The number of patients with Chagas disease residing in Europe has increased significantly due to migration flows. Globally, Chagas cardiomyopathy has worse prognosis than other types of dilated cardiomyopathies and about 30% of patients develop cardiac involvement after a variable latency period (10–30 years). However, there is lack of data regarding the evolution of patients with Chagas disease living in a non-endemic area and potential early predictors of disease progression. OBJETIVE To describe the natural course of Chagas disease, the incidence rate of transformation into cardiac form and to assess if early predictors of myocardial involvement translate into a worse long-term prognosis in our non-endemic cohort. Clinical and echocardiographic follow-up was performed in 202 individuals from endemic areas of Chagas disease. At baseline, electrocardiogram, BNP and a comprehensive echocardiography including diastolic function and longitudinal myocardial strain were performed. Four different groups were defined: healthy controls (N=77); Chagas indeterminate form (positive serology, normal ECG and left ventricle (LV) dimensions and LV ejection fraction (>50%) and no segmental abnormalities, N=92); Chagas patients with abnormal ECG but normal LV dimensions and motility (N=15); and Chagas patients with LV diameter>55 mm or LV ejection fraction<50% or segmental abnormalities (N=18). The primary clinical outcome included advanced atrioventricular block, sustained ventricular tachycardia, heart failure, heart transplant, death or progression of cardiac disease defined as LV systolic dysfunction or new segmental abnormalities. Kaplan Meier with Long rank test and Cox regression analysis was used. Mean age was 37±9 and 34% were male. Median follow-up was 69 months (range 1 to 147). The primary endpoint occurred in a total of 17 (8.4%) individuals: 5 (5.4%) in the Indeterminate group; 3 (20%) in the abnormal ECG group; and 9 (50%) in the group with abnormal LV dimension or motility, with no events among controls (long-rank test<0.01, Figure 2). Six patients evolved from the indeterminate phase to cardiac involvement (2 with isolated ECG changes and 4 with abnormal echocardiography without previous changes in ECG (Figure 1). On echocardiography, there were no differences regarding changes in LV dimensions or LV ejection fraction between Chagas patients with normal baseline echo and controls, but a significantly reduction of Em was observed (−1.6±3.0 vs. 0.2±1.0) in the former. Excluding patients with abnormal echo at baseline, BNP (HR=1.03, p=0.001), Em (HR=0.78, p=0.05) and left atrial diameter (1.23, p=0.01) were predictors of the combined event. Conversion from the indeterminate to Chagas cardiomyopathy in our cohort was approximately 1.1%/year, but it may happen directly with contractility disturbances. BNP and comprehensive echocardiography may help to early detect disease progression. Figure 1. Distribution of patients and KM curves Type of funding source: None

Abstract Background Brain natriuretic peptide (BNP) and novel echocardiographic techniques such as speckle-tracking and a comprehensive evaluation of diastolic function can detect early myocardial involvement in patients with Chagas disease. However, there is lack of longitudinal studies that can confirm whether this early myocardial involvement translates into a worse prognosis. Purpose To assess if early myocardial involvement detected by BNP or a comprehensive echocardiographic evaluation was associated with future events in Chagas disease. Methods 182 consecutive individuals from endemic areas who underwent T. cruzi screening where prospectively included from 2007 to 2014. ECG, BNP and a comprehensive echocardiography including diastolic function and longitudinal myocardial strain were performed. Four different groups were defined: healthy controls (N=77); Chagas indeterminate form (positive serology, normal ECG and left ventricle (LV) diameter (<55 mm), LV ejection fraction (>50%) and no segmental abnormalities, N=88); Chagas patients with abnormal ECG but normal LV dimensions and motility (N=7); and Chagas patients with LV diameter>55 mm or LV ejection fraction<50% or segmental abnormalities (N=13). The primary outcome included advanced atrioventricular block, sustained ventricular tachycardia, heart failure, heart transplant or death. Kaplan Meier with Long rank test and Cox regression analysis was used. Results Mean age was 37±9 and 34% were male. Median follow-up was 63 months (range 1 to 137). The primary endpoint occurred in a total of 11 (10%) individuals: 2 (2.4%) in the Indeterminate group; 3 (43%) in the abnormal ECG group; and 6 (46%) in the group with abnormal LV dimension or motility, with no events among controls (long-rank test<0.01, Figure). In the global population, age, BNP, diastolic dysfunction parameters and longitudinal strain at the inferior and lateral walls were significant predictors. In the cohort of Chagas patients with normal standard echocardiography (N=92), ECG abnormalities (HR=49, p=0.001), Em (HR=0.68, p=0.03), deceleration time (HR=0.01, p=0.01), left atrial diameter (HR=1.24, p<0.01) and longitudinal strain at the midventricular lateral wall (HR=0.75, p=0.028) remained significantly associated with outcome. Cumulative survival without events Conclusions Outcome was significantly more frequent in Chagas patients with abnormalities in ECG or standard echocardiography. In early forms of the disease, myocardial involvement detected by BNP or a comprehensive echocardiography was associated with prognosis, and may help to individualize treatment and follow-up.

BackgroundBenznidazole is one of the two most effective antiparasitic drugs for Chagas' disease treatment. However, knowledge about its toxicity profile is mostly based on post-marketing observational studies.ObjectivesOur study combines data from two prospective clinical trials designed to assess the safety of the drug newly produced by ELEA Laboratories (Abarax®).MethodsEligible participants were selected using a consecutive sampling strategy in the CINEBENZ and BIOMARCHA studies between 2013 and 2016 (EUDRACT 2011-002900-34 and 2012-002645-38, respectively, and clinicaltrials.gov NCT01755403 and NCT01755377, respectively). Enrolled subjects received treatment with 5 mg/kg/day benznidazole orally in two divided doses for 8 weeks and were followed up fortnightly.ResultsWe observed 305 adverse reactions in 85 of 99 participants (85.9%). Each patient had a median of three adverse reactions, 89.5% were mild and the median duration was 12 days. Most adverse reactions appeared in the first month of treatment except arthritis and peripheral neuropathy. Twenty-six patients did not complete treatment: 2 were withdrawn, 1 for ectopic pregnancy and 1 for epilepsy relapse due to cysticercosis; 2 were lost to follow-up; and 22 were owing to adverse reactions, two of them severe. We observed some unexpected adverse reactions that have not been described previously, such as psychiatric symptoms, erectile dysfunction, menstrual cycle alterations and lung infiltration.ConclusionsThere is a very high frequency of adverse reactions to benznidazole. Most adverse reactions are mild, but the treatment burden is significant and unexpected reactions are not rare. Severe reactions are uncommon, but they can be life-threatening. Further studies are necessary to optimize treatment.

ABSTRACT The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h−1). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.)

ABSTRACT Chagas disease is a parasitic infection that leads to a significant public health problem in countries where the disease is endemic and where it is nonendemic. Benznidazole is the most commonly used drug for the etiological treatment of Chagas disease. Patients treated with benznidazole suffer frequent adverse drug reactions. Although arthralgia is common, arthritis has been reported as a very rare side effect. The objective of this study was to describe arthritis in a cohort of Trypanosoma cruzi-infected patients treated with benznidazole.

Migration is a channel through which Chagas disease is imported, and vertical transmission is a channel through which the disease is spread in non-endemic countries. This study presents the economic evaluation of Chagas disease screening in pregnant women from Latin America and in their newborns in a non endemic area such as Spain. The economic impact of Chagas disease screening is tested through two decision models, one for the newborn and one for the mother, against the alternative hypothesis of no screening for either the newborn or the mother. Results show that the option "no test" is dominated by the option "test". The cost effectiveness ratio in the "newborn model" was 22€/QALYs gained in the case of screening and 125€/QALYs gained in the case of no screening. The cost effectiveness ratio in the "mother model" was 96€/QALYs gained in the case of screening and 1675€/QALYs gained in the case of no screening. Probabilistic sensitivity analysis highlighted the reduction of uncertainty in the screening option. Threshold analysis assessed that even with a drop in Chagas prevalence from 3.4% to 0.9%, a drop in the probability of vertical transmission from 7.3% to 2.24% and with an increase of screening costs up to €37.5, "test" option would still be preferred to "no test". The current study proved Chagas screening of all Latin American women giving birth in Spain and of their infants to be the best strategy compared to the non-screening option and provides useful information for health policy makers in their decision making process.

Abstract Background: Chagas disease is endemic in Latin America, affecting 16–18 million people with more than 100 million exposed to risk of infection. Its etiological agent is Trypanosoma cruzi. To date, benznidazole is the only treatment of Chagas disease available in Europe. Methods: A high-performance reversed-phase isocratic liquid chromatographic method for benznidazole analysis in human plasma is described. The mobile phase consists of 60% ultrafiltered water and 40% acetonitrile. Samples were precipitated with trichloroacetic acid (0.3 M) (1/1, v/v). The injection volume was 100 μL. Benzocaine was used as internal standard. Results: The assay was linear over a benznidazole concentration range of 1.6–100 μg/mL. The method showed good agreement of results (n=15): inaccuracy (5.6%), intra- and inter-day variability (1.1% and 3.9%, respectively), recovery (94.9%), limit of detection (0.8 μg/mL), lower limit of quantitation (1.6 μg/mL) and acceptable stability over 24 h in the auto-sampler. Only 25 samples (58%) showed values within the therapeutic range. Three samples were subtherapeutic and 15 were in the toxic range. Conclusions: The method offers a fast and simple approach to determining benznidazole in human plasma which could be of use in pharmacokinetic and safety studies.

Établir l’intérêt du transit colique avec marqueurs dans l’étude de la constipation à la phase chronique de la maladie de Chagas. Le lavement baryté et le transit colique avec marqueurs sont réalisés à 18 émigrants latino-américains diagnostiqués de maladie de Chagas avec constipation (émission de moins de trois selles par semaine). Les lavements barytés étaient normaux chez 2 patients (11,11 %), 12 (66,66 %) présentaient un dolichocôlon et 4 (22,22 %) un dolichomégacôlon. Le transit colique avec marqueurs a été pathologique dans seulement 3 malades (16,66 %). Il existe une claire association entre la clinique de constipation el les données radiologiques du lavement baryté. Par contre, les résultats du transit colique avec marqueurs semblent peu fiables.

Souligner l’intérêt des explorations barytées dans la caractérisation radiologique des manifestations digestives à la phase chronique de la maladie de Chagas. Le transit œsophagien minuté et le lavement baryté sont réalisés à 32 émigrants latino-américains diagnostiqués de maladie de Chagas avec symptomatologie digestive. Les études radiologiques ont été normales sur 3 patients (9,4 %) et une anse sigmoïdienne deroulée est observée sur 5 (16 %). Deux malades (6,2 %) présentaient altération de la motilité œsophagique et pathologie du côlon synchronique (1 dolicocôlon et 1 dolicomégacôlon) et 22 (68,1 %) altération colique isolée (19 dolicocôlon et 3 dolicomégacôlon). L’étude radiologique digestive est seulement nécessaire sur les patients avec maladie de Chagas qui présentent symptomatologie et l’affection colique est la plus fréquente.

Chagas’ disease represents one of the main causes of mortality in Latin America and is becoming a relevant public health problem in EEUU and Europe because of the migratory movements. About one third of Chagas infected people develop a severe and potentially lethal cardiac dysfunction. Early identification of myocardium damage in asymptomatic patients (undetermined phase) would be very important for risk stratification and treatment. Our aim was to establish the usefulness of diastolic function measurement and the implementation of Doppler tissue imaging (DTI) techniques to identify patients with early myocardium damage. Thirty-one patients were studied; including 21 recent diagnosed asymptomatic chagasic patients and 10 non infected control individuals. All patients were assessed with a conventional 2D-echocardiography with diastolic function analysis and images acquisition for applying DTI. Comparisons of continuous variables between two groups were performed by T-test analysis or the Mann-Whitney U test according to normality. Conventional 2D-echocardiogram showed normality of left ventricular (LV) dimensions and LV ejection fraction for all 31 patients, without differences between both groups. However, chagasic patients presented a statistically significant lengthening of the deceleration time of early diastolic filling (DT), a higher left atrium volume (LAV) and a reduced early diastolic mitral annular velocity (Em) comparing to controls individuals. When evaluating the systolic velocity of longitudinal contractility, DTI showed a trend to lower systolic velocity at inferior and anterior walls (table). In patients with Chagas’ disease who are in the undetermined phase, LA volumes and diastolic dysfunction allowed to identify early cardiac abnormalities. Doppler tissue imaging might also be a potentially useful tool for detecting incipient myocardial alteration in this context.