Cost-effectiveness study of therapeutic approaches for mucosal leishmaniasis.

This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

Treatment of Childhood Brucellosis: A Systematic Review.

BACKGROUND: Proper treatment for brucellosis is crucial to eradicate the infection and prevent complications, but there is a notable gap in evidence for pediatric treatment. This study aims to address this gap by reviewing current literature, analyzing the efficacy and safety of brucellosis treatment in children, and identifying areas that require further investigation. METHODS: A systematic review, following preferred reporting items for systematic reviews and meta-analyses and Cochrane Handbook guidelines, assessed antimicrobial regimens' efficacy and safety for treating human brucellosis in children. Original human studies with clinical outcomes after drug therapy intervention for children up to 10 years were included. Searches were conducted in Medline, Embase, Cochrane Library and LILACS databases for studies indexed until March 6, 2023. Study selection, data extraction, and bias risk assessment were performed by pairs of reviewers. The quality assessment used Joanna Briggs Institute tools and grading of recommendations assessment, development and evaluation system. Data were analyzed using R software. RESULTS: A total of 1773 records were reviewed, yielding 11 eligible studies encompassing 1156 children. All included studies presented an observational design. The most reported treatment approaches included sulfamethoxazole-trimethoprim with rifampicin or aminoglycosides, with summarized failure rates of 2% (95% confidence interval: 0.0-0.49) and 13% (95% confidence interval: 0.06-0.29), respectively (very low certainty of evidence). Adverse events and time to defervescence were not reported. CONCLUSIONS: Sulfamethoxazole-trimethoprim + rifampicin were the most prescribed antibiotics for brucellosis for pediatrics. The study highlights the need for more research with robust designs, and emphasizes uncertainty regarding the efficacy of antimicrobial regimens, emphasizing the importance of further investigations to guide specific treatment protocols for this population.

Blood transfusion in the care of patients with visceral leishmaniasis: a review of practices in therapeutic efficacy studies.

Blood transfusion remains an important aspect of patient management in visceral leishmaniasis (VL). However, transfusion triggers considered are poorly understood. This review summarises the transfusion practices adopted in VL efficacy studies using the Infectious Diseases Data Observatory VL clinical trials library. Of the 160 studies (1980-2021) indexed in the IDDO VL library, description of blood transfusion was presented in 16 (10.0%) (n=3459 patients) studies. Transfusion was initiated solely based on haemoglobin (Hb) measurement in nine studies, combining Hb measurement with an additional condition (epistaxis/poor health/clinical instability) in three studies and the criteria was not mentioned in four studies. The Hb threshold range for triggering transfusion was 3-8 g/dL. The number of patients receiving transfusion was explicitly reported in 10 studies (2421 patients enrolled, 217 underwent transfusion). The median proportion of patients who received transfusion in a study was 8.0% (Interquartile range: 4.7% to 47.2%; range: 0-100%; n=10 studies). Of the 217 patients requiring transfusion, 58 occurred before VL treatment initiation, 46 during the treatment/follow-up phase and the time was not mentioned in 113. This review describes the variation in clinical practice and is an important initial step in policy/guideline development, where both the patient's Hb concentration and clinical status must be considered.

Promoting safe and appropriate use of miltefosine to treat tegumentary leishmaniasis in Brazil: A best practice quality improvement project.

INTRODUCTION: Miltefosine is a new drug that was recently approved for the treatment of tegumentary leishmaniasis (TL) by the Brazilian health system. It has a teratogenic potential and requires follow-up of patients undergoing treatment. Improving compliance with best practices is essential to ensure the safe and appropriate use of this drug. OBJECTIVE: This project aimed to implement best practices for the safe and appropriate use of miltefosine in the treatment of TL in the state of Minas Gerais, Brazil. METHODS: This project was guided by the JBI Evidence Implementation Framework. Five best practice criteria were established based on the best available evidence. A baseline audit was conducted to measure current practice against best practice. Barriers to best practice were then identified and a follow-up audit was conducted to evaluate changes after the implementation of improvement strategies. Two sites were analyzed: a leishmaniasis reference service in Belo Horizonte, the capital of Minas Gerais, and the 28 regional offices. RESULTS: The baseline audit evaluated data from 197 miltefosine requests distributed across 13 regional sites. All requests from the reference service were compliant (100%). This is in contrast to the 60% compliance rate at the regional offices. The improvement strategies included intensifying direct communication with the regional health professionals, which increased the average compliance rate to 79.5%, 6 months after the interventions were introduced. CONCLUSION: This best practice implementation project effectively increased the compliance rate for the audited procedures. Communication from the reference site with the regional health professionals successfully increased compliance with best practices and promoted the safe and appropriate use of miltefosine. These strategies should analyzed and applied to improve other programs. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A184.

A link between circulating immune complexes and acute kidney injury in human visceral leishmaniasis.

Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania infantum. Clinically, VL evolves with systemic impairment, immunosuppression and hyperactivation with hypergammaglobulinemia. Although renal involvement has been recognized, a dearth of understanding about the underlying mechanisms driving acute kidney injury (AKI) in VL remains. We aimed to evaluate the involvement of immunoglobulins (Igs) and immune complexes (CIC) in the occurrence of AKI in VL patients. Fourteen VL patients were evaluated between early treatment and 12 months post-treatment (mpt). Anti-Leishmania Igs, CIC, cystatin C, C3a and C5a were assessed and correlated with AKI markers. Interestingly, high levels of CIC were observed in VL patients up to 6 mpt. Concomitantly, twelve patients met the criteria for AKI, while high levels of cystatin C were observed up to 6 mpt. Plasmatic cystatin C was positively correlated with CIC and Igs. Moreover, C5a was correlated with cystatin C, CIC and Igs. We did not identify any correlation between amphotericin B use and kidney function markers in VL patients, although this association needs to be further explored in subsequent studies. Our data reinforce the presence of an important renal function impairment during VL, suggesting the involvement of Igs, CIC, and C5a in this clinical condition.

Efficacy of antibiotic prophylaxis to preventing brucellosis in accidental exposure: A systematic review.

BACKGROUND: Antibiotic prophylaxis to prevent brucellosis after accidental exposure to Brucella is an important topic in public health. This study aimed to systematically review the efficacy of antibiotic prophylaxis following accidental exposure to Brucella in preventing human brucellosis disease. METHODS: The study protocol was registered in PROSPERO (CRD42023456812). The outcomes included the incidence of brucellosis disease, adverse events rate, and antibiotic prophylaxis adherence. A comprehensive literature search, conducted until 20 November, 2023, involved Medline, Embase, Cochrane Library, and LILACS databases. Descriptive analysis and meta-analysis using R software were performed, risk of bias was assessed using JBI Critical appraisal tools, and certainty of evidence was assessed using the GRADE tool. RESULTS: Among 3102 initially identified records, eight studies involving 97 individuals accidentally exposed, all focused on high-risk accidental exposure to Brucella in laboratory settings, were included in the review. All studies reported the prophylactic treatment comprising doxycycline at a dosage of 100 mg twice daily, combined with rifampicin at 600 mg, both administered over 21 days. Prophylaxis adherence was reported in 86% of cases, and incidence of brucellosis post-treatment was 0.01. Adverse events, mainly gastrointestinal, occurred in 26% of cases. Critical appraisal revealed limitations in reporting demographics and clinical information. The certainty of evidence was rated as 'very low,' emphasising the need for caution in interpreting the observed outcomes due to study design constraints and the absence of comparative groups. CONCLUSIONS: PEP is an alternative practice reported in the literature, used in accidents with high-risk exposure to Brucella. The currently available evidence of the efficacy of antibiotic prophylaxis is insufficient to support a recommendation for or against the widespread use of antibiotic prophylaxis, so caution is needed in interpreting results due to the very low certainty of evidence, primarily stemming from case series and lack of comparative groups.

Local amphotericin B therapy for Cutaneous Leishmaniasis: A systematic review.

BACKGROUND: Cutaneous leishmaniasis (CL) is characterized by potentially disfiguring skin ulcers carrying significant social stigma. To mitigate systemic drug exposure and reduce the toxicity from available treatments, studies addressing new local therapeutic strategies using available medications are coming up. This review systematically compiles preclinical and clinical data on the efficacy of amphotericin B (AmB) administered locally for cutaneous leishmaniasis. METHODOLOGY: Structured searches were conducted in major databases. Clinical studies reporting cure rates and preclinical studies presenting any efficacy outcome were included. Exclusion criteria comprised nonoriginal studies, in vitro investigations, studies with fewer than 10 treated patients, and those evaluating AmB in combination with other antileishmanial drug components. PRINCIPAL FINDINGS: A total of 21 studies were identified, encompassing 16 preclinical and five clinical studies. Preclinical assessments generally involved the topical use of commercial AmB formulations, often in conjunction with carriers or controlled release systems. However, the variation in the treatment schedules hindered direct comparisons. In clinical studies, topical AmB achieved a pooled cure rate of 45.6% [CI: 27.5-64.8%; I2 = 79.7; p = 0.002), while intralesional (IL) administration resulted in a 69.8% cure rate [CI: 52.3-82.9%; I2 = 63.9; p = 0.06). In the direct comparison available, no significant difference was noted between AmB-IL and meglumine antimoniate-IL administration (OR:1.7; CI:0.34-9.15, I2 = 79.1; p = 0.00), however a very low certainty of evidence was verified. CONCLUSIONS: Different AmB formulations and administration routes have been explored in preclinical and clinical studies. Developing therapeutic technologies is evident. Current findings might be interpreted as a favorable proof of concept for the local AmB administration which makes this intervention eligible to be explored in future well-designed studies towards less toxic treatments for leishmaniasis.

Efficacy and safety of therapeutic strategies for human brucellosis: A systematic review and network meta-analysis.

BACKGROUND: Human brucellosis is a neglected, re-emerging, and endemic zoonosis in many countries. The debilitating and disabling potential of the disease is a warning about its morbidity, generating socioeconomic impact. This review aims to update the current evidence on the efficacy and safety of therapeutic options for human brucellosis using the network meta-analysis (NMA). METHODOLOGY: A systematic search was conducted in four different databases by independent reviewers to assess overall therapy failure, adverse events, and time to defervescence associated with different therapies. Randomized clinical trials (RCTs) evaluating any therapeutic drug intervention were selected, excluding non-original studies or studies related to localized forms of the disease or with less than 10 participants. Data were analyzed by frequentist statistics through NMA by random effects model. The risk of bias and certainty of evidence was assessed, this review was registered at PROSPERO. RESULTS: Thirty-one (31) RCTs involving 4167 patients were included. Three networks of evidence were identified to evaluate the outcomes of interest. Triple therapy with doxycycline + streptomycin + hydroxychloroquine for 42 days (RR: 0.08; CI 95% 0.01-0.76) had a lower failure risk than the doxycycline + streptomycin regimen. Doxycycline + rifampicin had a higher risk of failure than doxycycline + streptomycin (RR: 1.96; CI 95% 1.27-3.01). No significant difference was observed between the regimens when analyzing the incidence of adverse events and time to defervescence. In general, most studies had a high risk of bias, and the results had a very low certainty of evidence. CONCLUSIONS: This review confirmed the superiority of drugs already indicated for treating human brucellosis, such as the combination of doxycycline and aminoglycosides. The association of hydroxychloroquine to the dual regimen was identified as a potential strategy to prevent overall therapy failure, which is subject to confirmation in future studies.

Diagnosis of human brucellosis: Systematic review and meta-analysis.

BACKGROUND: Brucellosis, a widely spread zoonotic disease, poses significant diagnostic challenges due to its non-specific symptoms and underreporting. Timely and accurate diagnosis is crucial for effective patient management and public health control. However, a comprehensive comparative review of available diagnostic tests is lacking. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review addressed the following question: 'What is the accuracy of the available tests to confirm human brucellosis?' Two independent reviewers examined articles published up to January 2023. The review included original studies reporting symptomatic patients with brucellosis suspicion, through any index test, with sensitivity and/or specificity as outcomes. As exclusion criteria were considered: sample size smaller than 10 patients, studies focusing on complicated brucellosis, and those lacking essential information about index or comparator tests. Sensitivity and specificity were assessed, with consideration for the index test, and 'culture' and 'culture and standard tube agglutination test (SAT)' were used as reference standards. Bias assessment and certainty of evidence were carried out using the QUADAS-2 and GRADE tools, respectively. A total of 38 studies reporting diagnostic test performance for human brucellosis were included. However, the evidence available is limited, and significant variability was observed among studies. Regarding the reference test, culture and/or SAT are deemed more appropriate than culture alone. Rose Bengal, IgG/IgM ELISA, and PCR exhibited equally high performances, indicating superior overall diagnostic accuracy, with very low certainty of the evidence. CONCLUSIONS/SIGNIFICANCE: This systematic review underscores the potential of the Rose Bengal test, IgG/IgM ELISA, and PCR as promising diagnostic tools for brucellosis. However, the successful implementation and recommendations for their use should consider the local context and available resources. The findings highlight the pressing need for standardization, improved reporting, and ongoing advancements in test development to enhance the accuracy and accessibility of brucellosis diagnosis.

Quality of life of patients with cutaneous leishmaniasis: A comparative analysis of the EQ-5D-3L and CLIQ questionnaires.

PURPOSE: To evaluate the performance of the Cutaneous Leishmaniasis Impact Questionnaire (CLIQ) using the EuroQol-5 Dimension (EQ-5D-3L) as a reference standard (criterion validation); to evaluate the responsiveness of the instruments and estimate a cut-off point for the CLIQ to be able to discriminate between high and low impacts of cutaneous leishmaniasis on patients. METHODS: Between 2020 and 2022, a longitudinal validation study was conducted at a reference centre for leishmaniasis in Brazil. The EQ-5D-3L and CLIQ questionnaires were administered before, during and after treatment for cutaneous leishmaniasis. The correlation between the instruments was assessed using Spearman's correlation coefficient, responsiveness was assessed using the Wilcoxon test, and CLIQ cut-off points were proposed based on results of the EQ-5Q-3L, dichotomized between patients reporting no problems' and 'some or extreme problems'. RESULTS: There were satisfactory correlation coefficients between the two instruments before (-0.596) and during treatment (-0.551) and a low correlation between the instruments after the end of treatment (-0.389). In general, the responsiveness of the instruments was satisfactory. The CLIC scores that maximized sensitivity and specificity for recognizing impaired health status before and during treatment were 7 points and 17 points, respectively. However, at the end of treatment, based on the results for the EQ-5D-3L, the CLIC was not able to discriminate between individuals with high and low impacts of the disease. CONCLUSION: The CLIQ corresponds well with the EQ-5D-3L when applied before and during treatment but does not seem to be appropriate for follow-up evaluations after the end of treatment.

Involving patients in drug development for Neglected Tropical Diseases (NTDs): A qualitative study exploring and incorporating preferences of patients with cutaneous leishmaniasis into Target Product Profile development.

BACKGROUND: Target Product Profiles (TPPs) are instrumental to help optimise the design and development of therapeutics, vaccines, and diagnostics - these products, in order to achieve the intended impact, should be aligned with users' preferences and needs. However, patients are rarely involved as key stakeholders in building a TPP. METHODOLOGY: Thirty-three cutaneous leishmaniasis (CL) patients from Brazil, Colombia, and Austria, infected with New-World Leishmania species, were recruited using a maximum variation approach along geographic, sociodemographic and clinical criteria. Semi-structured interviews were conducted in the respective patient's mother tongue. Transcripts, translated into English, were analysed using a framework approach. We matched disease experiences, preferences, and expectations of CL patients to a TPP developed by DNDi (Drug for Neglected Diseases initiative) for CL treatment. PRINCIPAL FINDINGS: Patients' preferences regarding treatments ranged from specific efficacy and safety endpoints to direct and significant indirect costs. Respondents expressed views about trade-offs between efficacy and experienced discomfort/adverse events caused by treatment. Reasons for non-compliance, such as adverse events or geographical and availability barriers, were discussed. Considerations related to accessibility and affordability were relevant from the patients' perspective. CONCLUSIONS/SIGNIFICANCE: NTDs affect disadvantaged populations, often with little access to health systems. Engaging patients in designing adapted therapies could significantly contribute to the suitability of an intervention to a specific context and to compliance, by tailoring the product to the end-users' needs. This exploratory study identified preferences in a broad international patient spectrum. It provides methodological guidance on how patients can be meaningfully involved as stakeholders in the construction of a TPP of therapeutics for NTDs. CL is used as an exemplar, but the approach can be adapted for other NTDs.

Implementation of health technologies in Brazil: analysis of federal guidelines for the public health system. / Implementação de tecnologias em saúde no Brasil: análise de orientações federais para o sistema público de saúde.

This study aimed to identify the regulatory framework and federal guidelines that support the process of implementing health technologies in the Unified Health System (SUS) through analysis of documents and legislation related to the National Health Technology Management Policy, published between 2009 and 2021. The search and selection of documents and subsequent data extraction were carried out. The documents were grouped into three categories: structural regulatory documents, recommendations on evaluation of technologies, and recommendations on clinical guidelines. In 38.8% of the regulatory documents, citations to implementation related mainly to SUS clinical guidelines were identified; however, no document dedicated to guiding implementation actions was identified. Recommendations related to implementations were identified in 27.1% of the reports and 66.1% of the guidelines, although without standardization and, in general, in little detail, focusing on resources and actions needed for making technology available rather than on methods and interventions for its implementation. The results evidence a gap in formal guidelines to guide the implementation process in Brazil, representing an opportunity for the development of models aligned with the reality of the SUS.

O objetivo foi identificar o arcabouço regulatório e as orientações federais que sustentam o processo de implementação de tecnologias em saúde no Sistema Único de Saúde (SUS), por meio da análise de documentos e legislações relacionados à Política Nacional de Gestão de Tecnologias de Saúde, publicados entre 2009 e 2021. Foi realizada busca e seleção dos documentos e posterior extração de dados, agrupados por três categorias: normativas estruturantes, recomendações na avaliação de tecnologias e recomendações nas diretrizes clínicas. Em 38,8% das normativas, foram identificadas citações à implementação relacionadas principalmente às diretrizes clínicas do SUS, mas nenhum documento dedicado a orientar as ações de implementação. As recomendações relacionadas às implementações foram identificadas em 27,1% dos relatórios e em 66,1% das diretrizes, mas sem padronização e, de modo geral, pouco detalhadas, com foco em recursos e ações necessárias para a disponibilização da tecnologia, ao invés de métodos e intervenções para implementação. Os resultados confirmam a existência de uma lacuna de diretrizes formais para guiar o processo de implementação no Brasil, o que se constitui em oportunidade para o desenvolvimento de modelos alinhados à realidade do SUS.

Implementação de tecnologias em saúde no Brasil: análise de orientações federais para o sistema público de saúde / Implementation of health technologies in Brazil: analysis of federal guidelines for the public health system

Resumo O objetivo foi identificar o arcabouço regulatório e as orientações federais que sustentam o processo de implementação de tecnologias em saúde no Sistema Único de Saúde (SUS), por meio da análise de documentos e legislações relacionados à Política Nacional de Gestão de Tecnologias de Saúde, publicados entre 2009 e 2021. Foi realizada busca e seleção dos documentos e posterior extração de dados, agrupados por três categorias: normativas estruturantes, recomendações na avaliação de tecnologias e recomendações nas diretrizes clínicas. Em 38,8% das normativas, foram identificadas citações à implementação relacionadas principalmente às diretrizes clínicas do SUS, mas nenhum documento dedicado a orientar as ações de implementação. As recomendações relacionadas às implementações foram identificadas em 27,1% dos relatórios e em 66,1% das diretrizes, mas sem padronização e, de modo geral, pouco detalhadas, com foco em recursos e ações necessárias para a disponibilização da tecnologia, ao invés de métodos e intervenções para implementação. Os resultados confirmam a existência de uma lacuna de diretrizes formais para guiar o processo de implementação no Brasil, o que se constitui em oportunidade para o desenvolvimento de modelos alinhados à realidade do SUS.

Abstract This study aimed to identify the regulatory framework and federal guidelines that support the process of implementing health technologies in the Unified Health System (SUS) through analysis of documents and legislation related to the National Health Technology Management Policy, published between 2009 and 2021. The search and selection of documents and subsequent data extraction were carried out. The documents were grouped into three categories: structural regulatory documents, recommendations on evaluation of technologies, and recommendations on clinical guidelines. In 38.8% of the regulatory documents, citations to implementation related mainly to SUS clinical guidelines were identified; however, no document dedicated to guiding implementation actions was identified. Recommendations related to implementations were identified in 27.1% of the reports and 66.1% of the guidelines, although without standardization and, in general, in little detail, focusing on resources and actions needed for making technology available rather than on methods and interventions for its implementation. The results evidence a gap in formal guidelines to guide the implementation process in Brazil, representing an opportunity for the development of models aligned with the reality of the SUS.

Cost-effectiveness study of therapeutic approaches for mucosal leishmaniasis / Estudo de custo-efetividade das abordagens terapêuticas para leishmaniose mucosa / Estudio de coste-efectividad de terapéuticas para la leishmaniasis mucosa

Abstract: This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

Resumo: O objetivo deste estudo foi estimar o custo-efetividade de quatro abordagens terapêuticas disponíveis para leishmaniose mucosa no Brasil: miltefosina, antimoniato de meglumina, com e sem associação à pentoxifilina e anfotericina B lipossomal. A perspectiva adotada foi a do Sistema Único de Saúde (SUS). O desfecho de interesse foi "paciente curado", que foi analisado por meio de um modelo de árvore de decisão. Estimativas de custos diretos e efetividade foram obtidas da literatura científica. O antimoniato de meglumina isolado foi a estratégia de comparação de base; a anfotericina B lipossomal apresentou razão de custo-efetividade incremental (RCEI) de USD 7.409,13 por paciente curado, e a combinação de antimoniato de meglumina com pentoxifilina apresentou RCEI de USD 85,13. A miltefosina foi dominada, com maior custo e efetividade semelhante quando comparada àquelas do antimoniato de meglumina. As análises de sensibilidade, variando o custo em ±25%, não alteraram os resultados. No entanto, quando o custo da miltefosina foi estimado em menos de USD 171,23, essa estratégia foi dominante sobre o antimoniato de meglumina isolado. Os resultados confirmam que o tratamento com anfotericina B lipossomal continua sendo a opção com maior RCEI entre as abordagens analisadas. Por sua vez, a miltefosina pode ser custo-efetiva com base na variação do preço de aquisição, o que merece atenção por ser a única opção oral disponível. A não consideração de outros aspectos impede o uso imediato desses resultados para subsidiar a tomada de decisão, mas apontam a necessidade de negociação dos preços dos medicamentos disponíveis para a leishmaniose mucosa e indicam a necessidade de incentivar a transferência de tecnologia ou outras ações que visem ampliar a atuação do complexo industrial nacional.

Resumen: El objetivo de este estudio fue estimar el coste-efectividad de cuatro terapéuticas disponibles para la leishmaniasis mucosa en Brasil: miltefosina, antimoniato de meglumina, asociado con y sin pentoxifilina, y anfotericina B liposomal. La perspectiva adoptada fue la del Sistema Único de Salud brasileño (SUS). El resultado de interés fue el "paciente curado", que se analizó mediante un modelo de árbol de decisión. Las estimaciones de costes directos y efectividad se obtuvieron de la literatura científica. El antimoniato de meglumina aislado fue la estrategia de comparación de referencia; el anfotericina B liposomal tuvo una razón coste-efectividad incremental (RCEI) de USD 7.409,13 por paciente curado, y la combinación de antimoniato de meglumina con pentoxifilina tuvo una RCEI de USD 85,13. Predominó la miltefosina, con un coste más elevado y una eficacia similar en comparación con la de antimoniato de meglumina. Los análisis de sensibilidad que variaron el coste en ±25% no alteraron los resultados. Sin embargo, cuando el coste de la miltefosina se estimó en menos de USD 171,23, esta estrategia resultó dominante sobre la antimoniato de meglumina aislada. Los resultados confirman que el tratamiento con anfotericina B liposomal sigue siendo la opción con el RCEI más elevado entre las terapéuticas evaluadas. A su vez, la miltefosina puede ser coste-efectiva en función de la variación del precio de compra, lo que merece atención al ser la única opción oral disponible. La falta de consideración de otros aspectos impide el uso inmediato de estos resultados para subvencionar la toma de decisiones, pero también apunta a la necesidad de negociar los precios de los fármacos disponibles para leishmaniasis mucosa y de fomentar la transferencia de tecnología u otras acciones dirigidas a ampliar el papel del sector industrial nacional.

Accuracy of serological tests in diagnosing mucosal leishmaniasis.

In this serum panel-based study, we evaluated the accuracy of serological tests originally developed for visceral leishmaniasis (VL), for diagnosis of mucosal leishmaniasis (ML). A total of five tests were evaluated, four of which are registered at the National Agency of Sanitary Surveillance (Agência Nacional de Vigilância Sanitária-ANVISA) (RIDASCREEN® Leishmania Ab from R-Biopharm AG., Leishmania ELISA IgG + IgM from Vircell S.L., IFI Leishmaniose Humana-BioManguinhos, and IT-LEISH® from Bio-Rad Laboratories, Inc.), and the other a direct agglutination test (DAT-LPC) prototype kit developed at Fiocruz. The panel was composed of 40 serum samples from patients with confirmed ML and 20 from patients with mucosal involvement and negative parasitological/molecular tests for leishmaniasis and confirmation of another etiology. All cases were treated from 2009 to 2016 in a referral center for leishmaniasis in Belo Horizonte, Minas Gerais, Brazil (Instituto René Rachou, Fiocruz). Diagnostic accuracy, based on the cut-off point for VL diagnosis, was 86.2% with RIDASCREEN® Leishmania Ab, 73.3% with Leishmania ELISA IgG + IgM, and 66.7% with IFI Leishmaniose Humana, while IT-LEISH® and DAT-LPC had the lowest accuracy (38.3%), despite high specificity (100% and 95%, respectively). New cut-off points defined with sera from ML patients improved accuracy from 86.2 to 89% (p = 0.64) and 73.3 to 88% (p = 0.04) for RIDASCREEN® Leishmania Ab and Leishmania ELISA IgG + IgM, respectively. Moreover, these tests presented greater sensitivity and immunoreactivity in patients with moderate/severe clinical ML forms. The data of this study suggest that ELISA assays can contribute to laboratory diagnosis, especially for patients with moderate or severe mucosal involvement.

A Randomized, Controlled, Noninferiority, Multicenter Trial of Systemic vs Intralesional Treatment With Meglumine Antimoniate for Cutaneous Leishmaniasis in Brazil.

BACKGROUND: Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). METHODS: Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10-20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. RESULTS: We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5-91.4) and 67.8% (53.3-78.3) per protocol (PP) and 70.6% (58.3-81.0) and 59.7% (47.0-71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6-88 + 8) and 71.2% (57.9-82.2) PP and 69.1% (55.2-78.5) and 64.2% (50.0-74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. CONCLUSIONS: IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. CLINICAL TRIALS REGISTRATION: REBEC: RBR-6mk5n4.

Serology for visceral leishmaniasis: How trusty is the accuracy reported by the manufacturers?

Timely and accurate diagnosis is one of the strategies for managing visceral leishmaniasis (VL). Given the specificities of this infection, which affects different vulnerable populations, the local assessment of the accuracy of the available diagnostic test is a requirement for the good use of resources. In Brazil, performance data are required for test registration with the National Regulatory Agency (ANVISA), but there are no minimum requirements established for performance evaluation. Here, we compared the accuracy reported in the manufacturer's instructions of commercially available VL-diagnostic tests in Brazil, and the accuracies reported in the scientific literature which were obtained after test commercialization. The tests were identified via the electronic database of ANVISA, and their accuracy was obtained from the manufacturer's instructions. A literature search for test accuracy was performed using two databases. A total of 28 VL diagnostic tests were identified through the ANVISA database. However, only 13 presented performance data in the manufacturer's instructions, with five immunoenzymatic tests, three indirect immunofluorescence tests, one chemiluminescence test, and four rapid tests. For most tests, the manufacturers did not provide the relevant information, such as sample size, reference standards, and study site. The literature review identified accuracy data for only 61.5% of diagnostic tests registered in Brazil. These observations confirmed that there are significant flaws in the process of registering health technologies and highlighted one of the reasons for the insufficient control of policies, namely, the use of potentially inaccurate and inappropriate diagnostic tools for a given scenario.

Cutaneous leishmaniasis treatment and therapeutic outcomes in special populations: A collaborative retrospective study.

BACKGROUND: Treatment guidance for children and older adult patients affected by cutaneous leishmaniasis (CL) is unclear due to limited representation of these groups in clinical trials. METHODS: We conducted a collaborative retrospective study to describe the effectiveness and safety of antileishmanial treatments in children ≤ 10 and adults ≥ 60 years of age, treated between 2014 and 2018 in ten CL referral centers in Latin America. RESULTS: 2,037 clinical records were assessed for eligibility. Of them, the main reason for non-inclusion was lack of data on treatment follow-up and therapeutic response (182/242, 75% of children and 179/468, 38% of adults). Data on 1,325 eligible CL patients (736 children and 589 older adults) were analyzed. In both age groups, disease presentation was mild, with a median number of lesions of one (IQR: 1-2) and median lesion diameter of less than 3 cm. Less than 50% of the patients had data for two or more follow-up visits post-treatment (being only 28% in pediatric patients). Systemic antimonials were the most common monotherapy regimen in both age groups (590/736, 80.2% of children and 308/589, 52.3% of older adults) with overall cure rates of 54.6% (95% CI: 50.5-58.6%) and 68.2% (95% CI: 62.6-73.4%), respectively. Other treatments used include miltefosine, amphotericin B, intralesional antimonials, and pentamidine. Adverse reactions related to the main treatment were experienced in 11.9% (86/722) of children versus 38.4% (206/537) of older adults. Most adverse reactions were of mild intensity. CONCLUSION: Our findings support the need for greater availability and use of alternatives to systemic antimonials, particularly local therapies, and development of strategies to improve patient follow-up across the region, with special attention to pediatric populations.

Serology for visceral leishmaniasis: How trusty is the accuracy reported by the manufacturers?

ABSTRACT Timely and accurate diagnosis is one of the strategies for managing visceral leishmaniasis (VL). Given the specificities of this infection, which affects different vulnerable populations, the local assessment of the accuracy of the available diagnostic test is a requirement for the good use of resources. In Brazil, performance data are required for test registration with the National Regulatory Agency (ANVISA), but there are no minimum requirements established for performance evaluation. Here, we compared the accuracy reported in the manufacturer's instructions of commercially available VL-diagnostic tests in Brazil, and the accuracies reported in the scientific literature which were obtained after test commercialization. The tests were identified via the electronic database of ANVISA, and their accuracy was obtained from the manufacturer's instructions. A literature search for test accuracy was performed using two databases. A total of 28 VL diagnostic tests were identified through the ANVISA database. However, only 13 presented performance data in the manufacturer's instructions, with five immunoenzymatic tests, three indirect immunofluorescence tests, one chemiluminescence test, and four rapid tests. For most tests, the manufacturers did not provide the relevant information, such as sample size, reference standards, and study site. The literature review identified accuracy data for only 61.5% of diagnostic tests registered in Brazil. These observations confirmed that there are significant flaws in the process of registering health technologies and highlighted one of the reasons for the insufficient control of policies, namely, the use of potentially inaccurate and inappropriate diagnostic tools for a given scenario.

The cure rate after different treatments for mucosal leishmaniasis in the Americas: A systematic review.

BACKGROUND: Mucosal or mucocutaneous leishmaniasis is the most severe form of tegumentary leishmaniasis due to its destructive character and potential damage to respiratory and digestive tracts. The current treatment recommendations are based on low or very low-quality evidence, and pentavalent antimonial derivatives remain strongly recommended. The aim of this review was to update the evidence and estimate the cure rate and safety profile of the therapeutic options available for mucosal leishmaniasis (ML) in the Americas. METHODOLOGY: A systematic review was conducted in four different databases and by different reviewers, independently, to evaluate the therapeutic efficacy and toxicity associated with different treatments for ML. All original studies reporting cure rates in more than 10 patients from American regions were included, without restriction of design, language, or publication date. The risk of bias was assessed by two reviewers, using different tools according to the study design. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. The protocol for this review was registered at the International Prospective Register of Systematic Reviews, PROSPERO: CRD42019130708. PRINCIPAL FINDINGS: Twenty-seven original studies from four databases fulfilled the selection criteria. A total of 1,666 patients with ML were treated predominantly with pentavalent antimonials in Brazil. Other interventions, such as pentamidine, miltefosine, imidazoles, aminosidine sulfate, deoxycholate and lipidic formulations of amphotericin B (liposomal, lipid complex, colloidal dispersion), in addition to combinations with pentoxifylline, allopurinol or sulfa were also considered. In general, at least one domain with a high risk of bias was identified in the included studies, suggesting low methodological quality. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. It was confirmed that antimony is still the most used treatment for ML, with only moderate efficacy (possibly increased by combining with pentoxifylline). There is already evidence for the use of miltefosine for ML, with a cure rate similar to antimony, as observed in the only direct meta-analysis including 57 patients (OR: 1.2; 0.43-3.49, I2 = 0). It was possible to gather all descriptions available about adverse events reported during ML treatment, and the toxicity reflected the pattern informed in the manufacturers' technical information. CONCLUSIONS: This study provides an overview of the clinical experience in the Americas related to ML treatment and points out interventions and possible combinations that are eligible to be explored in future well-designed studies.