Characterization of Latin American migrants at risk for Trypanosoma cruzi infection in a non-endemic setting. Insights into initial evaluation of cardiac and digestive involvement.

BACKGROUND: Trypanosoma cruzi causes Chagas disease (CD), a potentially fatal disease characterized by cardiac disorders and digestive, neurological or mixed alterations. T. cruzi is transmitted to humans by the bite of triatomine vectors; both the parasite and disease are endemic in Latin America and the United States. In the last decades, population migration has changed the classic epidemiology of T. cruzi, contributing to its global spread to traditionally non-endemic countries. Screening is recommended for Latin American populations residing in non-endemic countries. METHODS: The present study analyzes the epidemiological characteristics of 2,820 Latin American individuals who attended the International Health Service (IHS) of the Hospital Clinic de Barcelona between 2002 and 2019. The initial assessment of organ damage among positive cases of T. cruzi infection was analyzed, including the results of electrocardiogram (ECG), echocardiogram, barium enema and esophagogram. RESULTS: Among all the screened individuals attending the clinic, 2,441 (86.6%) were born in Bolivia and 1,993 (70.7%) were female. Of individuals, 1,517 (81.5%) reported previous exposure to the vector, which is a strong risk factor associated with T. cruzi infection; 1,382 individuals were positive for T. cruzi infection. The first evaluation of individuals with confirmed T. cruzi infection, showed 148 (17.1%) individuals with Chagasic cardiomyopathy, the main diagnostic method being an ECG and the right bundle branch block (RBBB) for the most frequent disorder; 16 (10.8%) individuals had a normal ECG and were diagnosed of Chagasic cardiomyopathy by echocardiogram. CONCLUSIONS: We still observe many Latin American individuals who were at risk of T. cruzi infection in highly endemic areas in their countries of origin, and who have not been previously tested for T. cruzi infection. In fact, even in Spain, a country with one of the highest proportion of diagnosis of Latin American populations, T. cruzi infection remains underdiagnosed. The screening of Latin American populations presenting with a similar profile as reported here should be promoted. ECG is considered necessary to assess Chagasic cardiomyopathy in positive individuals, but echocardiograms should also be considered as a diagnostic approach given that it can detect cardiac abnormalities when the ECG is normal.

Benznidazole for the treatment of Chagas disease.

INTRODUCTION: Chagas disease affects 6-7 million people, mainly in the Americas, and benznidazole is one of the two therapeutic options available. Trypanocide treatment aims to eliminate the parasite from the body to prevent the establishment or progression of visceral damage, mainly cardiac and/or digestive. Remarkably, it helps interrupt vertical transmission when administered to women of childbearing age. AREAS COVERED: We discuss the basic and scarce data regarding chemical, pharmacokinetic, and pharmacodynamic structure. We also collect the most important data from previous phase II and III studies, as well as studies currently underway and upcoming. We reflect on the main indications for treatment and its challenges, such as the profile of adverse effects in adults, the pharmaceutical formulations, the search for reliable biomarkers, as well as regulatory aspects and access barriers. Alternative strategies such as shorter regimens, lower doses, and fixed doses are currently being evaluated to improve access and the safety profile of this treatment. EXPERT OPINION: Benznidazole is likely to continue to be the drug of choice for Chagas disease in the coming years. However, it would probably be with a different treatment scheme.

Emerging agents for the treatment of Chagas disease: what is in the preclinical and clinical development pipeline?

INTRODUCTION: Chagas disease treatment relies on the lengthy administration of benznidazole and/or nifurtimox, which have frequent toxicity associated. The disease, caused by the parasite Trypanosoma cruzi, is mostly diagnosed at its chronic phase when life-threatening symptomatology manifest in approximately 30% of those infected. Considering that both available drugs have variable efficacy by then, and there are over 6 million people infected, there is a pressing need to find safer, more efficacious drugs. AREAS COVERED: We provide an updated view of the path to achieve the aforementioned goal. From state-of-the-art in vitro and in vivo assays based on genetically engineered parasites that have allowed high throughput screenings of large chemical collections, to the unfulfilled requirement of having treatment-response biomarkers for the clinical evaluation of drugs. In between, we describe the most promising pre-clinical hits and the landscape of clinical trials with new drugs or new regimens of existing ones. Moreover, the use of monkey models to reduce the pre-clinical to clinical attrition rate is discussed. EXPERT OPINION: In addition to the necessary research on new drugs and much awaited biomarkers of treatment efficacy, a key step will be to generalize access to diagnosis and treatment and maximize efforts to impede transmission.

State-of-the-art in host-derived biomarkers of Chagas disease prognosis and early evaluation of anti-Trypanosoma cruzi treatment response.

Chagas disease is caused by infection with the parasite Trypanosoma cruzi, which might lead to a chronic disease state and drive to irreversible damage to the heart and/or digestive tract tissues. Endemic in 21 countries in the Americas, it is the neglected disease with a highest burden in the region. Current estimates point at ~6 million people infected, of which ~30% will progress onto the symptomatic tissue disruptive stage. There is no vaccine but there are two anti-parasitic drugs available: benznidazole and nifurtimox. However, their efficacy is variable at the chronic symptomatic stage and both have frequent adverse effects. Since there are no prognosis markers, drugs should be administered to all T. cruzi-infected individuals in the indeterminate and early symptomatic stages. Nowadays, there are no tests-of-cure either, which greatly undermines patients follow-up and the search of safer and more efficacious drugs. Therefore, the identification and validation of biomarkers of disease progression and/or treatment response on which to develop tests of prognosis and/or cure is a major research priority. Both parasite- and host-derived markers have been investigated. In the present manuscript we present an updated outlook of the latter.

Does Progressive Introduction of Benznidazole Reduce the Chance of Adverse Events in the Treatment of Chagas Disease?

In this retrospective cohort study, we aimed to assess whether introducing benznidazole at escalating doses reduces the probability of adverse events or treatment discontinuation compared with a full-dose scheme. We collected data from patients who had chronic Trypanosoma cruzi infection and underwent treatment from July 2008 to January 2017 in a referral center in Madrid. Dose was adjusted to body weight (5 mg/kg/day), with treatment introduction with full dose or escalating dose according to local consensus and protocols. Among the 62 patients treated, benznidazole was introduced at full dose in 28 patients and on escalating dose in the remaining 34. We found no statistical differences in the number of adverse events, treatment discontinuations, days of treatment, or sociodemographic profiles. There is insufficient evidence to support escalating dose as a strategy for reducing the adverse effects of benznidazole. Further research is needed to evaluate this approach.