Benznidazol en adultos con infección crónica por trypanosoma cruzy, con/sin patología demostrada / Benznidazole in adults with chronic infection by Trypanosoma cruzy, with / without proven pathology

CONTEXTO: La enfermedad de Chagas o tripanosomiasis americana es una parasitosis sistémica crónica, de transmisión vectorial y endémica. La infección por T. cruzi evoluciona en dos fases: aguda y crónica. El objetivo del tratamiento en la fase aguda es reducir la parasitemia. Durante la fase crónica, la infección es detectable por métodos serológicos y moleculares. El 30% de las fases crónicas evolucionan a patología demostrable. La eficacia de los tripanocidas para la fase crónica en relación a la patología cardíaca que se desarrolla es controversial, y constituye un punto de incertidumbre en la decisión clínica. El tratamiento tripanocida está constituido por dos drogas: Benznidazol y Nifurtimox. El tratamiento debe prolongarse por 60 días y los efectos adversos son frecuentes, sobre todo con la mayor edad de los pacientes. OBJETIVO: Evaluar eficacia y seguridad de benznidazol en el tratamiento de la miocardiopatía chagásica en pacientes con chagas crónico. METODOLOGÍA: Se formuló una pregunta P.I.C.O. con la siguiente población como foco: pacientes 19- 55 años con chagas crónico (serología positiva) con o sin patología cardíaca demostrada, dado que en la provincia de Mendoza, por su situación epidemiológica respecto a Chagas, se plantea por parte los equipos de salud la necesidad de incorporar el tratamiento médico ya que los pacientes además sufren estigmatización entre otras cosas, por la presencia de la enfermedad. Se realizó una búsqueda electrónica de publicaciones en idiomas inglés y español. Se priorizó en ensayos clínicos randomizados, revisiones sistemáticas, metanálisis y Evaluaciones económicas, Guías de práctica clínica e Informes breves o completos de T.S. El Comité Provincial de Tecnologías Sanitarias (CoPTeS) en reunión plenaria convocó a infectólogos de los hospitales de Mendoza, a fin de presentar los hallazgos y conocer su perspectiva. EL CoPTeS ha considerado que en lo relativo a impacto en la Salud Pública, dado que el perfil epidemiológico de la enfermedad de Chagas a cambiado en Argentina y en Mendoza, con la transmisión congénita como la principal vía de incidencia, sobre la transfusional y la vectorial, la atención de pacientes serológicos positivos en el rango de 19- 50 años, permitiría disminuir la incidencia. CONCLUSIONES: EL CoPTeS sugiere la indicación e incorporación de Benznidazol en el tratamiento de los pacientes con Chagas crónico en la provincia de Mendoza bajo todos los criterios del presente informe: pacientes de 19-55 años de edad con Chagas crónico sin daño cardíaco específico determinado por prueba de laboratorio (ELISA ó IFI ) y que hayan recibido de su médico tratante adecuada información sobre los efectos y riesgos del tratamiento, mediante: establecimiento de un proceso de decisiones compartidas acerca del tratamiento y sus efectos (documentando en historia clínica), acuerden un seguimiento estricto del paciente durante el tratamiento (semanal), suscriban y reciban una Hoja de información al paciente y Formulario de Consentimiento Informado; pacientes mujeres en edad fértil no embarazadas, que se encuentren en fase crónica de la infección, conformar además un Registro Provincial de los pacientes en sistema adecuado a tal fin (electrónico), especificando respuesta al tratamiento y variables de seguridad y eficacia.(AU)

Nifurtimox versus benznidazole or placebo for asymptomatic Trypanosoma cruzi infection (Equivalence of Usual Interventions for Trypanosomiasis - EQUITY): study protocol for a randomised controlled trial.

BACKGROUND: Either benznidazole (BZN) or nifurtimox (NFX) is recommended as equivalent to treat Trypanosoma cruzi infection. Nonetheless, supportive data from randomised trials is limited to individuals treated with BZN in southern cone countries of Latin America. METHODS: The goal of this randomised, concealed, blind, parallel-group trial is to inform the trypanocidal efficacy and safety of NFX and its equivalence to BZN among individuals with T. cruzi positive serology (TC+). Eligible individuals are TC+, 20-65 years old, with no apparent symptoms/signs or uncontrolled risk factors for cardiomyopathy and at negligible risk of re-infection. Consenting individuals (adherent to a 10-day placebo run-in phase) receive a 120-day BID blinded treatment with NFX, BZN or matching placebo (2:2:1 ratio). The four active medication arms include (1) a randomly allocated sequence of 60-day, conventional-dose (60CD) regimes (BZN 300 mg/day or NFX 480 mg/day, ratio 1:1), followed or preceded by a 60-day placebo treatment, or (2) 120-day half-dose (120HD) regimes (BZN 150 mg/day or NFX 240 mg/day, ratio 1:1). The primary efficacy outcome is the proportion of participants testing positive at least once for up to three polymerase chain reaction (PCR) assays (1 + PCR) 12-18 months after randomisation. A composite safety outcome includes moderate to severe adverse reactions, consistent blood marker abnormalities or treatment abandons. The trial outside Colombia (expected to recruit at least 60% of participants) is pragmatic; it may be open-label and not include all treatment groups, but it must adhere to the randomisation and data administration system and guarantee a blinded efficacy outcome evaluation. Our main comparisons include NFX groups with placebo (for superiority), NFX versus BZN groups and 60CD versus 120HD groups (for non-inferiority) and testing for the agent-dose and group-region interactions. Assuming a 1 + PCR ≥ 75% in the placebo group, up to 25% among BZN-treated and an absolute difference of up to ≥ 25% with NFX to claim its trypanocidal effect, 60-80 participants per group (at least 300 from Colombia) are needed to test our hypotheses (80-90% power; one-sided alpha level 1%). DISCUSSION: The EQUITY trial will inform the trypanocidal effect and equivalence of nitroderivative agents NFX and BZN, particularly outside southern cone countries. Its results may challenge current recommendations and inform choices for these agents. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02369978 . Registered on 24 February 2015.

Therapeutic drug monitoring of benznidazole and nifurtimox: a systematic review and quality assessment of published clinical practice guidelines

Abstract The pharmacological management of adults with chronic-phase Chagas disease is challenging despite it being the recent focus of extensive research. One of the challenges in the current clinical practice guidelines (CPGs) landscape is the existence of non-evidence-based recommendations for the use of laboratory tests in treatment monitoring. This study aimed to systematically assess the quality and consistency of recommendations of CPGs on the pharmacological management of adults with chronic-phase Chagas disease. Systematic literature searches were conducted in MEDLINE, EMBASE, SciELO and Google to identify all published CPGs relevant to the pharmacological management of Chagas disease, between January 2010 and March 2016. Three independent reviewers assessed the quality of each CPG using the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. A total of five CPGs were included and the overall quality of the guidelines for therapeutic drug monitoring of Chagas disease was moderate-to-low. There was considerable variation in the quality of the CPGs across the AGREE II domains. The domains of scope/purpose, stakeholder involvement, and clarity of presentation were rated well, and the domains of applicability and editorial independence received poor ratings. This review showed that the methodological quality of CPGs for Chagas disease was generally inappropriate, and there was no explicit link between the best available evidence and current recommendations.

Access to benznidazole for Chagas disease in the United States-Cautious optimism?

Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism.

Therapeutic drug monitoring of benznidazole and nifurtimox: a systematic review and quality assessment of published clinical practice guidelines.

The pharmacological management of adults with chronic-phase Chagas disease is challenging despite it being the recent focus of extensive research. One of the challenges in the current clinical practice guidelines (CPGs) landscape is the existence of non-evidence-based recommendations for the use of laboratory tests in treatment monitoring. This study aimed to systematically assess the quality and consistency of recommendations of CPGs on the pharmacological management of adults with chronic-phase Chagas disease. Systematic literature searches were conducted in MEDLINE, EMBASE, SciELO and Google to identify all published CPGs relevant to the pharmacological management of Chagas disease, between January 2010 and March 2016. Three independent reviewers assessed the quality of each CPG using the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. A total of five CPGs were included and the overall quality of the guidelines for therapeutic drug monitoring of Chagas disease was moderate-to-low. There was considerable variation in the quality of the CPGs across the AGREE II domains. The domains of scope/purpose, stakeholder involvement, and clarity of presentation were rated well, and the domains of applicability and editorial independence received poor ratings. This review showed that the methodological quality of CPGs for Chagas disease was generally inappropriate, and there was no explicit link between the best available evidence and current recommendations.

Chagas disease and transfusion medicine: a perspective from non-endemic countries.

In the last decades, increasing international migration and travel from Latin America to Europe have favoured the emergence of tropical diseases outside their "historical" boundaries. Chagas disease, a zoonosis endemic in rural areas of Central and South America represents a clear example of this phenomenon. In the absence of the vector, one of the potential modes of transmission of Chagas disease in non-endemic regions is through blood and blood products. As most patients with Chagas disease are asymptomatic and unaware of their condition, in case of blood donation they can inadvertently represent a serious threat to the safety of the blood supply in non-endemic areas. Since the first cases of transfusion-transmitted Chagas disease were described in the last years, non-endemic countries began to develop ad hoc strategies to prevent and control the spread of the infection. United States, Spain, United Kingdom and France first recognised the need for Trypanosoma cruzi screening in at-risk blood donors. In this review, we trace an up-to-date perspective on Chagas disease, describing its peculiar features, from epidemiological, pathological, clinical and diagnostic points of view. Moreover, we describe the possible transmission of Chagas disease through blood or blood products and the current strategies for its control, focusing on non-endemic areas.

Access to care for Chagas disease in the United States: a health systems analysis.

There are 300,000 estimated cases of Chagas disease in the United States but limited data on access to care. This study analyzed trends in access to care for Chagas disease in the United States and assessed the national and state barriers to access. Data on cases in blood donors and drug releases were obtained from the AABB (formerly American Association of Blood Banks) and U.S. Centers for Disease Control and Prevention (CDC), respectively. Semi-structured in-depth interviews were conducted with 30 key informants at the national level and in five states where treatment had been released. Interview responses were analyzed according to the health systems dimensions of regulation, financing, payment, organization, and persuasion. Data indicate that 1,908 cases were identified in the blood donation system from 2007 to 2013 and that CDC released 422 courses of benznidazole or nifurtimox during this period. The barriers to access at the national level include limited diagnostic and institutionalized referral and care processes, lack of financing for patient-care activities, and limited awareness and training among providers. This study demonstrates that access to treatment of Chagas disease in the United States is limited. The lack of licensing is only one of several barriers to access, highlighting the need for a health systems perspective when scaling up access to these essential medicines.

Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis.

Despite the fact that eflornithine was considered as the safer drug to treat human African trypanosomiasis (HAT) and has been freely available since 2001, the difficulties in logistics and cost burden associated with this drug meant that the toxic melarsoprol remained the drug of choice. The World Health Organization responded to the situation by designing a medical kit containing all the materials needed to use eflornithine, and by implementing a training and drugs distribution programme which has allowed a transition to this much safer treatment. The introduction of the combination of nifurtimox and eflornithine (NECT) has accelerated the shift from melarsoprol to the best treatment available, due to reduced dosage and treatment time for eflornithine that has significantly lessened the cost and improved the burden of logistics encountered during treatment and distribution. The decrease in the use of more dangerous but cheaper melarsoprol has meant a rise in the per patient cost of treating HAT. Although NECT is cheaper than eflornithine monotherapy, an unexpected consequence has been a continuing rise in the per patient cost of treating HAT. The ethical decision of shifting to the best available treatment imposes a financial burden on HAT control programmes that might render long-term application unsustainable. These factors call for continuing research to provide new safer and more effective drugs that are simple to administer and cheaper when compared to current drugs.

Costo-efectividad del screening y tratamiento de mujeres embarazadas y recién nacidos por trasmisión de chagas congénito / Cost-effectiveness of screening and treatment of pregnant women and newborns by transmission of congenital chagas

Objetivo: El objetivo principal del presente estudio es la evaluación costo-efectividad de introducir screening y tratamiento para la detección de la transmisión congénita de Chagas. En este sentido la intervención consiste primeramente en screening a mujeres embarazadas para detectar la enfermedad de Chagas y en el caso de confirmación diagnóstica se procede al screening del recién nacido de madres confirmadas como positivas. La intervención considera el tratamiento con Nifurtimox (NFX) y seguimiento de los recién nacidos positivos. Asimismo, se procede a tratar a la madre con posterioridad al período de lactancia materna. Metodología: En términos generales el estudio se ajusta a la metodología internacionalmente validada para la realización de evaluaciones económicas en salud (Drummond et al. 2005; Gold et al. 1996). Al mis- mo tiempo, adhiere a las recomendaciones locales sobre evaluaciones económicas, recientemente publicadas (MINSAL, 2011a). En este respecto cabe hacer notar que la Guía (en su versión de borrador) recomienda la consideración de la perspectiva del paciente, además del sistema de salud. En este sentido, lo ideal habría sido implementar recolección de costos (vía entrevistas o encuestas) directamente de los pacientes, pero dado las limitaciones de tiempo y recursos para este estudio, como así mismo la reciente modificación a la Guía en este sentido, no se estimaron los costos del paciente. Conclusión: La evaluación económica realizada, nos permite concluir que la estrategia de screening por enfermedad de Chagas en mujeres embarazadas de zonas endémicas resulta ser costo efectiva en relación a la situación actual sin screening.