Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial.

BACKGROUND: More than six million people worldwide, particularly in vulnerable communities in Latin America, are infected with Trypanosoma cruzi, the causative agent of Chagas disease. Only a small portion have access to diagnosis and treatment. Both drugs used to treat this chronic, neglected infection, benznidazole and nifurtimox, were developed more than 50 years ago, and adverse drug reactions during treatment pose a major barrier, causing 20% of patients to discontinue therapy. Fexinidazole proved efficacious in an earlier, interrupted clinical trial, but the doses evaluated were not well tolerated. The present study evaluated fexinidazole at lower doses and for shorter treatment durations. METHODS: In this randomised, double-blind, phase 2 trial, we included adult patients (18-60 years old) with confirmed T cruzi infection by serology and PCR and without signs of organ involvement. We evaluated three regimens of fexinidazole-600 mg once daily for 10 days (6·0 g total dose), 1200 mg daily for 3 days (3·6 g), and 600 mg daily for 3 days followed by 1200 mg daily for 4 days (6·6 g)-and compared them with a historical placebo control group (n=47). The primary endpoint was sustained negative results by PCR at end of treatment and on each visit up to four months of follow-up. This study is registered with ClinicalTrials.gov, NCT03587766, and EudraCT, 2016-004905-15. FINDINGS: Between Oct 16, 2017, and Aug 7, 2018, we enrolled 45 patients (n=15 for each group), of whom 43 completed the study. Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%) of 46 in the historical control group. Mean parasite load decreased sharply following treatment but rebounded beginning 10 weeks after treatment. Five participants had seven grade 3 adverse events: carpal tunnel, sciatica, device infection, pneumonia, staphylococcal infection, and joint and device dislocation. Two participants discontinued treatment due to adverse events unrelated to fexinidazole. INTERPRETATION: The fexinidazole regimens in this study had an acceptable safety profile but did not prove effective against T cruzi infection. Development of fexinidazole monotherapy for treating T cruzi infection has been stopped. FUNDING: The Drugs for Neglected Diseases initiative.

Integrated pest management strategies targeting the Florida kissing bug, Triatoma sanguisuga: Preventing this vector of Chagas disease from invading your home.

Triatomines (Hemiptera: Reduviidae: Triatominae), commonly called "kissing bugs", are blood-sucking pests and vectors of the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (CD). Eleven species of kissing bugs occur throughout the southern half of the USA, four of which are well known to invade human dwellings. Certain kissing bugs in the USA are known to transmit T. cruzi to humans and other animals and their bites can also lead to serious allergic reactions, including anaphylaxis. In Florida, the kissing bug Triatoma sanguisuga frequently invades homes, bites residents, and has been found infected with T. cruzi, placing humans and companion animals at risk for CD. This review outlines integrated pest management (IPM) strategies for minimizing human exposure to T. sanguisuga and CD. A comprehensive IPM plan for kissing bugs includes detailed inspections, removal of vertebrate host nesting areas, and kissing bug harborage, home improvements to exclude kissing bugs from entering structures, pest removal, and judicious use of pesticides. This approach can limit or eliminate kissing bug entry into residential structures, thereby preventing kissing bug bites, and CD infections in humans and companion animals.

Laboratory evaluation of eleven rapid diagnostic tests for serological diagnosis of Chagas disease in Colombia.

BACKGROUND: Chagas disease is a public health challenge in Colombia, where only an estimated 1.2% of people at risk have accessed diagnosis, while less than 0.5% of affected people have obtained treatment. The development of simplified diagnostic algorithms would enable progress in access to diagnosis; however, the current diagnostic algorithm relies on at least two laboratory-based tests that require qualified personnel, processing equipment, and infrastructure, which are still generally lacking at the primary care level. Rapid diagnostic tests (RDTs) for Chagas disease could simplify diagnosis, but their performance in the epidemiological context of Colombia is not well known. METHODOLOGY: A retrospective analytical observational study of RDTs was performed to estimate the operational characteristics of 11 commercially available RDTs designed for in vitro detection of anti-T. cruzi IgG antibodies. The study was performed under controlled laboratory conditions using human serum samples. PRINCIPAL FINDINGS: Eleven RDTs were assessed, ten using 585 serum samples and one using 551 serum samples. Employing the current national diagnostic algorithm as a reference standard for serological diagnosis of chronic infection, the sensitivity of the assessed RDTs ranged from 75.5% to 99.0% (95% CI 70.5-100), while specificity ranged from 70.9% to 100% (95% CI 65.3-100). Most tests (7/11, 63.6%) had sensitivity above 90%, and almost all (10/11, 90.9%) had specificity above 90%. Five RDTs had both sensitivity and specificity above 90%. CONCLUSIONS/SIGNIFICANCE: The evaluation of these 11 commercially available RDTs under controlled laboratory conditions is a first step in the assessment of the diagnostic performance of RDTs in Colombia. As a next step, field studies will be conducted on available RDTs with sensitivity and specificity greater than 90% in this study, to evaluate performance in real world conditions, with the final goal to allow simplified diagnostic algorithms.

Case Report: Chagas Disease in a Traveler Who Developed Esophageal Involvement Decades after Acute Infection.

Travelers to Chagas disease endemic regions of Latin America may be at risk for Trypanosoma cruzi infection. We report a 67-year-old woman who screened positive for T. cruzi infection while donating blood. The patient had a history of an unusual febrile illness and marked swelling of the face sustained at age 10 after camping in northern Mexico that led to a 3-week hospitalization without a diagnosis. More than 4 decades later, rapid diagnostic tests and commercial and confirmatory serology for Chagas disease were all positive for T. cruzi infection. On evaluation, the patient described a progressive chronic cough, gastroesophageal reflux, and dysphagia for > 10 years. There was no evidence of any cardiac complications. However, esophageal manometry demonstrated significant dysmotility, with 90% of swallows being ineffective with evidence of esophageal pressurization and retrograde peristalsis in several swallows, suggesting early autonomic disruption due to Chagas disease esophagopathy. In this report, we highlight the importance of travel-related Chagas disease among travelers to endemic regions and the need to further identify potential risks of transmission among this at-risk population.

Chagas Disease and Domestic Medical Screening Guidance for Newly Arrived Individuals Under a Humanitarian-Based Immigration Status: A Call for Action.

Chagas disease is considered one of the most important neglected tropical diseases in the Western Hemisphere, given its morbidity, mortality, and societal and economic burden. The United States has the fifth highest global burden of Chagas disease. Every year, thousands of migrant people from Latin America and throughout the globe travel to the U.S.- Mexico border searching for asylum. The U.S. CDC's Guidance for the U.S. Domestic Medical Examination for Newly Arriving Refugees provides recommendations to safeguard the health of individuals who enter the United States with a humanitarian-based immigration status as defined by the CDC's guidance under Key Considerations and Best Practices. We encourage the inclusion of Trypanosoma cruzi infection screening recommendations in this guidance as an important step toward understanding the risk and burden of Chagas disease in this vulnerable population, strengthening their access to care and contributing to the 2030 objectives of the WHO's neglected tropical diseases road map.

The multidimensional comprehension of Chagas disease. Contributions, approaches, challenges and opportunities from and beyond the Information, Education and Communication field.

Chagas is a complex, multidimensional phenomenon in which political, economic, environmental, biomedical, epidemiological, psychological, and sociocultural factors intersect. Nonetheless, the hegemonic conceptualisation has long envisioned Chagas as primarily a biomedical question, while ignoring or downplaying the other dimensions, and this limited view has reinforced the disease's long neglect. Integrating the multiple dimensions of the problem into a coherent approach adapted to field realities and needs represents an immense challenge, but the payoff is more effective and sustainable experiences, with higher social awareness, increased case detection and follow-up, improved adherence to care, and integrated participation of various actors from multiple action levels. Information, Education, and Communication (IEC) initiatives have great potential for impact in the implementation of multidimensional programs of prevention and control successfully customised to the diverse and complex contexts where Chagas disease persists.

Recommendations for Screening and Diagnosis of Chagas Disease in the United States.

BACKGROUND: Chagas disease affects an estimated 326 000-347 000 people in the United States and is severely underdiagnosed. Lack of awareness and clarity regarding screening and diagnosis is a key barrier. This article provides straightforward recommendations, with the goal of simplifying identification and testing of people at risk for US healthcare providers. METHODS: A multidisciplinary working group of clinicians and researchers with expertise in Chagas disease agreed on 6 main questions, and developed recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, after reviewing the relevant literature on Chagas disease in the United States. RESULTS: Individuals who were born or resided for prolonged time periods in endemic countries of Mexico and Central and South America should be tested for Trypanosoma cruzi infection, and family members of people who test positive should be screened. Women of childbearing age with risk factors and infants born to seropositive mothers deserve special consideration due to the risk of vertical transmission. Diagnostic testing for chronic T. cruzi infection should be conducted using 2 distinct assays. CONCLUSIONS: Increasing provider-directed screening for T. cruzi infection is key to addressing this neglected public health challenge in the United States.

On-site experience of a project to increase access to diagnosis and treatment of Chagas disease in high-risk endemic areas of Colombia.

Colombia has one of the largest burdens of Chagas disease globally, with about 438,000 people affected according to 2015 estimates. Despite this, < 1% of the population has had access to diagnosis and treatment. A patient-centered roadmap for Chagas disease was developed from 2015 onwards to address access barriers and increase diagnostic and therapeutic coverage and was implemented in five municipalities where Chagas disease is endemic. The mean number of people tested per year increased from 37 before the project to 262 following implementation, and the average days between medical order and diagnostic confirmation results decreased from 258 to 19. The mean days from diagnostic confirmation to treatment initiation decreased from 354 before the project to 135 after implementation. The 5,654 people tested included 3,467 women of childbearing age. The prevalence of T. cruzi infection was 11.5%, and thus far 266 people have received antitrypanosomal treatment. Collaborative creation and implementation of a patient-centered roadmap can address access barriers in specific contexts, helping to reduce the invisibility and burden of this neglected disease.

The multidimensional comprehension of Chagas disease. Contributions, approaches, challenges and opportunities from and beyond the Information, Education and Communication field

Chagas is a complex, multidimensional phenomenon in which political, economic, environmental, biomedical, epidemiological, psychological, and sociocultural factors intersect. Nonetheless, the hegemonic conceptualisation has long envisioned Chagas as primarily a biomedical question, while ignoring or downplaying the other dimensions, and this limited view has reinforced the disease's long neglect. Integrating the multiple dimensions of the problem into a coherent approach adapted to field realities and needs represents an immense challenge, but the payoff is more effective and sustainable experiences, with higher social awareness, increased case detection and follow-up, improved adherence to care, and integrated participation of various actors from multiple action levels. Information, Education, and Communication (IEC) initiatives have great potential for impact in the implementation of multidimensional programs of prevention and control successfully customised to the diverse and complex contexts where Chagas disease persists.

The Chagas disease study landscape: A systematic review of clinical and observational antiparasitic treatment studies to assess the potential for establishing an individual participant-level data platform.

BACKGROUND: Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects ~6-7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing individual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. METHODOLOGY/PRINCIPAL FINDINGS: This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials.gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251 (1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome; parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30-180] for the first assessment, 180 days [IQR: 60-500] for second, and 270 days [IQR: 18-545] for the third assessment. CONCLUSIONS/SIGNIFICANCE: This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable in-depth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection.

"You Don't Have a Normal Life": Coping with Chagas Disease in Los Angeles, California.

Chagas disease is the neglected tropical disease of greatest public health impact in the United States, where it affects over 300,000 people. Diverse barriers limit healthcare access for affected people; fewer than 1% have obtained testing or treatment. We interviewed 50 people with Chagas disease in Los Angeles, California, and administered a cultural consensus analysis questionnaire. Participants were asked about their experiences and perceptions of Chagas disease, access to healthcare, and strategies for coping with the disease. In participants' narratives, the physical and emotional impacts of the disease were closely interwoven. Participant explanatory models highlight difficulties in accessing care, despite a desire for biomedical treatment. Obtaining testing and treatment for Chagas disease poses substantial challenges for US patients.

COVID-19: Implications for People with Chagas Disease.

As the global COVID-19 pandemic advances, it increasingly impacts those vulnerable populations who already bear a heavy burden of neglected tropical disease. Chagas disease (CD), a neglected parasitic infection, is of particular concern because of its potential to cause cardiac, gastrointestinal, and other complications which could increase susceptibility to COVID-19. The over one million people worldwide with chronic Chagas cardiomyopathy require special consideration because of COVID-19's potential impact on the heart, yet the pandemic also affects treatment provision to people with acute or chronic indeterminate CD. In this document, a follow-up to the WHF-IASC Roadmap on CD, we assess the implications of coinfection with SARS-CoV-2 and Trypanosoma cruzi, the etiological agent of CD. Based on the limited evidence available, we provide preliminary guidance for testing, treatment, and management of patients affected by both diseases, while highlighting emerging healthcare access challenges and future research needs.

COVID-19: Implications for People with Chagas Disease

As the global COVID-19 pandemic advances, it increasingly impacts the vulnerable populations who already bear a heavy burden of neglected tropical diseases. Chagas disease (CD), a neglected parasitic infection, is of particular concern because of its potential to cause cardiac, gastrointestinal, and other complications which could increase susceptibility to COVID-19. The over one million people worldwide with chronic Chagas cardiomyopathy require special consideration because of COVID-19's potential impact on the heart, yet the pandemic also affects treatment provision to people with acute or chronic indeterminate CD. In this document, a follow-up to the WHF-IASC Roadmap on CD, we assess the implications of coinfection with SARS-CoV-2 and Trypanosoma cruzi, the etiological agent of CD. Based on the limited evidence available, we provide preliminary guidance for testing, treatment, and management of patients affected by both diseases, while highlighting emerging healthcare access challenges and future research needs.

Domestic Triatoma sanguisuga-Human Exposure in the South Carolina Coastal Region.

A collaborative investigation was initiated in rural coastal South Carolina in response to a reported triatomine bite. The eastern conenose bug, Triatoma sanguisuga, was identified and tested for Trypanosoma cruzi. The insect was negative by PCR, and no additional triatomines were found in the vicinity of the home. This is the first published report of a bite from T. sanguisuga in South Carolina despite the fact that triatomine vectors have been documented in the state since the 1850s, and specimens have been collected from homes in the past. Sylvatic T. cruzi reservoirs are common throughout the southeastern United States, and this case brings to light the possibility of human contact with infected triatomines in the state of South Carolina for public health and clinical and entomology professionals.

Awareness of Chagas disease and socioeconomic characteristics of Bolivian immigrants living in Sao Paulo, Brazil.

In this study which is part of a research project on Chagas disease (CD) among Bolivian immigrants in Sao Paulo, we describe socioeconomic characteristics, knowledge of CD and implications for acess to health care. We applied a structured questionnaire to a sample of 472 Bolivian adults (> 18 years) living in Sao Paulo and enrolled at the Barra Funda School Health Center. Participants' median age was 28.5 years, 75.0% were from the Bolivian department of La Paz, and >90% worked in the garment industry. Respondents had lived in Sao Paulo for a median of 5.8 years. Only 169 (35.8%) were familiar with CD, while roughly half (50.4%) had lived in natural materials houses in Bolivia, 225 (47.7%) indicated familiarity with the vector, 23.9% had seen the vector in their homes in Bolivia, and 6.4% reported having been bitten by a triatomine bug. Factors associated with awareness of CD were analyzed by chi square tests, and those with p values <0.25 were included in a multivariable logistic regression model. In the multivariable logistic regression analysis, having a relative with CD (OR=4.3, 95% CI=1.5-12.0), having lived in a house with mud or wood walls (OR=0.4, 95% CI=0.2-0.8), and having heard of the triatomine bug, or vinchuca, (OR=10.0, 95% CI=5.1-19.5) were significantly associated with awareness of CD. This study shows a low familiarity with CD among Bolivian migrants living in Sao Paulo, Brazil. Raising awareness of the disease through specific communication strategies should be an essential component of public health programs to reduce the burden of CD in this and other vulnerable populations.

WHF IASC Roadmap on Chagas Disease.

Background: Chagas Disease is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, with some of the most serious manifestations affecting the cardiovascular system. It is a chronic, stigmatizing condition, closely associated with poverty and affecting close to 6 million people globally. Although historically the disease was limited to endemic areas of Latin America recent years have seen an increasing global spread. In addition to the morbidity and mortality associated with the disease, the social and economic burdens on individuals and society are substantial. Often called the 'silent killer', Chagas disease is characterized by a long, asymptomatic phase in affected individuals. Approximately 30% then go on develop chronic Chagas cardiomyopathy and other serious cardiac complications such as stroke, rhythm disturbances and severe heart failure. Methods: In a collaboration of the World Hearth Federation (WHF) and the Inter-American Society of Cardiology (IASC) a writing group consisting of 20 diverse experts on Chagas disease (CD) was convened. The group provided up to date expert knowledge based on their area of expertise. An extensive review of the literature describing obstacles to diagnosis and treatment of CD along with proposed solutions was conducted. A survey was sent to all WHF Members and, using snowball sampling to widen the consultation, to a variety of health care professionals working in the CD global health community. The results were analyzed, open comments were reviewed and consolidated, and the findings were incorporated into this document, thus ensuring a consensus representation. Results: The WHF IASC Roadmap on Chagas Disease offers a comprehensive summary of current knowledge on prevention, diagnosis and management of the disease. In providing an analysis of 'roadblocks' in access to comprehensive care for Chagas disease patients, the document serves as a framework from which strategies for implementation such as national plans can be formulated. Several dimensions are considered in the analysis: healthcare system capabilities, governance, financing, community awareness and advocacy. Conclusion: The WHF IASC Roadmap proposes strategies and evidence-based solutions for healthcare professionals, health authorities and governments to help overcome the barriers to comprehensive care for Chagas disease patients. This roadmap describes an ideal patient care pathway, and explores the roadblocks along the way, offering potential solutions based on available research and examples in practice. It represents a call to action to decision-makers and health care professionals to step up efforts to eradicate Chagas disease.

Mandatory Notification of Chronic Chagas Disease: Confronting the Epidemiological Silence in the State of Goiás, Brazil.

OBJECTIVES: This paper presents the results of the design and implementation process for the policy of compulsory notification of chronic Chagas disease in the Brazilian state of Goiás (Resolution No. 004/2013-GAB/SES-GO). METHODS: The narrative was based on information provided by key actors that were part of the different stages of the process, built on contextual axes based on participants' reflections about the establishment of the most accurate and coherent notification mechanisms. RESULTS: The notification policy addressed the absence of historical data from patients in the state Chagas program, an increase in cases identified through serology, and weaknesses in vector control. Two key challenges involved human resources capacity and dissemination to public agencies and health care workers. Effective training and communication processes were key ingredients for successful implementation. CONCLUSIONS: The lack of public health measures aimed at the epidemiological surveillance of chronic Chagas cases constitutes a significant barrier for patients to access appropriate diagnosis, management and follow-up, and hampers the planning of necessary activities within health systems. The implementation of the notification policy in Goiás allows authorities to determine the real magnitude of Chagas disease in the population, so that an appropriate public health response can be mounted to meet the needs of affected people, thereby ending the epidemiological silence of Chagas disease.

Chagas Disease and Healthcare Rights in the Bolivian Immigrant Community of São Paulo, Brazil.

Chagas disease (CD) poses a major public health challenge for the Americas and non endemic regions around the world. This study discusses the legal framework surrounding access to healthcare for CD for Bolivian migrants living in São Paulo, Brazil. While recent guidelines stipulating care for CD exist, there is a lack of legal provisions to ensure they are regularly implemented. Bolivian migrants in SP have specific needs, including language differences and a high level of mobility. Interviews were conducted with ten participants representing public health institutions or organizations working with the Bolivian migrant community. Additionally, a review was conducted of legal, official, and health policy documents pertaining to rights of Bolivian migrants in SP. Although the right to healthcare is constitutionally guaranteed for all, in practice, immigrants, especially those without documentation, encounter barriers to initiating treatment for CD. Providing the primary health care system (SUS) card would not only improve access to healthcare for Bolivian migrants, but also provide a potential pathway toward regularization of status. The approval of clinical protocols and therapeutic guidelines for CD (2018) represents an opportunity to improve care for all Brazilians with CD. Programs with multidisciplinary teams should be developed taking into account the specific social and cultural needs of this population.

Interventions to bring comprehensive care to people with Chagas disease: Experiences in Bolivia, Argentina and Colombia.

Chagas disease (CD) affects over six million people and is a leading cause of heart failure in the Americas. Few are able to access diagnosis and treatment for CD, resulting in a missed opportunity to prevent morbimortality. Integration of testing and treatment with the primary healthcare level is a key step in ensuring affected people receive timely antitrypansomal therapy, which increasing evidence shows can prevent chronic complications from the disease and halt congenital transmission. This article describes three collaborative projects focused on increasing access to testing and treatment for CD through primary healthcare facilities in Bolivia, Argentina, and Colombia.