostic techniques to support surveil- lance systems. • Evidence-based decisions for strengthening health surveillance systems, mapping the diseases to identify remaining foci, and identifying overlap - ping of diseases in geopolitical areas (“hot spots” or areas of co-endemic - ity) for integrated action. • Reducing gaps in tool-ready neglected diseases in deficit areas in the region. • Ensuring that the necessary resources are available for the primary care system to integrate NTD control and help reduce inequalities in health. • Pursuing inter-programmatic interventions that integrate the various ex- isting plans into a comprehensive vision based on the epidemiology and social determinants of each area identified for intervention (hot spots); interventions should tackle the factors and mechanisms through which social conditions affect the community’s health and, where possible, ad - dress them through social and health policies. • Pursuing community participation and intersectoral partnerships: the com- munity, stakeholders and all actors and potential partners within and outside the health sector should be enlisted to make actions sustainable. • Pursuing horizontal cooperation: identify which countries share problems or borders where the selected diseases occur, to promote joint actions and intercountry plans.

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123 APPENDIX A • The increase in donor support from global partners in the fight against neglected tropical diseases and other infections related to poverty. Progress, Priorities, and Lines of Action for Elimination PAHO partnered with the Inter American Development Bank (IDB) and the Global Network for Neglected Tropical Diseases (GNNTD, or Global Network [GN]) based in the Sabin Vaccine Institute beginning in 2008. With the IDB and the GN the partners have established a Trust Fund for Neglected Infectious Dis- eases in the IDB and are working to capitalize the fund in 2011. Additionally the partners have worked together and with Ministries of Health to develop a POA and demonstration project in the State of Chiapas México projects, and another demonstration project in the metropolitan area of Recife, northeast Brazil, which are meant to demonstrate or show proof of principle of integrated approaches to NTD control and elimination in the LAC Region. The Chiapas demonstration project covers trachoma, Chagas disease, leishmaniasis, rabies transmitted by dogs, onchocerciasis, and STHs. The project in metropolitan Recife tackles schis- tosomiasis, STHs, LF, and leprosy/Hansen’s disease. Each project will become operational in 2011. Meanwhile, several countries, including Guyana, Suriname, Dominican Republic, and Haiti, are developing integrated POAs to combat mul - tiple NTDs, and more countries will begin the process in 2011. In collaboration with the GNNTD, in 2010 PAHO began a process to map NTDs down to lower administrative levels (municipal levels) in several coun- tries. With the Swiss Tropical Institute and Louisiana State University, PAHO is using environmental and social parameters and Bayesian modeling to map the expected distribution and prevalence of Chagas disease, schistosomiasis and STH in Brazil, Bolivia, and Colombia. This modeling approach is expected to be extended to additional countries in 2011. Additionally, PAHO has worked with the Autonomous University of Yucatán, México, to study the social determinants of STHs, Chagas disease, and dengue in peri-urban and rural communities near the city of Mérida. To operationalize the strategies and interventions needed to eliminate NTDs in the region, PAHO also prepared a report in 2010 analyzing progress in control and elimination of five NTDs amenable to preventive chemotherapy, prioritizing the associated endemic countries with respect to these five diseases and identify - ing lines of action to take to achieve elimination by 2015 (PAHO, 2010). This report, referred to as the Prioritization Report, is a qualitative analysis of gaps and needs in technical cooperation and is presented in order to make prog- ress toward the elimination goals for these five diseases in 33 countries in LAC: onchocerciasis, schistosomiasis, trachoma, LF, and soil-transmitted helminthiasis. As a result of the analysis, countries were classified and prioritized into four groups.

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124 NEGLECTED TROPICAL AND ZOONOTIC DISEASES Group 1 This group concentrates the majority of population at risk for the main NTDs. These countries have 66.8 and 67.4 percent of preschool-age children (Pre-SAC) and school-age children (SAC) populations, respectively, at risk in LAC for STHs. Four countries have foci of onchocerciasis with 421,000 people at risk. Three countries have foci of schistosomiasis with up to 25 million people at risk. Three countries have foci of trachoma with up to 50 million people living in risk areas, and four countries have foci of LF with more than 9 million people at risk. This group includes countries working to eliminate onchocerciasis, LF, and trachoma, and one country with the possibil - ity to eliminate schistosomiasis; Suriname is expecting external verification of LF elimination. This group needs technical cooperation to develop and imple - ment integrated, interprogrammatic, and intersectoral plans to combat neglected infectious diseases (NIDs) including STHs (Table A1-2). TABLE A1-2 Diseases, Foci, Population at Risk, and Treatment Coverage in Group 1 Countries Diseases in Population at Countries of Group 1 Foci Risk Treatment Coverage Onchocerciasis This group has 9 of 421,000 people Second Round 2009: Brazil 13 onchocerciasis foci 89%; Guatemala 93%; in LAC: Brazil (1), México 93%; Ecuador 96% Ecuador (1), Guatemala (4), and México (3) Transmission interrupted in 6 foci: México (2), Guatemala (3), Ecuador (1) Lymphatic filariasis This group has all of More than 9 MDA in 2009: Haiti 3 the lymphatic filariasis million people million people treated; foci: Brazil, Dominican Brazil 177,000; Guyana: Republic, Haiti, and 129,189; Dominican Guyana. Republic has not carried out Suriname is expecting MDA for LF since 2007, validation of elimination. transmission interruption is being evaluated Schistosomiasis Foci in 3 countries: Nearly 25 Treatment coverage: Brazil Brazil, Suriname, and million people 83% cases treated of cases Saint Lucia. at risk detected; 21 cases were Transmission to be treated in 2009 in Suriname evaluated in Dominican Republic Trachoma Foci in Brazil, 50 million people No data available at Guatemala, and México live in risk areas national level SOURCE: Modified from PAHO (2010).

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125 APPENDIX A Group 2 This group has 26.8 and 26.1 percent of Pre-SAC and SAC populations, respectively, at risk for STHs in LAC. Two countries have foci of onchocerciasis with 115,070 people at risk. One country has foci of schistosomiasis. There is no evidence of LF transmission in this group of countries. However, recently Miller et al. (2010) provided clinical evidence of trachoma in an Amerindian indigenous community in the Department of Vaupés, Colombia documenting the presence of trachoma for the first time in Colombia. This group includes countries also eliminating onchocerciasis and targeting schistosomiasis. These countries need technical cooperation to improve current interprogrammatic and intersectoral coordination and to include STHs into NID- integrated actions (Table A1-3). As mentioned above, most of the LAC countries have no updated results of nationwide surveys of prevalence and intensity of infection of STH and schis- tosomiasis and trachoma. Groups 1 and 2 have the greatest gaps in sanitation coverage and a clear opportunity to integrate intersectoral and interprogrammatic actions for integrated NTD control, in the framework of primary health care sys - tems and addressing the social determinants of health. Group 3 This group has 5.4 percent of Pre-SAC and SAC population at risk for STHs in LAC. There is no evidence of the presence of onchocerciasis, schisto - somiasis, trachoma, or LF. These countries need technical cooperation to focus activities for NIDs at local level and rural areas, with emphasis on STHs. Group 4 This group has 1.03 and 1.1 percent of Pre-SAC and SAC populations, respectively, at risk for STHs in LAC. There is no evidence of the presence of onchocerciasis, schistosomiasis, trachoma, or LF. Costa Rica and Trinidad and Tobago are expecting external verification of LF elimination. TABLE A1-3 Diseases, Foci, Population at Risk, and Treatment Coverage in Group 2 Countries Diseases in Population Group 2 Foci at Risk Treatment Coverage Onchocerciasis This group has the remaining 4 115,070 Second Round 2009: Venezuela of the 13 foci of onchocerciasis people at South focus 85%, Northeast focus in LAC: Colombia (1) and risk 95%, North–central focus 99%. Venezuela (3) The Colombian focus is in post- treatment surveillance Transmission interrupted in Colombia focus Schistosomiasis Foci in Venezuela No data No data available available SOURCE: PAHO (2010).

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512 NEGLECTED TROPICAL AND ZOONOTIC DISEASES The biology of T. cruzi and the features of the infection also provide no support for a differential susceptibility to treatment during the acute and chronic phases; parasites are not quiescent in the chronic phase but rather continue to cycle in and out of host cells, to replicate and metabolize, and thus presumably are equally susceptible to antimicrobials irrespective of the length of the infec - tion. Most important, the substantial evidence from observational studies of long- term posttreatment follow-up of chronic-stage treatment provides unequivocal verification of the ability of treatment to substantially impact disease progression (reviewed in Tarleton et al., 2007). Although these latter studies may be criticized for their nonrandomized design, their conclusions should not simply be discarded on this basis. Despite the evidence for the efficacy of BZ and NX, these are far from ideal drugs. Both have substantial, although often manageable (Viotti et al., 2009), side effects, and treatment failure occurs in a variable number of cases. The bio - chemical basis of treatment failure is not fully understood; there are isolates of T. cruzi that are naturally more resistant to these compounds (both in vitro and in vivo) and in some cases this increased resistance is associated with decreased nitroreductase activity in these isolates (Wilkinson et al., 2008). The combination of misinformation about the efficacy of treatment in the chronic phase, the pos - sibility of adverse effects from treatment, the lack of reliable methods to assess treatment efficacy, and the known variability in efficacy and the undependable supply of compounds virtually ensure that these drugs will continue to be pro - foundly underutilized, despite their effectiveness. Because drug treatment is the only effective means of preventing the development of clinical disease, it should be used in all acute and chronic infection cases where side effects or other aspects of the treatment do not put the patients at a greater health risk. It is unethical not to make better use of the tools that we already have in hand, and access to treat - ment, not only in Latin America but throughout the world, must be improved (Gascon et al., 2010). There have been no new drugs developed for the treatment of T. cruzi in- fection in decades and the investigations of compounds as potential treatments nearly always stop well short of demonstration of parasitological cure in animals models. Fortunately, this is one of the areas that show real promise for rapid prog- ress in the coming years. With respect to compound discovery, excellent systems are now available for high-capacity in vitro screening of compound libraries, rapid in vivo compound testing, and rigorous analysis of cure in both acute and chronic infections in experimental hosts (Figure A21-1) (Canavaci, 2010). High- throughput screens of large compound libraries (containing from 300,000 to more than 1,000,000 compounds) have been completed or are in progress. And plans have been announced to conduct two clinical trials of new compounds, the already licensed antifungal posaconazole by Merck and the ergosterol biosynthesis inhibi- tor ravuconazole pro-drug E1224 by the Drugs for Neglected Diseases Initiative (DNDi) and Eisai. This progress is being made possible by a combination of the

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513 APPENDIX A FIGURE A21-1 Amastigotes of T. cruzi within host cells. (left) CL strain parasites ex- pressing the tandom Tomato red protein and useful for both in vitro and in vivo screening assays (Canavaci et al., 2010). (right) Example of high-content microscopic screening using DNA stains to detect T. cruzi replication within host cells. persistence of individual investigators who have developed the testing protocols and provided the initial discovery data for the compounds going to clinical trials, large pharmaceutical companies who have the compound libraries, testing capacity, and chemical expertise, and public–private partnerships like DNDi that have helped coordinate some of these efforts. The interest of the pharmaceutical industry in Chagas disease is exciting, but this interest could wane as quickly as it has come, especially if the initial clinical trials are not promising; there may be limited tolerance for failure. Funding for these efforts is also still tenuous; industry is donating resources but will likely need partners and other funders to get new compounds approved and to the clinic. Preclinical studies must rigorously evaluate efficacy using the best available model systems that also allow for definitive conclusions and comparative data between different candidate drugs. With these data in hand, the various entities can make coordinated and informed decisions, conserving resources by ensuring that only the best compounds go forward in development. Assessing Treatment Efficacy A principal consequence of the highly effective immune control of parasite load in T. cruzi infection is that detection of parasites or parasite products is challenging in the absence of treatment and totally unreliable as a measure of effectiveness following treatment; a positive parasitemia or PCR-indicated treat- ment failure but a negative test does not indicate successful cure. Given this fact, the development of a test that absolutely certifies parasitological cure following patient treatment is going to be difficult, if not impossible. However, this is not a situation that is unique to Chagas disease and is no justification for not treating

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514 NEGLECTED TROPICAL AND ZOONOTIC DISEASES using the current drugs or for not developing and testing new treatments. Surro - gates of cure will likely have to be the principal metric for treatment outcomes. Two measures have been used extensively to assess treatment success: decreases in the titers of anti–T. cruzi antibodies (Andrade, 1996; Sosa Estani et al., 1998) and the prevention of progression of symptomatic disease (Viotti et al., 1998). Both criteria are useful on a population basis to demonstrate the benefit of therapy and, on an individual basis, conversion to negative serology is a convincing indicator of parasitological cure. However, both outcomes take years (or even decades) of observation (e.g., the rate of progression to more severe disease is estimated at ~3 percent of subjects per year; Pinto Dias, 2006). A decade-long follow-up period is not an acceptable endpoint for the testing of new drugs. Development of antipathogen immune responses is an accepted marker of infection—indeed the basis of diagnosis for many infections—including T. cruzi. A decline in these immune responses can also reflect the clearance of the infection. The maintenance of antipathogen T cell and antibody responses long after infec - tion cure, an important characteristic of an effective immune response, consider- ably complicates the use of immunological parameters to monitor cure. However, careful examination of the characteristics of these responses during infection and following infection clearance suggests some distinctive aspects that may be useful in assessing cure. For example, by analyzing the antibody responses to multiple, individual T. cruzi proteins (Cooley et al., 2008), posttreatment changes that are not evident from conventional serological tests can be detected within one year after treatment (Laucella et al., 2009). Because these decreased antibody levels are not observed in untreated individuals and occur at a rate that is similar to the rate of cure as assessed by long-term follow-up of progression in clinical disease in drug-treated subjects (Viotti et al., 1994, 2006), this assay appears to be an excel- lent candidate for further evaluation as an indicator of treatment efficacy. The attributes of antipathogen T cell responses also follow a predictable pattern after infection cure, with persisting T cells acquiring the phenotype of long-term (central) memory cells and with the loss of effector and shorter-lived effector memory T cells when antigen is no longer in the system (Wherry et al., 2004). A decline in effector T cells specific for T. cruzi has been documented in BZ-treated subjects and strongly correlates with decreasing antibody levels (Laucella et al., 2009). T cell responses are more cumbersome to measure than are serologic responses and are sometimes undetectable in subjects even before treatment (Laucella et al., 2009), making this a less dependable marker for cure. Nevertheless, these studies support further investigations of immunological pa - rameters as possible markers of treatment efficacy in T. cruzi infection. These and other biomarkers of treatment success are likely to become the primary endpoints for clinical trials of new drugs for treating T. cruzi infection. None of these sur- rogate markers is likely to be directly confirmable as an indicator of cure (i.e., we cannot immunosuppress human subjects posttreatment to confirm cure, as is done in experimental models; Bustamante et al., 2008). Upcoming clinical trials, where

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515 APPENDIX A controlled follow-up and multiple endpoints and outcomes will be measured, should be used as opportunties to evaluate some possible surrogate markers. It could be argued that drug treatment in Chagas disease could be efficacious simply by decreasing parasite load and, consequently, the level of inflammation and tissue damage, even if it fails to completely clear T. cruzi infection. Although treatment without cure could be beneficial, most data argue against this possibil - ity. First, disease development is clearly linked to parasite persistence: as long as parasites are present, there is potential for more tissue destruction. Also, subjects with low and even undetectable parasite load still go on to develop clinical dis - ease. Indeed, there is no evidence of an association between disease severity and parasite load (Hidron et al., 2010; Murcia, 2010). Finally, a drop in parasite load brought about by drug treatment would be expected to be only temporary and last only as long as the drug is being given. It is possible that a new, lower set-point of parasite load would be established after treatment, but this does not seem to be consistently the case in either human (Murcia et al., 2010) or experimental in - fections (Bustamante and Tarleton, unpublished). Also, the changing nutritional, general health, and especially immunological status of infected subjects would be expected to modify the efficiency of infection control overtime. In short, lowering parasite levels is not a dependable and acceptable goal for drug treatment in T. cruzi infection; the objective needs to be parasitological cure. Vector Control Without question, the biggest success story in the control and prevention of Chagas disease has been vector control. Triatoma infestans is the vector species responsible for the majority of T. cruzi transmission to humans in South America and is found almost exclusively in and around housing, living in the cracks and crevices of adobe, mud, and thatch constructions, and feeding at night on the animal and human inhabitants (Figure A21-2). Widespread, consistent, and highly effective insecticidal spraying campaigns in the 1980s and 1990s, focus - ing largely on this domiciliary vector species, dramatically reduced incidence of T. cruzi infection in the area known as the Southern Cone of South America. As a result, Brazil, Uruguay, and Chile were declared free of transmission by T. infestans (Moncayo and Silveira, 2009) and the Pan American Health Organiza- tion and the World Health Organization set their sights on “elimination” of T. infestans–mediated transmission of T. cruzi by 2010. Such goals perpetuate another myth of T. cruzi infection—that vector trans- mission can be eliminated by insecticidal spraying alone. There is a long list of reasons that this is highly unlikely if not simply impossible. First, insecticidal spraying is time-consuming, labor-intensive, and expensive; multiperson crews must remove all belongings from structures before spraying the walls and roofs with residual insecticides. And this process has to be repeated every six months, perhaps forever, to eliminate reinfestations. The well-funded national campaigns

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516 NEGLECTED TROPICAL AND ZOONOTIC DISEASES FIGURE A21-2 A setting of active transmission in the Gran Chaco region and the pyrethroid-resistant Triatoma infestans collected from the structure. that made the Southern Cone Initiative successful have now been largely dis - mantled, and the responsibility of vector control has fallen to underfunded, under- equipped, and understaffed local governments (Gurtler et al., 2008). Second, T. infestans is not the only vector for T. cruzi and is not exclusively domiciliary. A dozen or more species of reduviid bugs are likely capable of vectoring T. cruzi infection, and these species each have unique behaviors and distribution patterns and thus distinctive ways of interfacing with humans. Discovery of sylvatic foci of T. infestans indicates that this species will not be eliminated as a transmis -

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517 APPENDIX A sion threat even if it is removed from all domestic dwellings by insecticide use (Noireau et al., 2005). Additionally, new settings for transmission in and near cities are making it clear that T. cruzi transmission is not restricted solely to rural settings (Bowman et al., 2008). Third, and the least surprising facet, resistance to insecticides is being reported in multiple settings (Figure A21-2) (Picollo, 2005). Whether this resistance is due exclusively to the decades of house spraying or if the agricultural use of insecticides is also contributing is not known. There are alternative insecticides, but these are often more expensive and are too noxious to the inhabitants of houses to be widely accepted. Thus, although vector control by insecticide use has been an unqualified success, it is not a long-term solution, particularly when applied in isolation from other vector transmission and infection control tools. The unique behavioral characteristics of various vector species and the increasing variety of settings in which transmission is being reported emphasizes that one size does not fit all when it comes to dealing with the vectors of T. cruzi and with transmission con- trol in general. For example, in the Grand Chaco region of Northern Argentina, companion animals, not humans, have been identified as the major infection source of bugs that subsequently transmit the infection to the human residents of the house (Cohen and Gurtler, 2001). Recent outbreaks resulting from apparent oral transmission are often presented as evidence of a “new” route of transmis - sion (Aguilar et al., 2007; Benchimol Barbosa, 2006; Shikanai-Yasuda et al., 1991). More likely, oral transmission is a common, if not the dominant, route of transmission in humans that is just now being more widely recognized. The transmission characteristics in different environments have to be better studied, and integrated plans for each specific local situation must be designed. In this process, there needs to be better use of simple tools where effective (e.g., bug col- lars on domestic animals and insecticidal screens and nets on houses and beds), along with the evaluation of more innovative approaches, such as the vaccina- tion or intermittent treatment of companion animals to prevent them from being sources of infection. The identification and aggressive treatment of parasitemic humans, especially the minority of “supertransmitters” who are highly infective for insects, is needed (Cerisola et al., 1974). The development of cheap house construction methods and materials that discourage infestations is a clear long- term solution to permanently decrease the opportunities for human infection. Finally, an improved infrastructure for and commitment to supporting vector and transmission control in all countries of the Americas is needed. Summary: Leadership and Policy Making Although the problems are many, the outlook for making an impact on Cha - gas disease is nonetheless bright. This is not a difficult infection to understand; the vectors are large insects that primarily feed within a house and that transmit the infection indirectly and inefficiently via their feces, not their bite. Infection

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518 NEGLECTED TROPICAL AND ZOONOTIC DISEASES rarely kills acutely, so there is plenty of time to treat the infection and the goal of treatment—to eradicate, not manage the infection—is obvious, even if difficult to certify. Current diagnostics are usable but need improvement, particularly with respect to assessing treatment efficacy. Drugs are available that are effective in many cases. Because these are the only option for the 20 million individuals already infected and for those who will become infected in the future, these should be more widely used despite their potential side effects. The explosion in interest in new drug development in the past few years and announced plans for clinical trials are extremely encouraging that safer drugs are on the horizon. Vector control has already shown its utility; it just needs to be conducted more intelligently and with better integration with other treatment and preventative pro- grams. Not discussed above are the opportunities for a human vaccine for Chagas disease; the jury is still out on this possibility. Given the perceived requirement that elimination and not simply better control of an existing infection is the goal, prophylactic or therapeutic vaccines would have to totally prevent infection or promote complete parasite clearance in those already infected. This is a big task for a vaccine. Until such abilities can be demonstrated in experimental infections, vaccines for T. cruzi will likely remain just a hope. A particularly vexing problem in Chagas disease is in the areas of leader- ship and policy. National (including in the United States) and international poli - cies have been ineffective at best, harmful at worst. Perpetuating the myths that chronic Chagas disease cannot be treated with current drugs and that transmission can (or has) been largely eliminated does not accurately reflect the bulk of the data. Policies that rely almost exclusively on insecticidal spraying and speak of eradication/elimination within years when this is impossible, no matter what the time frame, is careless. These practices minimize the severity of the problem, obstruct the use of current drugs and the development of new ones, encourage the elimination or decentralization of vector control programs, and discourage the involvement of large nonprofit funders in new or continuing control and preven - tion efforts. A policy of “more of the same” will not achieve the progress that is necessary and possible. National and international policy makers have to do a much better job at honestly assessing the problems and the realistic opportunities and coordinating the effort to build upon these. Establishment of research and development priorities based upon rigorous and educated evaluations and devel - oping the funding mechanisms to move beyond planning to implementation is crucial for making real progress. Success will require not only funding but also political will and local buy-in. Scientists must execute the appropriate studies and provide the data and clear interpretations that can guide policy develop - ment and implementation. T. cruzi infection and Chagas disease are manageable problems—there is a success story waiting to be written here if the job is done carefully and correctly.

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522 NEGLECTED TROPICAL AND ZOONOTIC DISEASES Wincker, P., C. Britto, J. B. Pereira, M. A. Cardoso, W. Oelemann, and C. M. Morel. 1994. Use of a simplified polymerase chain reaction procedure to detect Trypanosoma cruzi in blood samples from chronic chagasic patients in a rural endemic area. American Journal of Tropical Medicine and Hygiene 51(6):771–777. Zarate-Blades, C. R., N. Blades, M. S. Nascimento, J. F. da Silveira, and E. S. Umezawa. 2007. Diagnostic performance of tests based on Trypanosoma cruzi excreted-secreted antigens in an endemic area for Chagas’ disease in Bolivia. Diagnostic Microbiology and Infectious Disease 57(2):229–232.