Chagas Disease: Epidemiology and Barriers to Treatment.

Chronic human infection by the protozoan parasite Trypanosoma cruzi, known as Chagas disease, results in heart failure and death in 20%-30% of affected individuals. Recognition and treatment of the infection are difficult. Disease control requires elimination of the vector, the reduviid bug, that infests housing of poor quality in endemic areas. In South America, control has largely succeeded in the Southern Cone countries-Argentina, Chile, Uruguay, southern Brazil and São Paulo, and Paraguay-but lags severely in the Northern Triangle (Central American) countries: El Salvador, Honduras, and Guatemala. Surges in poverty and violence in Central America have increased immigration of persons at risk for Chagas disease to the United States, and immigrants to the United States with Chagas disease face multiple barriers to obtaining effective care. These include issues with financing and payment for health care, limited effectiveness of screening and diagnosis, limited effectiveness of available treatment, and lack of provider awareness, public health education, and research. Each of these barriers presents a unique public health challenge.

Access to Chagas disease treatment in the United States after the regulatory approval of benznidazole.

Approximately 300,000 persons in the United States (US) are infected with Trypanosoma cruzi, the protozoan that causes Chagas disease, but less than 1% are estimated to have received antiparasitic treatment. Benznidazole was approved by the US Food and Drug Administration (FDA) for treatment of T. cruzi infection in 2017 and commercialized in May 2018. This paper analyzes factors that affect access to benznidazole following commercialization and suggests directions for future actions to expand access. We applied an access framework to identify barriers, facilitators, and key actors that influence the ability of people with Chagas disease to receive appropriate treatment with benznidazole. Data were collected from the published literature, key informants, and commercial databases. We found that the mean number of persons who obtained benznidazole increased from just under 5 when distributed by the CDC to 13 per month after the commercial launch (from May 2018 to February 2019). Nine key barriers to access were identified: lack of multi-sector coordination, failure of health care providers to use a specific order form, lack of an emergency delivery system, high medical costs for uninsured patients, narrow indications for use of benznidazole, lack of treatment guidelines, limited number of qualified treaters, difficulties for patients to make medical appointments, and inadequate evaluation by providers to determine eligibility for treatment. Our analysis shows that access to benznidazole is still limited after FDA approval. We suggest six areas for strategic action for the pharmaceutical company that markets benznidazole and its allied private foundation to expand access to benznidazole in the US. In addition, we recommend expanding the existing researcher-clinician network by including government agencies, companies and others. This paper's approach could be applied to access programs for benznidazole in other countries or for other health products that target neglected populations throughout the world.

Congenital Chagas Disease in the United States: The Effect of Commercially Priced Benznidazole on Costs and Benefits of Maternal Screening.

Chagas disease, caused by Trypanosoma cruzi, is transmitted by insect vectors, and through transfusions, transplants, insect feces in food, and mother to child during gestation. An estimated 30% of infected persons will develop lifelong, potentially fatal cardiac or digestive complications. Treatment of infants with benznidazole is highly efficacious in eliminating infection. This work evaluates the costs of maternal screening and infant testing and treatment for Chagas disease in the United States, including the cost of commercially available benznidazole. We compare costs of testing and treatment for mothers and infants with the lifetime societal costs without testing and consequent morbidity and mortality due to lack of treatment or late treatment. We constructed a decision-analytic model, using one tree that shows the combined costs for every possible mother-child pairing. Savings per birth in a targeted screening program are $1,314, and with universal screening, $105 per birth. At current screening costs, universal screening results in $420 million in lifetime savings per birth-year cohort. We found that a congenital Chagas screening program in the United States is cost saving for all rates of congenital transmission greater than 0.001% and all levels of maternal prevalence greater than 0.06% compared with no screening program.

Practices of cattle keepers of southwest Nigeria in relation to bovine trypanosomosis.

Significant increases in human and livestock populations coupled with agricultural practices have changed the socioeconomic perspectives of livestock diseases. Evaluating the socioeconomic impact of bovine trypanosomosis and its vectors (Glossina, Tabanus and Stomoxys) from the perspective of the livestock owners is of great significance. Participatory rural appraisal was conducted among 209 livestock owners (focus groups) to determine the behavioural practices of animal husbandary to bovine trypanosomosis. In Nigeria, common Trypanosoma species found in cattle are Trypanosoma vivax, Trypanosoma congolense and Trypanosoma brucei. Trypanosomosis peaks were reported by owners to be in the months of March-August. A total of 70.8% (95%CI 64.32-76.56%) cattle owners perceived trypanosomosis as a major disease in their herd, 13.4% (95%CI 9.43-18.68%) practiced transhumance in the wet season and 93.9% (95%CI 88.58-96.92%) make use of trypanocides, and approximately US$ 8.4 million is spent annually on trypanocides in southwest Nigeria livestock industry. About 60.5% (95%CI 51.84-68.48) make use of insecticides against transmitting vectors, and only 1.9% (95%CI 0.75-4.82%) have ever heard of any form of government intervention scheme. Estimated losses ≥ US$ 426 (80-100% loss) can be incurred on a single animal depending on the size and market value. There is significant increase (16.2%, 95%CI 11.15-23.00%, P < 0.05) in the mortality rate of bovine trypanosomosis when compared to other livestock diseases. It will therefore be useful to involve the livestock owners with devising new and integrated measures for reducing the impact of this trypanosomosis.

Access to benznidazole for Chagas disease in the United States-Cautious optimism?

Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism.

Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America.

After more than one century since its discovery, Chagas disease is still extremely prevalent in 21 Latin American countries. Chagas disease is one of the most concerning public health problems in Latin America; the overall cost of CD treatment is approximately 7 billion United States dollars per year and it has a strong social impact on populations. Little progress has been made regarding the access to diagnosis and treatment at the primary health care level, calling into question the current policies to ensure the right to health and access to essential medications. In this article, diverse dimensions of access to treatment for Chagas disease are reviewed, illustrating the present state of benznidazole medication in relation to global production capacity, costs, and needs. The findings are based on an investigation requested by Médecins Sans Frontières Brazil through a consultancy in 2015, aiming to estimate the current costs of benznidazole production.

Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America

Abstract After more than one century since its discovery, Chagas disease is still extremely prevalent in 21 Latin American countries. Chagas disease is one of the most concerning public health problems in Latin America; the overall cost of CD treatment is approximately 7 billion United States dollars per year and it has a strong social impact on populations. Little progress has been made regarding the access to diagnosis and treatment at the primary health care level, calling into question the current policies to ensure the right to health and access to essential medications. In this article, diverse dimensions of access to treatment for Chagas disease are reviewed, illustrating the present state of benznidazole medication in relation to global production capacity, costs, and needs. The findings are based on an investigation requested by Médecins Sans Frontières Brazil through a consultancy in 2015, aiming to estimate the current costs of benznidazole production.

Cost analysis of options for management of African Animal Trypanosomiasis using interventions targeted at cattle in Tororo District; south-eastern Uganda.

BACKGROUND: Tsetse-transmitted African trypanosomes cause both nagana (African animal Trypanosomiasis-AAT) and sleeping sickness (human African Trypanosomiasis - HAT) across Sub-Saharan Africa. Vector control and chemotherapy are the contemporary methods of tsetse and trypanosomiasis control in this region. In most African countries, including Uganda, veterinary services have been decentralised and privatised. As a result, livestock keepers meet the costs of most of these services. To be sustainable, AAT control programs need to tailor tsetse control to the inelastic budgets of resource-poor small scale farmers. To guide the process of tsetse and AAT control toolkit selection, that now, more than ever before, needs to optimise resources, the costs of different tsetse and trypanosomiasis control options need to be determined. METHODS: A detailed costing of the restricted application protocol (RAP) for African trypanosomiasis control in Tororo District was undertaken between June 2012 and December 2013. A full cost calculation approach was used; including all overheads, delivery costs, depreciation and netting out transfer payments to calculate the economic (societal) cost of the intervention. Calculations were undertaken in Microsoft Excel without incorporating probabilistic elements. RESULTS: The cost of delivering RAP to the project was US$ 6.89 per animal per year while that of 4 doses of a curative trypanocide per animal per year was US$ 5.69. However, effective tsetse control does not require the application of RAP to all animals. Protecting cattle from trypanosome infections by spraying 25%, 50% or 75% of all cattle in a village costs US$ 1.72, 3.45 and 5.17 per animal per year respectively. Alternatively, a year of a single dose of curative or prophylactic trypanocide treatment plus 50% RAP would cost US$ 4.87 and US$ 5.23 per animal per year. Pyrethroid insecticides and trypanocides cost 22.4 and 39.1% of the cost of RAP and chemotherapy respectively. CONCLUSIONS: Cost analyses of low cost tsetse control options should include full delivery costs since they constitute 77.6% of all project costs. The relatively low cost of RAP for AAT control and its collateral impact on tick control make it an attractive option for livestock management by smallholder livestock keepers.

Economic evaluation of Chagas disease screening in Spain.

Although Spain is the European country with the highest Chagas disease burden, the country does not have a national control program of the disease. The purpose of this study is to evaluate the efficiency of several strategies for Chagas disease screening among Latin American residents living in Spain. The following screening strategies were evaluated: (1) non-screening; (2) screening of the Latin American pregnant women and their newborns; (3) screening also the relatives of the positive pregnant women; (4) screening also the relatives of the negative pregnant women. A cost-utility analysis was carried out to compare the four strategies from two perspectives, the societal and the Spanish National Health System (SNHS). A decision tree representing the clinical evolution of Chagas disease throughout patient's life was built. The strategies were compared through the incremental cost-utility ratio, using euros as cost measurement and quality-adjusted life years as utility measurement. A sensitivity analysis was performed to test the model parameters and their influence on the results. We found the "Non-screening" as the most expensive and less effective of the evaluated strategies, from both the societal and the SNHS perspectives. Among the screening evaluated strategies the most efficient was, from both perspectives, to extent the antenatal screening of the Latin American pregnant women and their newborns up to the relatives of the positive women. Several parameters influenced significantly on the sensitivity analyses, particularly the chronic treatment efficacy or the prevalence of Chagas disease. In conclusion, for the general Latin American immigrants living in Spain the most efficient would be to screen the Latin American mothers, their newborns and the close relatives of the mothers with a positive serology. However for higher prevalence immigrant population the most efficient intervention would be to extend the program to the close relatives of the negative mothers.

A literature review of economic evaluations for a neglected tropical disease: human African trypanosomiasis ("sleeping sickness").

Human African trypanosomiasis (HAT) is a disease caused by infection with the parasite Trypanosoma brucei gambiense or T. b. rhodesiense. It is transmitted to humans via the tsetse fly. Approximately 70 million people worldwide were at risk of infection in 1995, and approximately 20,000 people across Africa are infected with HAT. The objective of this review was to identify existing economic evaluations in order to summarise cost-effective interventions to reduce, control, or eliminate the burden of HAT. The studies included in the review were compared and critically appraised in order to determine if there were existing standardised methods that could be used for economic evaluation of HAT interventions or if innovative methodological approaches are warranted. A search strategy was developed using keywords and was implemented in January 2014 in several databases. The search returned a total of 2,283 articles. After two levels of screening, a total of seven economic evaluations were included and underwent critical appraisal using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist 6: Economic Evaluations. Results from the existing studies focused on the cost-effectiveness of interventions for the control and reduction of disease transmission. Modelling was a common method to forecast long-term results, and publications focused on interventions by category, such as case detection, diagnostics, drug treatments, and vector control. Most interventions were considered cost-effective based on the thresholds described; however, the current treatment, nifurtomix-eflornithine combination therapy (NECT), has not been evaluated for cost-effectiveness, and considerations for cost-effective strategies for elimination have yet to be completed. Overall, the current evidence highlights the main components that play a role in control; however, economic evaluations of HAT elimination strategies are needed to assist national decision makers, stakeholders, and key funders. These analyses would be of use, as HAT is currently being prioritized as a neglected tropical disease (NTD) to reach elimination by 2020.

Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis.

Despite the fact that eflornithine was considered as the safer drug to treat human African trypanosomiasis (HAT) and has been freely available since 2001, the difficulties in logistics and cost burden associated with this drug meant that the toxic melarsoprol remained the drug of choice. The World Health Organization responded to the situation by designing a medical kit containing all the materials needed to use eflornithine, and by implementing a training and drugs distribution programme which has allowed a transition to this much safer treatment. The introduction of the combination of nifurtimox and eflornithine (NECT) has accelerated the shift from melarsoprol to the best treatment available, due to reduced dosage and treatment time for eflornithine that has significantly lessened the cost and improved the burden of logistics encountered during treatment and distribution. The decrease in the use of more dangerous but cheaper melarsoprol has meant a rise in the per patient cost of treating HAT. Although NECT is cheaper than eflornithine monotherapy, an unexpected consequence has been a continuing rise in the per patient cost of treating HAT. The ethical decision of shifting to the best available treatment imposes a financial burden on HAT control programmes that might render long-term application unsustainable. These factors call for continuing research to provide new safer and more effective drugs that are simple to administer and cheaper when compared to current drugs.

Economic assessment of the performance of trypanotolerant cattle breeds in a pastoral production system in Kenya.

Cattle are the major source of food security and income for pastoral farmers in sub-Saharan Africa. However, infectious and parasitic diseases remain a major constraint to improved cattle productivity in the region. The use of animal health economics to support decision-making on cost-effective disease control options is increasingly becoming important in the developing world. Trypanotolerant indigenous Orma/zebu cattle in a trypanosomosis-endemic area of Kenya were evaluated for economic performance using gross-margin analysis and partial-farm budgeting. Orma/zebu and Sahiwal/zebu cross-bred cattle were exposed to similar husbandry practices and monitored for growth rate, incidence of common infections (trypanosomosis, anaplasmosis, babesiosis, East Coast Fever and helminthosis) and the cost of treatment assessed. Interview questionnaires were also used to assess the preference rating of the 2 breeds. Results indicated that incidence of infection was trypanosomosis 3%, anaplasmosis 58%, babesiosis 11%, East Coast Fever 22% and helminthosis 28%, with no significant difference between breeds. The Orma/zebu and Sahiwal/zebu breeds had comparable economic benefits, hence a pastoralist in Magadi division is likely to get similar returns from both breeds. This study therefore recommends adoption of not only the Sahiwal/zebu but also the Orma/zebu breed for cattle improvement in trypanosomosis endemic areas and conservation of indigenous genetic resources.

Eflornithine is a cost-effective alternative to melarsoprol for the treatment of second-stage human West African trypanosomiasis in Caxito, Angola.

OBJECTIVE: To compare the cost-effectiveness of eflornithine and melarsoprol in the treatment of human African trypanosomiasis. METHOD: We used data from a Médecins Sans Frontières treatment project in Caxito, Angola to do a formal cost-effectiveness analysis, comparing the efficiency of an eflornithine-based approach with melarsoprol. Endpoints calculated were: cost per death avoided; incremental cost per additional life saved; cost per years of life lost (YLL) averted; incremental cost per YLL averted. Sensitivity analysis was done for all parameters for which uncertainty existed over the plausible range. We did an analysis with and without cost of trypanocidal drugs included. RESULTS: Effectiveness was 95.6% for melarsoprol and 98.7% for eflornithine. Cost/patient was 504.6 for melarsoprol and 552.3 for eflornithine, cost per life saved was 527.5 USD for melarsoprol and 559.8 USD for eflornithine without cost of trypanocidal drugs but it increases to 600.4 USD and 844.6 USD per patient saved and 627.6 USD and 856.1 USD per life saved when cost of trypanocidal drugs are included. Incremental cost-effectiveness ratio is 1596 USD per additional life saved and 58 USD per additional life year saved in the baseline scenario without cost of trypanocidal drugs but it increases to 8169 USD per additional life saved and 299 USD per additional life year saved if costs of trypanocidal drugs are included. CONCLUSION: Eflornithine saves more lives than melarsoprol, but melarsoprol is slightly more cost-effective. Switching from melarsoprol to eflornithine can be considered as a cost-effective option according to the WHO choice criteria.

Human African trypanosomiasis: pharmacological re-engagement with a neglected disease.

This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease.