Strategies to enhance access to diagnosis and treatment for Chagas disease patients in Latin America

Introduction: Chagas disease, caused by infection with the parasite Trypanosoma cruzi, represents a huge public health problem in the Americas, where millions of people are affected. Despite the availability of two drugs against the infection (benznidazole and nifurtimox), multiple factors impede their effective usage: (1) gaps in patient and healthcare provider awareness; (2) lack of access to diagnosis; (3) drug toxicity and absence of treatment algorithms to address adverse effects; (4) failures in drug supply and distribution; and (5) inconsistent drug efficacy against the symptomatic chronic stage. Areas covered: We review new approaches and technologies to enhance access to diagnosis and treatment to reduce the disease burden. We also provide an updated picture of recently published and ongoing anti-T. cruzi drug clinical trials. Although there has been progress improving the research and development (R&D) landscape, it is unclear whether any new treatments will emerge soon. Literature search methodologies included multiple queries to public databases and the use of own-built libraries. Expert opinion: Besides R&D, there is a major need to continue awareness and advocacy efforts by patient associations, local and national governments, and international agencies. Overall, health systems strengthening is essential to ensure vector control commitments, as well as patient access to diagnosis and treatment

The chagas disease study landscape: A systematic review of clinical and observational antiparasitic treatment studies to assess the potential for establishing an individual participant-level data platform

Background: Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects ~6–7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing individual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. Methodology/Principal findings This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials. gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251(1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome; parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30–180] for the first assessment, 180 days [IQR: 60–500] for second, and 270 days [IQR: 18–545] for the third assessment. Conclusions/Significance This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable indepth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection.Fil: Maguire, Brittany J.. University of Oxford; Reino UnidoFil: Dahal, Prabin. University of Oxford; Reino UnidoFil: Rashan, Sumayyah. University of Oxford; Reino UnidoFil: Ngu, Roland. University of Oxford; Reino UnidoFil: Boon, Anca. University of Oxford; Reino UnidoFil: Forsyth, Colin. No especifíca;Fil: Strub Wourgraft, Nathalie. No especifíca;Fil: Chatelain, Eric. No especifíca;Fil: Barreira, Fabiana. No especifíca;Fil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Guerin, Philippe J.. University of Oxford; Reino Unid

Fixed vs adjusted-dose benznidazole for adults with chronic Chagas disease without cardiomyopathy: A systematic review and meta-analysis

Chagas disease is a neglected disease that remains a public health threat, particularly in Latin America. The most important treatment options are nitroimidazole derivatives, such as nifurtimox and benznidazole (BZN). Some studies suggest that for adults seropositive to T. cruzi but without clinically evident chronic Chagas cardiomyopathy (CCC), a simple fixed-dose scheme of BZN could be equivalent to a weight-adjusted dose. We compared the efficacy and safety of a fixed dose of BZN with an adjusted dose for T. cruzi seropositive adults without CCC. We used the Cochrane methods, and reported according to the PRISMA statement. We included randomized controlled trials (RCTs) allocating participants to fixed and/or adjusted doses of BZN for T. cruzi seropositive adults without CCC. We searched (December 2019) Cochrane, MEDLINE, EMBASE, LILACS, Clinicaltrials.gov, and International Clinical Trials Registry Platform (ICTRP), and contacted Chagas experts. Selection, data extraction, and risk of bias assessment, using the Cochrane tool, were performed independently by pairs of reviewers. Discrepancies were solved by consensus within the team. Primary outcomes were parasite-related outcomes and efficacy or patient-related safety outcomes. We conducted a meta-analysis using RevMan 5.3 software and used GRADE summary of finding tables to present the certainty of evidence by outcome. We identified 655 records through our search strategy and 10 studies (four of them ongoing) met our inclusion criteria. We did not find any study directly comparing fixed vs adjusted doses of BZN, however, some outcomes allowed subgroup comparisons between fixed and adjusted doses of BZN against placebo. Moderate-certainty evidence suggests no important subgroup differences for positive PCR at one year and for three safety outcomes (drug discontinuation, peripheral neuropathy, and mild rash). The same effect was observed for any serious adverse events (low-certainty evidence). All subgroups showed similar effects (I2 0% for all these subgroup comparisons but 32% for peripheral neuropathy), supporting the equivalence of BZN schemes. We conclude that there is no direct evidence comparing fixed and adjusted doses of BZN. Based on low to very low certainty of evidence for critical clinical outcomes and moderate certainty of evidence for important outcomes, fixed and adjusted doses may be equivalent in terms of safety and efficacy. An individual patient data network meta-analysis could better address this issue.Fil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Barreira, Fabiana. No especifíca;Fil: Perelli, Lucas. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bardach, Ariel Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Gascón, Joaquim. Hospital Clínic Barcelona; EspañaFil: Molina, Israel. Hospital Universitari Vall d’Hebron Research Institute; EspañaFil: Morillo, Carlos. McMaster University; CanadáFil: Prado, Nilda. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Riarte, Adelina Rosa. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Torrico, Faustino. Universidad Mayor de San Simón; BoliviaFil: Ribeiro, Isabela. No especifíca;Fil: Villarreal, Juan Carlos. Universidad Autónoma de Bucaramanga; ColombiaFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentin

New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial

Background: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. Methods: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18–50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. Findings: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73–99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73–99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64–95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65–95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67–97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64–95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. Interpretation: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. Funding: Drugs for Neglected Diseases initiative (DNDi). Translation: For the Spanish translation of the abstract see Supplementary Materials section.Fil: Torrico, Faustino. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; Bolivia. Universidad Mayor de San Simón; BoliviaFil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España. Universidad de Barcelona; EspañaFil: Barreira, Fabiana. DNDi Latin America; BrasilFil: Blum, Bethania. DNDi Latin America; BrasilFil: Almeida, Igor C. University of Texas at El Paso; Estados UnidosFil: Alonso Vega, Cristina. DNDi Latin America; Brasil. Instituto de Salud Global de Barcelona; EspañaFil: Barboza, Tayná. DNDi Latin America; BrasilFil: Bilbe, Graeme. Drugs For Neglected Diseases Initiative; SuizaFil: Correia, Erika. DNDi Latin America; BrasilFil: Garcia, Wilson. Universidad Mayor de San Simón; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente ; BoliviaFil: Ortiz, Lourdes. Universidad Autónoma Juan Misael Saracho; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; BoliviaFil: Parrado, Rudy. Universidad Mayor de San Simón; BoliviaFil: Ramirez Gomez, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaFil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Vaillant, Michel. Luxembourg Institute Of Health; LuxemburgoFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. DNDi Latin America; Brasi

Response to `letter to the editor: 'Strategies to enhance access to diagnosis and treatment for Chagas disease patients in Latin America'´

Dear Editor, We appreciate the comments on our recent review article about strategies to enhance access to diagnosis and treatment for Chagas disease patients [1,2]. We also appreciate the opportunity to respond to them, and expand the discussion on this crucial topic given that it is estimated that no more than 1% of the infected population by Trypanosoma cruzi (of ~7 million people) ultimately get access to treatment [3]. The letter comments mainly refer to two of the sections of the review article: diagnostics to detect the infection (section 2), and treatment opportunities and possibilities (section 7)

Estudo prospectivo comparativo de sistema especialista de prescrição médica na redução de erro e sobrecarga de trabalho médico

Erros médicos preveníveis(EMP) em hospitais excedem às mortes causadas por acidentes \ud automobilísticos, câncer de mama e AIDS. O Institute of Medicine estima até 98.000 mortes \ud causadas por EMP. O risco é aumentado quando os EMPs ocorrem em pacientes criticamente \ud enfermos ou com medicações que variam com o peso do paciente. A demora da primeira \ud prescrição é uma preocupação em UTI. Fadiga e sobrecarga podem comprometer a segurança \ud numa UTI pediátrica. Objetivos: Comparar a funcionalidade de um Sistema Especialista(SE) \ud experimental com a prescrição médica convencional Materiais/Métodos: Após termo de \ud consentimento, pediatras de um hospital universitário são convidados a fazer a prescrição de 10 \ud itens medicamentosos completos(soro de manutenção, adenosina, adrenalina, atropina, \ud difenilhidantoína, vancomicina , ceftadizima, anfotericina_B, dobutamina, fentanil) para uma \ud criança hipotética. Comparou-se a prescrição convencional com a prescrição feita no SE, após \ud um treinamento prévio de 2 minutos. Uma equipe(médicos, enfermeiras e farmacêuticas) \ud avaliaram os EMPs. Comparações feitas pelo X2, teste exato de fisher, teste t-student pareado ou \ud Wilconson, quando aplicáveis. Significância considerada: p<0.05. Resultados:13 médicos \ud residentes e 7 assistentes participaram do estudo com tempo médio de formação de 10,1+/-9 anos \ud . Constatados 57 casos de EMP (9 ilegibilidades, 23 omissões, 6 erros de dose, 14 erros de \ud diluição e 5 erros de velocidade de infusão) pela prescrição convencional comparado com 1 \ud duplicação de medicação na prescrição por SE(p<0,001). O tempo médio de prescrição dos 10 \ud medicamentos utilizando a abordagem ONE TOUCH do SE foi de 22,4 +/- 5,6 segundos_[13-36 \ud segundos] e estava significantemente abaixo do tempo de prescrição convencional (média:557 +/- \ud 164 segundos; p=0,00088). O tempo médio de prescrição com SE foi 27 vezes(IC95% 21,5-\ud 32,5)) mais rápido que a convencional com economia de 89,1 minutos em uma UTI de 10 leitos. \ud Conclusão:Embora não infalível, o uso de SE requer pouco tempo de treinamento e resulta em \ud significante diminuição de erros e sobrecarga de trabalho

II Diretriz Brasileira de Transplante Cardíaco

Universidade de São Paulo Faculdade de Medicina Hospital das ClínicasIIHospital de Messejana Dr. Carlos Alberto Studart GomesUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaInstituto Dante Pazzanese de CardiologiaUniversidade Federal de Minas Gerais Hospital das ClínicasFaculdade de Medicina de São José do Rio PretoPontifícia Universidade Católica do ParanáIHospital Israelita Albert EinsteinInstituto Nacional de Cardiologia, Fundação Universitária do Rio Grande do Sul Instituto de CardiologiaReal e Benemérita Sociedade de Beneficência Portuguesa, São PauloHospital Pró-Cardíaco do Rio de JaneiroSanta Casa do Rio de JaneiroUNIFESP, EPMSciEL