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.

A phase II multicenter randomized study to evaluate the safety and efficacy of combining thermotherapy and a short course of miltefosine for the treatment of uncomplicated cutaneous leishmaniasis in the New World.

BACKGROUND: Systemic pentavalent antimonials, mainly meglumine antimoniate, continue to be the first-choice drugs for treatment of cutaneous leishmaniasis (CL) despite their toxicity, difficulty of administration and high cost. In the search for therapeutic alternatives, combining two treatment interventions has emerged as a potential alternative to either reduce the use of antimonials with the associated toxicities, or to increase efficacy. Here, we report the results of a recently completed trial assessing the efficacy and safety of a combination of thermotherapy (TT) plus a short course of miltefosine (MLT) for the treatment of uncomplicated CL in Colombia and Peru. METHODS: A multicenter, randomized, evaluator-blinded, phase II, controled clinical trial was conducted. Adult volunteers with a parasitologically confirmed diagnosis of uncomplicated CL were randomly allocated to receive either a single session of TT or a combination of TT plus a short course of MLT (3 weeks). Therapeutic response outcomes and safety were assessed. RESULTS: 130 subjects were included in the study, of whom 64 were randomly assigned to the TT arm and 66 to the TT + MLT arm. Cure at 3 months' follow-up was achieved in 57.8% (n = 37) and 80.3% (n = 53) in the TT and TT + MLT groups, respectively, in the intention to treat analysis. The TT + MLT regimen was better that TT alone (p = 0.0055). The presence of vesicles at the site of heat application was the most common adverse event reported associated with the use of TT; while vomiting (31.8%) and elevation of liver enzymes (28.8%) were the most frequent adverse events reported associated with the use of MLT. CONCLUSION: The combination of TT plus a short course of MLT was shown to be significantly better than TT alone for the treatment of uncomplicated CL in the New World. TRIAL REGISTRATION: Registered in clinicaltrials.gov NCT02687971.

In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil.

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower than previously demonstrated in India. The present study investigated the susceptibility to miltefosine in 73 Brazilian strains of Leishmania infantum from different geographic regions, using intracellular amastigote and promastigote assays. The EC50 for miltefosine of 13 of these strains evaluated in intracellular amastigotes varied between 1.41 and 4.57 µM. The EC50 of the 73 strains determined in promastigotes varied between 5.89 and 23.7 µM. No correlation between in vitro miltefosine susceptibility and the presence of the miltefosine sensitive locus was detected among the tested strains. The relatively low heterogeneity in miltefosine susceptibility observed for the 73 strains tested in this study suggests the absence of decreased susceptibility to miltefosine in Brazilian L. infantum and does not exclude future clinical evaluation of miltefosine for VL treatment in Brazil.

Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives.

Research in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today's reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.

Harmonized clinical trial methodologies for localized cutaneous leishmaniasis and potential for extensive network with capacities for clinical evaluation.

INTRODUCTION: Progress with the treatment of cutaneous leishmaniasis (CL) has been hampered by inconsistent methodologies used to assess treatment effects. A sizable number of trials conducted over the years has generated only weak evidence backing current treatment recommendations, as shown by systematic reviews on old-world and new-world CL (OWCL and NWCL). MATERIALS AND METHODS: Using a previously published guidance paper on CL treatment trial methodology as the reference, consensus was sought on key parameters including core eligibility and outcome measures, among OWCL (7 countries, 10 trial sites) and NWCL (7 countries, 11 trial sites) during two separate meetings. RESULTS: Findings and level of consensus within and between OWCL and NWCL sites are presented and discussed. In addition, CL trial site characteristics and capacities are summarized. CONCLUSIONS: The consensus reached allows standardization of future clinical research across OWCL and NWCL sites. We encourage CL researchers to adopt and adapt as required the proposed parameters and outcomes in their future trials and provide feedback on their experience. The expertise afforded between the two sets of clinical sites provides the basis for a powerful consortium with potential for extensive, standardized assessment of interventions for CL and faster approval of candidate treatments.

[Estimating demand for anti-Chagas drugs: a contribution for access in Latin America]. / Estimación de la demanda de medicamentos antichagásicos: una contribución para el acceso en América Latina.

OBJECTIVE: Describe a tool to estimate demand for benznidazole and nifurtimox to treat Chagas disease, and report on its implementation in a group of Latin American countries. METHODS: The project was carried out in the following stages: 1) development of a tool to estimate demand, and definition of the evaluation and decision variables to estimate demand 2) data collection via a questionnaire completed by representatives of control programs, complemented with data from the literature; 3) presentation of the tool, followed by validation, and adaptation by representatives of the control programs in order to plan drug procurement for 2012 and 2013; and 4) further analysis of the obtained data, especially regarding benznidazole, and comparison of country estimates. RESULTS: Fourteen endemic countries of Latin America took part in the third stage, and a consolidated estimate was made. The number of estimated treatments, based on the number of tablets per treatment established in the regimen of reference was: 867 in the group under 1 year of age; 2 042 835 in the group from 1 to 15 years old; 2 028 in the group from 15 to 20 years old; and 10 248 in adults over 20. This means that it is possible to provide benznidazole to less than 1% of people for whom treatment is indicated. CONCLUSIONS: The development and systematic use of demand management tools can play a key role in helping to provide access to the anti-Chagas drugs. There is a significant gap between the projected demand for drugs and current estimates of prevalence rates.

Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial.

BACKGROUND: There is insufficient evidence to support visceral leishmaniasis (VL) treatment recommendations in Brazil and an urgent need to improve current treatments. Drug combinations may be an option. METHODS: A multicenter, randomized, open label, controlled trial was conducted in five sites in Brazil to evaluate efficacy and safety of (i) amphotericin B deoxycholate (AmphoB) (1 mg/kg/day for 14 days), (ii) liposomal amphotericin B (LAMB) (3 mg/kg/day for 7 days) and (iii) a combination of LAMB (10 mg/kg single dose) plus meglumine antimoniate (MA) (20 mg Sb+5/kg/day for 10 days), compared to (iv) standard treatment with MA (20 mg Sb+5/kg/day for 20 days). Patients, aged 6 months to 50 years, with confirmed VL and without HIV infection were enrolled in the study. Primary efficacy endpoint was clinical cure at 6 months. A planned efficacy and safety interim analysis led to trial interruption. RESULTS: 378 patients were randomized to the four treatment arms: MA (n = 112), AmphoB (n = 45), LAMB (n = 109), or LAMB plus MA (n = 112). A high toxicity of AmphoB prompted an unplanned interim safety analysis and this treatment arm was dropped. Per intention-to-treat protocol final analyses of the remaining 332 patients show cure rates at 6 months of 77.5% for MA, 87.2% for LAMB, and 83.9% for LAMB plus MA, without statistically significant differences between the experimental arms and comparator (LAMB: 9.7%; CI95% -0.28 to 19.68, p = 0.06; LAMB plus MA: 6.4%; CI95% -3.93 to 16.73; p = 0.222). LAMB monotherapy was safer than MA regarding frequency of treatment-related adverse events (AE) (p = 0.045), proportion of patients presenting at least one severe AE (p = 0.029), and the proportion of AEs resulting in definitive treatment discontinuation (p = 0.003). CONCLUSIONS: Due to lower toxicity and acceptable efficacy, LAMB would be a more suitable first line treatment for VL than standard treatment. ClinicalTrials.gov identification number: NCT01310738. TRIAL REGISTRATION: ClinicalTrials.gov NCT01310738.

Estimación de la demanda de medicamentos antichagásicos: una contribución para el acceso en América Latina / Estimating demand for anti-Chagas drugs: a contribution for access in Latin America / Estimativa da demanda de medicamentos antichagásicos: uma contribuição para o acesso na América Latina

Objetivo. Describir una herramienta de estimación de la demanda de benznidazol y nifurtimox para la enfermedad de Chagas y relatar su aplicación en un conjunto de países de América Latina. Métodos. El proyecto se desarrolló en las siguientes etapas: 1) elaboración de una herramienta y definición de las variables de evaluación y decisión para estimación de la demanda, 2) recolección de datos a partir de un cuestionario a representantes de programas de control, complementado con datos de la literatura, 3) presentación, validación y adaptación de la herramienta por representantes de los programas de control, con la intención de planificar la adquisición de medicamentos para los años de 2012 y 2013, y 4) análisis complementar de los datos obtenidos, en especial benznidazol, y comparación de las estimaciones de los países. Resultados. Catorce países endémicos de América Latina participaron de la tercera etapa, con definición de una estimación consolidada. El número de tratamientos estimados a partir del número de comprimidos por tratamiento establecido en el esquema de referencia resultó ser de 867 en menores de un año, 2 042 835 en el grupo de 1 a 15 años, 2 028 en el grupo de 15 a 20 años y de 10 248 en adultos mayores de 20 años. Este cuantitativo representa la posibilidad de tratar menos de 1% de las personas con indicación para tratamiento con benznidazol. Conclusiones. El desarrollo y el uso sistemático de herramientas de gestión de la demanda pueden jugar un papel clave en el apoyo al acceso a los medicamentos en la enfermedad de Chagas. Existe una brecha significativa entre las previsiones de demanda de medicamentos y estimaciones actuales de las tasas de prevalencia.

Objective. Describe a tool to estimate demand for benznidazole and nifurtimox to treat Chagas disease, and report on its implementation in a group of Latin American countries. Methods. The project was carried out in the following stages: 1) development of a tool to estimate demand, and definition of the evaluation and decision variables to estimate demand 2) data collection via a questionnaire completed by representatives of control programs, complemented with data from the literature; 3) presentation of the tool, followed by validation, and adaptation by representatives of the control programs in order to plan drug procurement for 2012 and 2013; and 4) further analysis of the obtained data, especially regarding benznidazole, and comparison of country estimates. Results. Fourteen endemic countries of Latin America took part in the third stage, and a consolidated estimate was made. The number of estimated treatments, based on the number of tablets per treatment established in the regimen of reference was: 867 in the group under 1 year of age; 2 042 835 in the group from 1 to 15 years old; 2 028 in the group from 15 to 20 years old; and 10 248 in adults over 20. This means that it is possible to provide benznidazole to less than 1% of people for whom treatment is indicated. Conclusions. The development and systematic use of demand management tools can play a key role in helping to provide access to the anti-Chagas drugs. There is a significant gap between the projected demand for drugs and current estimates of prevalence rates.

Objetivo. Descrever uma ferramenta de estimativa da demanda de benznidazol e nifurtimox para a doença de Chagas e descrever a sua aplicação em um conjunto de países da América Latina. Métodos. O projeto foi desenvolvido nas seguintes etapas: 1) elaboração de uma ferramenta e definição das variáveis de avaliação e decisão para a estimativa da demanda, 2) compilação de dados a partir de um questionário apresentado a representantes de programas de controle, complementado com dados da literatura, 3) apresentação, validação e adaptação da ferramenta por representantes dos programas de controle, com a intenção de planejar a aquisição de medicamentos para os anos de 2012 e 2013 e 4) análise complementar dos dados obtidos, especialmente sobre o benznidazol, e comparação das estimativas nos países. Resultados. Quatorze países endêmicos da América Latina participaram da terceira etapa, sendo definida uma estimativa consolidada. O número de tratamentos estimados a partir do número de comprimidos por tratamento estabelecido no regime de referência foi de 867 em pacientes menores de um ano, 2.042.835 no grupo com idade entre 1 e 15 anos, 2.028 no grupo entre 15 e 20 anos e 10.248 em adultos maiores de 20 anos. Esta quantidade representa a possibilidade de tratar menos de 1% das pessoas com indicação para tratamento com benznidazol. Conclusões. O desenvolvimento e o uso sistemático de ferramentas de gestão da demanda podem ser fundamentais para apoiar o acesso aos medicamentos para a doença de Chagas. Existe uma disparidade significativa entre as previsões de demanda de medicamentos e as estimativas atuais das taxas de prevalência.