A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease.

BACKGROUND: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. METHODS: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months. RESULTS: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. CONCLUSIONS: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days. CLINICAL TRIALS REGISTRATION: NCT02498782.

Five-year serological and clinical evolution of chronic Chagas disease patients in Cochabamba, Bolivia.

BACKGROUND: Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected infectious disease that exerts the highest public health burden in the Americas. There are two anti-parasitic drugs approved for its treatment-benznidazole and nifurtimox-but the absence of biomarkers to early assess treatment efficacy hinders patients´ follow-up. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal, observational study among a cohort of 106 chronically T. cruzi-infected patients in Cochabamba (Bolivia) who completed the recommended treatment of benznidazole. Participants were followed-up for five years, in which we collected clinical and serological data, including yearly electrocardiograms and optical density readouts from two ELISAs (total and recombinant antigens). Descriptive and statistical analyses were performed to understand trends in data, as well as the relationship between clinical symptoms and serological evolution after treatment. Our results showed that both ELISAs documented average declines up to year three and slight inclines for the following two years. The recorded clinical parameters indicated that most patients did not have any significant changes to their cardiac or digestive symptoms after treatment, at least in the timeframe under investigation, while a small percentage demonstrated either a regression or progression in symptoms. Only one participant met the "cure criterion" of a negative serological readout for both ELISAs by the final year. CONCLUSIONS/SIGNIFICANCE: The study confirms that follow-up of benznidazole-treated T. cruzi-infected patients should be longer than five years to determine, with current tools, if they are cured. In terms of serological evolution, the single use of a total antigen ELISA might be a more reliable measure and suffice to address infection status, at least in the region of Bolivia where the study was done. Additional work is needed to develop a test-of-cure for an early assessment of drugs´ efficacy with the aim of improving case management protocols.

New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia.

INTRODUCTION: Chagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs. METHODS AND ANALYSIS: New ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping. ETHICS AND DISSEMINATION: The TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions. TRIAL REGISTRATION NUMBER: NCT03981523.

Community-based entomological surveillance in three Chagas disease-endemic regions in sub-Andean Bolivia.

BACKGROUND: Chagas disease is endemic throughout most of Bolivia, with prevalence rates of 25% observed in some geographic areas located mainly in the sub-Andean region. METHODS: Community-based entomological surveillance was carried out in the sub-Andean departments of Cochabamba (municipalities of Cochabamba, Punata and Sacaba), Tarija (municipality of Tarija) and Chuquisaca (municipality of Sucre). The surveillance parameters evaluated were: (i) the proportion of cards with the presence of triatomines; (ii) the distribution of positive cards by area; and (iii) the proportion of cards with the presence of infected triatomines. RESULTS: Of the cards returned, in 852 (3.1%) there was a mention of the presence of triatomines. The species Triatoma infestans, Triatoma sordida and Triatoma guasayana were identified in 812 (95.3%), 39 (4.6%) and 1 (0.1%), respectively. The median monthly positivity rate of the cards during 2011-2018 was higher in Punata (9.1%; IQR=3.2-15.4%). The median monthly rate was highest in 2012 (2.7%; IQR=0-5.6%). Fifty positive cards (5.8%) presented insects that were positive for trypanosomatids, mainly in Cochabamba and Punata. CONCLUSIONS: The report of triatomines foci by inhabitants represents an effective surveillance system coordinated by a network of specialized and multidisciplinary health centers. These strategies, which should be included in the health policies of endemic countries, enable extending and deepening the dialogue among technicians, communities and their local authorities.

Characterization of digestive disorders of patients with chronic Chagas disease in Cochabamba, Bolivia.

BACKGROUND: Chagas disease (CD) is endemic in Latin America and particularly common in Bolivia, but there is little information on the characteristics of chronic digestive involvement. OBJECTIVES: To determine the prevalence and characterize digestive manifestations in chronic CD patients in Cochabamba, Bolivia. METHODS: Eighty-five T. cruzi-seropositive individuals with or without digestive symptoms (G1 group), and fifteen T. cruzi-seronegative patients with similar digestive symptoms to those seen in CD (G2 group) were included in the study. All patients underwent a detailed history including past medical history, epidemiological information, hygiene and dietary habits, a complete physical examination, two serological tests for T. cruzi, video endoscopy, barium swallow, and barium enema. FINDINGS: We observed digestive manifestations in T. cruzi seropositive and seronegative patients. Colonic manifestations were detected in both groups, highlighting the relevance of other confounder factors in the region. Constipation was present in 52.9% of G1 patients, 62.4% presented two or more upper digestive tract symptoms, and 5.9% of them presented esophageal manifestations. Helicobacter pylori infection was detected in 58.8% of G1 patients, and all patients presented gastritis on endoscopy. CONCLUSIONS: Prevalence of digestive involvement in CD patients is higher than expected. However, digestive symptoms are not always caused by T. cruzi infection and require differential diagnoses.

A strategy for scaling up access to comprehensive care in adults with Chagas disease in endemic countries: The Bolivian Chagas Platform.

BACKGROUND: Bolivia has the highest prevalence of Chagas disease (CD) in the world (6.1%), with more than 607,186 people with Trypanosoma cruzi infection, most of them adults. In Bolivia CD has been declared a national priority. In 2009, the Chagas National Program (ChNP) had neither a protocol nor a clear directive for diagnosis and treatment of adults. Although programs had been implemented for congenital transmission and for acute cases, adults remained uncovered. Moreover, health professionals were not aware of treatment recommendations aimed at this population, and research on CD was limited; it was difficult to increase awareness of the disease, understand the challenges it presented, and adapt strategies to cope with it. Simultaneously, migratory flows that led Bolivian patients with CD to Spain and other European countries forced medical staff to look for solutions to an emerging problem. INTERVENTION: In this context, thanks to a Spanish international cooperation collaboration, the Bolivian platform for the comprehensive care of adults with CD was created in 2009. Based on the establishment of a vertical care system under the umbrella of ChNP general guidelines, six centres specialized in CD management were established in different epidemiological contexts. A common database, standardized clinical forms, a and a protocolized attention to adults patients, together with training activities for health professionals were essential for the model success. With the collaboration and knowledge transfer activities between endemic and non-endemic countries, the platform aims to provide care, train health professionals, and create the basis for a future expansion to the National Health System of a proven model of care for adults with CD. RESULTS: From 2010 to 2015, a total of 26,227 patients were attended by the Platform, 69% (18,316) were diagnosed with T. cruzi, 8,567 initiated anti-parasitic treatment, more than 1,616 health professionals were trained, and more than ten research projects developed. The project helped to increase the number of adults with CD diagnosed and treated, produce evidence-based clinical practice guidelines, and bring about changes in policy that will increase access to comprehensive care among adults with CD. The ChNP is now studying the Platform's health care model to adapt and implement it nationwide. CONCLUSIONS: This strategy provides a solution to unmet demands in the care of patients with CD, improving access to diagnosis and treatment. Further scaling up of diagnosis and treatment will be based on the expansion of the model of care to the NHS structures. Its sustainability will be ensured as it will build on existing local resources in Bolivia. Still human trained resources are scarce and the high staff turnover in Bolivia is a limitation of the model. Nevertheless, in a preliminary two-years-experience of scaling up this model, this limitations have been locally solved together with the health local authorities.

Entomological surveillance with community engagement at Chagas Platform Centers for comprehensive care in the mesothermal valleys of three regions of the endemic area of Triatoma infestans in Bolivia

Background: The detection of residual foci inside the houses, or the reinfestation of triatomines is one of the main entomological surveillance challenges. Actions aimed at increasing the probability of vector detection and to detect re-infestation when the density of vector populations is low, is a priority objective for Chagas control programs. Methods: Families belonging to local communities were responsible of triatomine specimens capture, following a strategic methodology based on entomological surveillance with community participation developed by the National Chagas Programme of the Ministry of Health of Bolivia. The main objective of the study is to evaluate the entomological surveillance strategy with community engagement implemented in Chagas Platform Centers for comprehensive care (CPs). The degree of intradomicillary residual vector infestation, the main seasonal period of triatomines capture, and natural infection by trypanosomatids rates were evaluated. Results: In rural and peri-urban Punata, in the Department of Cochabamba, the houses infestation rate by triatomines exceeds the national average and is above the recommendations of PAHO / WHO. The observations during the seasons of the year showed that Spring season (September to December) was the period where there was a higher average of T. infestans positive houses detected by the families participating in the study in the three departments of Bolivia. The presence of infected triatomines with Trypanosomatideos in positive houses was 6% in the study area, still finding active domestic cycles in rural and peri-urban areas and not in urban areas where triatomines with parasites were not reported during the seven years of monitoring. Conclusions: Reporting infestation foci by the inhabitants is the simplest and most direct way of participation of the community in entomological surveillance. These strategies should be included in the health policies of the countries, as well as extending and deepening the dialogue between technicians, communities and their local authorities.