BackgroundBolivia 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.InterventionIn 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.ResultsFrom 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.ConclusionsThis 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.

Nifurtimox is a recommended treatment for Chagas disease, but data from treated children are limited. We investigated the efficacy, safety and tolerability of nifurtimox administered as divisible, dispersible 30 mg and 120 mg tablets in children with Chagas disease. In this blinded, controlled study conducted January 2016–July 2018, 330 patients aged <18 years from 25 medical centres across three South American countries were randomised 2:1 to nifurtimox 10–20 mg/kg/day (aged <12 years) or 8–10 mg/kg/day (aged ≥12 years) for 60 days (n = 219), or for 30 days plus placebo for 30 days (n = 111) (ClinicalTrials.gov NCT02625974). The primary outcome was anti-Trypanosoma cruzi serological response (negative seroconversion or seroreduction ≥20% in mean optical density from baseline determined by two conventional enzyme-linked immunosorbent assays) at 12 months in the 60-day treatment group versus historical placebo controls. Nifurtimox for 60 days achieved negative seroconversion (n = 10) and seroreduction (n = 62) in 72 patients (serological response 32.9%; 95% confidence interval [CI] 26.4%, 39.3%, of all treated patients), confirming superiority relative to the upper 95% CI of 16% for controls. In patients aged <8 months, 10/12 treated for 60 days (83.3%) and 5/7 treated for 30 days (71.4%) achieved negative seroconversion. Overall serological response was lower for 30-day than for 60-day nifurtimox (between-treatment difference 14.0% [95% CI 3.7%, 24.2%]). The frequency of T. cruzi-positive quantitative polymerase chain reactions decreased substantially from baseline levels (60-day regimen 53.4% versus 1.4%; 30-day regimen 51.4% versus 4.5%). Study drug-related treatment-emergent adverse events (TEAEs), which were observed in 62 patients (28.3%) treated for 60 days and 29 patients (26.1%) treated for 30 days, were generally mild or moderate and resolved without sequelae; 4.2% of all TEAEs led to nifurtimox discontinuation. Age- and weight-adjusted nifurtimox for 60 days achieved a serological response at 12 months post-treatment that was superior to historical placebo, was well tolerated and had a favourable safety profile in children with Chagas disease. Although, at 1 year serological follow-up, efficacy of the shorter nifurtimox treatment was not comparable to the 60-day treatment regimen for the overall study population, further long-term follow-up of the patients will provide important information about the progress of serological conversion in children treated with nifurtimox, as well as the potential efficacy difference between the two regimens over time.

Background Chagas disease (CD) has significant global health impact, but safe and effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods This double-blind, randomised, 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 one of six 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 population (ITT). 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 &gt;2 weeks. A total of 40 patients received from 3 days to 8 weeks of treatment with fexinidazole. Delayed onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients, versus none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (“1200mg-2week”) and 100.0% (“1800mg-2week”). 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 = 0.0056). 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 of &lt;10 days.

IntroductionChagas 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 analysisNew 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 disseminationThe 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 numberNCT03981523.

Background Most people with chronic Chagas disease do not receive specific care and therefore are undiagnosed and do not receive accurate treatment. This manuscript discusses and evaluates a collaborative strategy to improve access to healthcare for patients with Chagas in Bolivia, a country with the highest prevalence of Chagas in the world. Methods With the aim of reinforcing the Chagas National Programme, the Bolivian Chagas Platform was born in 2009. The first stage of the project was to implement a vertical pilot program in order to introduce and consolidate a consensual protocol-based healthcare, working in seven centers (Chagas Platform Centers). From 2015 on the model was extended to 52 primary healthcare centers, through decentralized, horizontal scaling-up. To evaluate the strategy, we have used the WHO ExpandNet program. Results The strategy has significantly increased the number of patients cared for, with 181,397 people at risk of having T. cruzi infection tested and 57,871 (31·9%) new diagnostics performed. In those with treatment criteria, 79·2% completed the treatment. The program has also trained a significant number of health personnel through the specific Chagas guidelines (67% of healthcare workers in the intervention area). Conclusions After being recognized by the Chagas National Programme as a healthcare model aligned with national laws and priorities, the Bolivian platform of Chagas as an innovation, includes attributes that they have made it possible to expand the strategy at the national level and could also be adapted in other countries.

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.

Background There is some concern about the safety of nifurtimox (NF) for the offspring of treated women. Potential genotoxicity of NF was reported in in vitro models. However, the evidence to support the risks in fetal development is lacking for humans. In addition, a preventative effect over transplacental transmission was reported in girls and women with T.cruzi infection treated before pregnancy (mainly with benznidazole). Methods A multicenter, randomized, double-blind phase 3 clinical trial (NCT02625974) was set up to evaluate safety and efficacy of NF. A total of 330 patients, younger 18 years old, were enrolled, 67 were females of child-bearing age. The enrolled females of childbearing age agreed to use an effective method of contraception until 3 months after the last administration of NF. Pregnancy tests were performed at screening, during treatment and 30 days after end of treatment. Results No pregnancies were reported during treatment period. There were 5 pregnancies reported during the 1st year of post-treatment follow-up and another 21 pregnancies during the additional 3-year follow-up period. Two mothers did not consent to have their babies tested for T cruzi infection, and in one case an abortion was reported. Two women gave birth twice. There was information about transplacental transmission available in 18 babies. All mothers were T.cruzi RT-PCR negative at the end of the treatment period and remained negative during follow up. All newborns were live, healthy full-term and of weight appropriate for their gestational age, and had no perinatal complications except one baby who was healthy but small for gestational age. T.cruzi infection was ruled out by a negative direct parasitological test during the first days of life in 12 infants , and /or by ELISA T.cruzi serology at 8 -12 months of age in 14 infants, which was negative in all cases. Conclusion Our results showed that treatment of females on childbearing age with nifurtimox may prevent transplacental transmission of CD as was reported previously for benznidazole. Disclosures Jaime ALTCHEH, Sr., MD,PhD, Bayer: Advisor/Consultant.

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. MethodsFamilies 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.