Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized Phase II non-inferiority clinical trial.

BACKGROUND: Chagas disease (CD) continues to be a neglected infectious disease with one of the largest burdens globally. Despite the modest cure rates in adult chronic patients and its safety profile, benznidazole (BNZ) is still the drug of choice. Its current recommended dose is based on nonrandomized studies, and efficacy and safety of the optimal dose of BNZ have been scarcely analyzed in clinical trials. METHODS/DESIGN: MULTIBENZ is a phase II, randomized, noninferiority, double-blind, multicenter international clinical trial. A total of 240 patients with Trypanosoma CD in the chronic phase will be recruited in four different countries (Argentina, Brazil, Colombia, and Spain). Patients will be randomized to receive BNZ 150 mg/day for 60 days, 400 mg/day for 15 days, or 300 mg/day for 60 days (comparator arm). The primary outcome is the efficacy of three different BNZ therapeutic schemes in terms of dose and duration. Efficacy will be assessed according to the proportion of patients with sustained parasitic load suppression in peripheral blood measured by polymerase chain reaction. The secondary outcomes are related to pharmacokinetics and drug tolerability. The follow-up will be 12 months from randomization to end of study participation. Recruitment was started in April 2018. CONCLUSION: This is a clinical trial conducted for the assessment of different dose schemes of BNZ compared with the standard treatment regimen for the treatment of CD in the chronic phase. MULTIBENZ may help to clarify which is the most adequate BNZ regimen in terms of efficacy and safety, predicated on sustained parasitic load suppression in peripheral blood. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03191162. Registered on 19 June 2017.

Evaluación de la sensibilidad del antígeno recombinante sapa en el diagnóstico temprano de la infección congénita por trypanosoma cruzi / Evaluation of the sensitivity of recombinant sapa antigen in the early diagnosis of congenital infection by trypanosoma cruzi

INTRODUCCIÓN En Argentina nacen por año 800-1000 niños infectados por Trypanosoma cruzi por vía congénita. El diagnóstico de referencia actual implica un seguimiento hasta los 10 meses de vida, período en el cual hay una pérdida del 50-75% de los casos por no concurrencia a control, por diferentes motivos. A su vez, los niños diagnosticados y tratados antes del año de vida tienen una posibilidad de éxito del 99%. OBJETIVOS Evaluar una técnica de serología (ELISA) para detectar anticuerpos (Ac) Antisana (shed acute phase antigen), aplicable en los primeros meses de vida del niño y de fácil implementación en el nivel de atención primaria de salud. MÉTODOS Se obtuvieron muestras de 177 madres y sus hijos en tres períodos según la edad del niño A) <3 meses de vida, B) 3-7 meses, C) ≥10 meses. Se analizaron las muestras por las técnicas patrón oro (PO) y por ELISA-SAPA en 64 binomios que completaron el seguimiento. RESULTADOS De 96 madres analizadas, el 64,6% fueron reactivas para Ac anti-SAPA. Entre los 84 niños con seguimiento completo, se observó una tasa de transmisión congénita de 4,8% por técnicas PO. Se analizaron 64 niños por ELISA-SAPA, y del análisis comparativo con las técnicas PO la asignación de infección fue concordante en 57 casos (85,9%) y en 7 casos (14,1%) fue discordante. Se incluyó un caso de infección congénita, detectado a la edad de 10 días por micrométodo y con ELISA-SAPA reactivo. Entre los casos de no coincidencia SAPA-PO hubo 2 falsos positivos, 4 dudosos no infectados y 1 reactivo no concluyente por serología convencional a los 10 meses. No se observó ningún falso negativo por ELISA-SAPA (caso infectado no detectado). Los casos dudosos y falsos positivos eran niños de 3-4 meses con madres con alta carga de Ac anti-SAPA, por lo que se plantea revisar ciertos parámetros en la aplicación de la técnica.d DISCUSIÓN La técnica ELISA-SAPA mostró resultados promisorios para su aplicación a edades tempranas y en el nivel de atención primaria de salud.

Evaluación del impacto de la participación comunitaria en la vigilancia de Chagas / Evaluation of the impact of community participation in the surveillance of Chagas

El objetivo del presente estudio es efectuar el análisis del impacto de la vigilancia en sus diferentes modalidades en el control de la infección por T. cruzi y la densidad vectorial (Triatoma infestans). Material y métodos: El trabajo fue desarrollado en el Departamento de Capayán, en la provincia de Catamarca, Argentina. Se seleccionaron aleatoriamente 5 comunidades rurales y 3 comunidades peri-urbanas para desarrollar el estudio. Indicadores utilizados: a) infestación domiciliaria en los meses 24, 48 y 96; y b) Infección por T.cruzi de menores de 14 años. Resultados: Se observa persistencia de triatomineos durante el periodo de seguimiento y cuando se comparan los datos del estudio de base (2007) con los obtenidos en el año 2009 y 2012 existe significancia estadística (p <0.04) entre áreas. Se capturaron 1.89 insectos/intradomicilio en áreas con vigilancia activa versus 5.21 insectos/intradomicilio en áreas donde la misma no existió. Se demuestra la existencia de infecciones recientes en niños menores de 4 años e hijos de mujeres negativas para T. cruzi en áreas sin vigilancia activa (3 niños). Conclusión: En la presente investigación se demuestra el impacto de la vigilancia activa en sus diferentes modalidades por la no existencia de casos nuevos vectoriales en el período de seguimiento. (AU)

The aim of this study is to perform the analysis of the impact of surveillance in its various forms in the control of infection by T. cruzi and vector density (Triatoma infestans). Material and Methods: The work was developed in the Department of Capayán, in the Province of Catamarca, Argentina. Eight rural communities were selected to develop the study. Indicators used: a) house infestation in 24 months, 48 and 96; b) T. cruzi infection in children under 14 years. Results: Persistence of triatomine It is observed during the monitoring period as the baseline study (2007) thus obtained in 2009 compared to 2012 there is statistical significance (p <0.04) between areas. 1.89 insect / intradomicile were captured in areas with active surveillance versus 5.21 insect/intradomicile in areas where it did not exist. The existence of recent infections in children under four years of negative women and children for T. cruzi in areas without active surveillance (3 children) is demonstrated. Conclusion: In this research, the impact of active surveillance in its various forms by Vector exists no new cases in the follow-up period shown. (AU)

Randomized trial of benznidazole for chronic Chagas' cardiomyopathy

BACKGROUND:The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven.METHODS:We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event.RESULTS:The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons)...

Towards a paradigm shift in the treatment of chronic Chagas disease.

Treatment for Chagas disease with currently available medications is recommended universally only for acute cases (all ages) and for children up to 14 years old. The World Health Organization, however, also recommends specific antiparasite treatment for all chronic-phase Trypanosoma cruzi-infected individuals, even though in current medical practice this remains controversial, and most physicians only prescribe palliative treatment for adult Chagas patients with dilated cardiomyopathy. The present opinion, prepared by members of the NHEPACHA network (Nuevas Herramientas para el Diagnóstico y la Evaluación del Paciente con Enfermedad de Chagas/New Tools for the Diagnosis and Evaluation of Chagas Disease Patients), reviews the paradigm shift based on clinical and immunological evidence and argues in favor of antiparasitic treatment for all chronic patients. We review the tools needed to monitor therapeutic efficacy and the potential criteria for evaluation of treatment efficacy beyond parasitological cure. Etiological treatment should now be mandatory for all adult chronic Chagas disease patients.

Frequency of the congenital transmission of Trypanosoma cruzi: a systematic review and meta-analysis.

BACKGROUND: Chagas disease is caused by the parasite Trypanosoma cruzi and is endemic in much of Latin America. With increased globalisation and immigration, it is a risk in any country, partly through congenital transmission. The frequency of congenital transmission is unclear. OBJECTIVE: To assess the frequency of congenital transmission of T. cruzi. SEARCH STRATEGY: PubMed, Journals@Ovid Full Text, EMBASE, CINAHL, Fuente Academica and BIREME databases were searched using seven search terms related to Chagas disease or T. cruzi and congenital transmission. SELECTION CRITERIA: The inclusion criteria were the following: Dutch, English, French, Portuguese or Spanish language; case report, case series or observational study; original data on congenital T. cruzi infection in humans; congenital infection rate reported or it could be derived. This systematic review included 13 case reports/series and 51 observational studies. DATA COLLECTION AND ANALYSIS: Two investigators independently collected data on study characteristics, diagnosis and congenital infection rate. The principal summary measure--the congenital transmission rate--is defined as the number of congenitally infected infants divided by the number of infants born to infected mothers. A random effects model was used. MAIN RESULTS: The pooled congenital transmission rate was 4.7% (95% confidence interval: 3.9-5.6%). Countries where T. cruzi is endemic had a higher rate of congenital transmission compared with countries where it is not endemic (5.0% versus 2.7%). CONCLUSIONS: Congenital transmission of Chagas disease is a global problem. Overall risk of congenital infection in infants born to infected mothers is about 5%. The congenital mode of transmission requires targeted screening to prevent future cases of Chagas disease.

Trypanosoma cruzi discrete typing units in Chagas disease patients from endemic and non-endemic regions of Argentina.

Genetic diversity of Trypanosoma cruzi may play a role in pathogenesis of Chagas disease forms. Natural populations are classified into 6 Discrete Typing Units (DTUs) Tc I-VI with taxonomical status. This study aimed to identify T. cruzi DTUs in bloodstream and tissue samples of Argentinean patients with Chagas disease. PCR-based strategies allowed DTU identification in 256 clinical samples from 239 Argentinean patients. Tc V prevailed in blood from both asymptomatic and symptomatic cases and Tc I was more frequent in bloodstream, cardiac tissues and chagoma samples from immunosuppressed patients. Tc II and VI were identified in a minority of cases, while Tc III and Tc IV were not detected in the studied population. Interestingly, Tc I and Tc II/VI sequences were amplified from the same skin biopsy slice from a kidney transplant patient suffering Chagas disease reactivation. Further data also revealed the occurrence of mixed DTU populations in the human chronic infection. In conclusion, our findings provide evidence of the complexity of the dynamics of T. cruzi diversity in the natural history of human Chagas disease and allege the pathogenic role of DTUs I, II, V and VI in the studied population.

Characterization and epidemiologic subtyping of Shiga toxin-producing Escherichia coli strains isolated from hemolytic uremic syndrome and diarrhea cases in Argentina.

Argentina has a high incidence of hemolytic uremic syndrome (HUS); 12.2 cases per 100,000 children younger than 5 years old were reported in 2002. Shiga toxin (Stx)-producing Escherichia coli (STEC) is the primary etiologic agent of HUS, and STEC O157 is the predominant serogroup isolated. The main objective of the present work was to establish the phenotypic and genotypic characteristics of the STEC strains in general isolated from Argentine children during a prospective study and the clonal relatedness of STEC O157:H7 strains using subtyping techniques. One hundred and three STEC strains isolated from 99 children were included. The phenotypic and genotypic features were established, and a polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) was performed to determine stx2 variants. The clonal relatedness of E. coli O157 isolates was established by phage typing and pulsed-field gel electrophoresis (PFGE). The 103 STEC strains belonged to 18 different serotypes, and 59% were of serotype O157:H7. Stx2 was identified in 90.3%, and stx1 in 9.7%. Among the 61 STEC O157 strains, 93.4% harbored the stx2/stx2vh-a genes; PT4 (39.3%) and PT2 (29.5%) were the predominant phage types. Using PFGE with the enzyme XbaI, a total of 41 patterns with at least 80% similarity were identified, and seven clusters with identical profiles were established. Some of the clusters were further split by PFGE using BlnI as the second enzyme. Isolates with indistinguishable PFGE patterns were with one exception also indistinguishable by phage typing and stx genotyping. These findings confirmed that some isolates were genetically related. However, no epidemiological linkages were identified. STEC strains with different genotypes and belonging to diverse serotypes were isolated in Argentina. Some STEC O157 strains could not be distinguished by applying subtyping techniques such as PFGE and phage typing.

Transmisión congénita del Trypanosoma cruzi en Argentina / Congenital transmission of Trypanosoma cruzi infection in Argentina

Congenital transmission of Trypanosoma cruzi infection in Argentina has being increasing its relative importance with control of vectorial and transfusional transmission growth. It is for this reason that vertical transmission is seen, in the future, as a continuous source of infected newborns, even with vectorial and transfusional transmission completely controlled. Preventing vertical transmission of T.cruzi is not possible, but it can be precociously detected, permitting mother and child to be incorporated into the medical attention system, and so allowing the newborns treatment with practically 100% efficacy. It is estimated that between 800 and 1700 children infected with T. cruzi by congenital transmission are born in Argentina, per year. The implementation of an early strategy of detection for an effective and opportune treatment acquires great relevance as a Public Health measure.