From voice to ink (Vink): development and assessment of an automated, free-of-charge transcription tool.

BACKGROUND: Verbatim transcription of qualitative audio data is a cornerstone of analytic quality and rigor, yet the time and energy required for such transcription can drain resources, delay analysis, and hinder the timely dissemination of qualitative insights. In recent years, software programs have presented a promising mechanism to accelerate transcription, but the broad application of such programs has been constrained due to expensive licensing or "per-minute" fees, data protection concerns, and limited availability of such programs in many languages. In this article, we outline our process of adapting a free, open-source, speech-to-text algorithm (Whisper by OpenAI) into a usable and accessible tool for qualitative transcription. Our program, which we have dubbed "Vink" for voice to ink, is available under a permissive open-source license (and thus free of cost). RESULTS: We conducted a proof-of-principle assessment of Vink's performance in transcribing authentic interview audio data in 14 languages. A majority of pilot-testers evaluated the software performance positively and indicated that they were likely to use the tool in their future research. Our usability assessment indicates that Vink is easy-to-use, and we performed further refinements based on pilot-tester feedback to increase user-friendliness. CONCLUSION: With Vink, we hope to contribute to facilitating rigorous qualitative research processes globally by reducing time and costs associated with transcription and by expanding free-of-cost transcription software availability to more languages. With Vink running on standalone computers, data privacy issues arising within many other solutions do not apply.

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.

mHealth Monitoring of Treatment of Cutaneous Leishmaniasis Patients: A Community-Based Implementation Study.

Cutaneous leishmaniasis (CL) remains a global health problem. Compelled by the protracted healing process, initial and final outcomes of treatment are determined at 90 and 180 days, respectively, after initiation of treatment. Loss to follow-up during these intervals is substantial. Consequently, the effectiveness of treatment is largely unknown. We conducted an effectiveness-implementation hybrid design study of a community-based mobile health (mHealth) strategy to monitor adherence to anti-leishmanial treatment, adverse drug reactions, and therapeutic response compared with standard of care in two rural communities of Colombia. Three implementation outcomes were evaluated: usability and acceptability by qualitative methods and fidelity using quantitative methods. Fifty-seven patients were prospectively included in the mHealth intervention and 48 in the standard-of-care group. In addition, 24 community health leaders (CHLs), health workers, and patients participated in qualitative evaluations. The intervention significantly increased the proportion of patients having follow-up of therapeutic outcomes 90 and 180 days after initiating treatment from 4.2% (standard of care) to 82.5% (intervention), P < 0.001. The proportion of patients having records of treatment adherence, adverse drug reactions, and therapeutic response also increased significantly (P < 0.001). Fidelity to the intervention (recording of treatment adherence, adverse drug reactions, lesion photographs, and evaluation of therapeutic response) was 70-100%. The app was highly accepted by CHLs, health workers, and patients, who perceived that the app improved case identification and follow-up and met a public health need. Although usability was high, low connectivity affected real-time transmission of data. This community-based mHealth strategy facilitated access to health care for CL in rural areas and knowledge of treatment effectiveness.

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.

Anaerobic digestion of organic fraction combinations from food waste, for an optimal dynamic release of biogas, using H2 as an indicator.

The objective of this study is to assess the effects of mixing the three elemental organic waste fractions (fruit and vegetable, meat, and fish) during anaerobic digestion. Batch experiments were carried out with fraction mixtures of different proportions. The results were compared, concerning the single digestion of each fraction, the gas generation, and the process performance, using H2 as an indicator. It was determined that the optimal mixture was the one with the fractions in equal proportion. This mixture achieved a balanced composition, a faster process by 58 %, and a 12 % increase in methane production. It was also determined that, as a rule, mixtures increase the hydrolysis speed and that the meat fraction mixtures manage to make this substrate suitable for anaerobic treatment by increasing the rate of hydrolysis by 148 % and buffering the acidification inhibition that suffers in its single digestion.

Pentoxifylline in the Treatment of Cutaneous Leishmaniasis: A Randomized Clinical Trial in Colombia.

Addition of the immunomodulator pentoxifylline (PTX) to antimonial treatment of mucosal leishmaniasis has shown increased efficacy. This randomized, double-blind, placebo-controlled trial evaluated whether addition of pentoxifylline to meglumine antimoniate (MA) treatment improves therapeutic response in cutaneous leishmaniasis (CL) patients. Seventy-three patients aged 18−65 years, having multiple lesions or a single lesion ≥ 3 cm were randomized to receive: intramuscular MA (20 mg/kg/day × 20 days) plus oral PTX 400 mg thrice daily (intervention arm, n = 36) or MA plus placebo (control arm, n = 37), between 2012 and 2015. Inflammatory gene expression was evaluated by RT-qPCR in peripheral blood mononuclear cells from trial patients, before and after treatment. Intention-to-treat failure rate was 35% for intervention vs. 25% for control (OR: 0.61, 95% CI: 0.21−1.71). Per-protocol failure rate was 32% for PTX, and 24% for placebo (OR: 0.50, 95% CI: 0.13−1.97). No differences in frequency or severity of adverse events were found (PTX = 142 vs. placebo = 140). Expression of inflammatory mediators was unaltered by addition of PTX to MA. However, therapeutic failure was associated with significant overexpression of il1ß and ptgs2 (p < 0.05), irrespective of study group. No clinical benefit of addition of PTX to standard treatment was detected in early mild to moderate CL caused by Leishmania (V.) panamensis.

User perspectives and preferences on a novel TB LAM diagnostic (Fujifilm SILVAMP TB LAM)-a qualitative study in Malawi and Zambia.

Widely available tuberculosis (TB) diagnostics use sputum samples. However, many patients, particularly children and patients living with HIV (PLHIV), struggle to provide sputum. Urine diagnostics are a promising approach to circumvent this challenge while delivering reliable and timely diagnosis. This qualitative study in two high TB/HIV burden countries assesses values and preferences of end-users, along with potential barriers for the implementation of the novel Fujifilm SILVAMP TB-LAM (FujiLAM, Fujifilm, Japan) urine test. Between September 2020 and March 2021, we conducted 42 semi-structured interviews with patients, health care providers (HCPs) and decision makers (DMs) (e.g., in national TB programs) in Malawi and Zambia. Interviews were transcribed verbatim and analyzed using a framework approach supported by NVIVO. Findings aligned with the pre-existing Health Equity Implementation Framework, which guided the presentation of results. The ease and convenience of urine-based testing was described as empowering among patients and HCPs who lamented the difficulty of sputum collection, however HCPs expressed concerns that a shift in agency to the patient may affect clinic workflows (e.g., due to less control over collection). Implementation facilitators, such as shorter turnaround times, were welcomed by operators and patients alike. The decentralization of diagnostics was considered possible with FujiLAM by HCPs and DMs due to low infrastructure requirements. Finally, our findings support efforts for eliminating the CD4 count as an eligibility criterion for LAM testing, to facilitate implementation and benefit a wider range of patients. Our study identified barriers and facilitators relevant to scale-up of urine LAM tests in Malawi and Zambia. FujiLAM could positively impact health equity, as it would particularly benefit patient groups currently underserved by existing TB diagnostics. Participants view the approach as a viable, acceptable, and likely sustainable option in low- and middle-income countries, though adaptations may be required to current health care processes for deployment. Trial registration: German Clinical Trials Register, DRKS00021003. URL: https://www.drks.de/drks_web/setLocale_EN.do.

Integration of phlebotomine ecological niche modelling, and mapping of cutaneous leishmaniasis surveillance data, to identify areas at risk of under-estimation.

INTRODUCTION: Passive surveillance systems are thought to under-estimate the true incidence of American cutaneous leishmaniasis (ACL) by two- to five-fold. Ecological niche models based on remotely sensed data can identify environmental factors which favor phlebotomine vectors. Here we report an integrated approach to identifying areas at risk of cutaneous leishmaniasis by applying spatial analysis methods to niche model results, and local surveillance data, in two locations in Colombia with differing vector ecology. The objective was to identify townships in which later phases of the project could implement community-based surveillance to obtain direct estimates of under-reporting. MATERIALS AND METHODS: The study was carried out in one municipality in each of two departments of the Andean region of Colombia: Pueblo Rico in Risaralda, and Rovira in Tolima. Niche mapping by maximum entropy, based on published and unpublished existing locations of Pintomyia (Pifanomyia) longiflocosa and Psychodopygus panamensis, and using variables on land cover, climate and elevation. Field catches were done in each municipality to test predictions of high relative probability of presence. The niche model results were included as a predictor in a conditional autoregressive spatial model, in which the outcome variable was the number of cases by township, as detected by passive surveillance. RESULTS: Having rarefied 173 geolocated records, 46 of Pi. longiflocosa and 57 of Ps. panamensis were used for the niche modelling. At the national level, both species had high relative probability of presence on parts of the slopes of the three Andean cordilleras. Pi. longiflocosa also has a high relative probability of presence in the higher parts of the Magdalena valley, as does Ps. panamensis in some areas close to the Caribbean coast. At the local level, field catches confirmed that Pi. longiflocosa was the most abundant species in Rovira, and likewise Ps. panamensis in Pueblo Rico. The spatial regression showed that the incidence of ACL, according to surveillance, was positively, but not statistically significantly, associated with the relative probability of presence from the risk model. CONCLUSIONS: These niche maps bring together published and unpublished results on phlebotomine species which are important vectors in Colombia. Maps of the fitted values of incidence were used to guide the selection of townships in which further phases of the study will attempt to quantify the extent of under-estimation of ACL incidence.

Performance verification of the Abbott SARS-CoV-2 test for qualitative detection of IgG in Cali, Colombia.

BACKGROUND: Adequate testing is critically important for control of the SARS-CoV-2 pandemic. Antibody testing is an option for case management and epidemiologic studies, with high specificity and variable sensitivity. However, characteristics of local populations may affect performance of these tests. For this reason, the National Institute of Health (INS) and regulatory agencies in Colombia require verification of diagnostic accuracy of tests introduced to the Colombian market. METHODS: We conducted a validation study of the Abbott SARS-CoV-2 test for qualitative detection of IgG using the Abbott Architect i2000SR. Participants and retrospective samples were included from patients with suspected SARS-CoV-2 infection, age ≥18 years, and ≥8 days elapsed since initiation of symptoms. Pre-pandemic plasma samples (taken before October 2019) were used as controls. We estimated the sensitivity, specificity and agreement (kappa) of the Abbott IgG test compared to the gold standard (RT-PCR). RESULTS: The overall sensitivity was 83.1% (95% CI: 75.4-100). Sensitivity among patients with ≥14 days since the start of symptoms was 85.7%, reaching 88% in samples collected from patients with COVID-19 symptoms onset >60 days. Specificity was 100% and the kappa index of agreement was 0.804 (95% CI: 0.642-0.965). CONCLUSIONS: Our findings show high sensitivity and specificity of the Abbott IgG test in a Colombian population, which meet the criteria set by the Colombian INS to aid in the diagnosis of COVID-19. Data from our patient groups also suggest that IgG response is detectable in a high proportion of individuals (88.1%) during the first two months following onset of symptoms.

Enhancing Energy Recovery in Form of Biogas, from Vegetable and Fruit Wholesale Markets By-Products and Wastes, with Pretreatments.

Residues and by-products from vegetables and fruit wholesale markets are suitable for recovery in the form of energy through anaerobic digestion, allowing waste recovery and introducing them into the circular economy. This suitability is due to their composition, structural characteristics, and to the biogas generation process, which is stable and without inhibition. However, it has been observed that the proportion of methane and the level of degradation of the substrate is low. It is decided to study whether the effect of pretreatments on the substrate is beneficial. Freezing, ultrafreezing and lyophilization pretreatments are studied. A characterization of the substrates has been performed, the route of action of pretreatment determined, and the digestion process studied to calculate the generation of biogas, methane, hydrogen and the proportions among these. Also, a complete analysis of the process has been performed by processing the data with mathematical and statistical methods to obtain disintegration constants and levels of degradation. It has been observed that the three pretreatments have positive effects, when increasing the solubility of the substrate, increasing porosity, and improving the accessibility of microorganisms to the substrate. Generation of gases are greatly increased, reaching a methane enrichment of 59.751%. Freezing seems to be the best pretreatment, as it increases the biodegradation level, the speed of the process and the disintegration constant by 306%.

Data management plan for a community-level study of the hidden burden of cutaneous leishmaniasis in Colombia.

OBJECTIVES: Cutaneous leishmaniasis is a vector-borne parasitic disease whose lasting scars can cause stigmatization and depressive symptoms. It is endemic in remote rural areas and its incidence is under-reported, while the effectiveness, as opposed to efficacy, of its treatments is largely unknown. Here we present the data management plan (DMP) of a project which includes mHealth tools to address these knowledge gaps in Colombia. The objectives of the DMP are to specify the tools and procedures for data collection, data transfer, data entry, creation of analysis dataset, monitoring and archiving. RESULTS: The DMP includes data from two mobile apps: one implements a clinical prediction rule, and the other is for follow-up and treatment of confirmed cases. A desktop interface integrates these data and facilitates their linkage with other sources which include routine surveillance as well as paper and electronic case report forms. Multiple user and programming interfaces are used, as well as multiple relational and non-relational database engines. This DMP describes the successful integration of heterogeneous data sources and technologies. However the complexity of the project meant that the DMP took longer to develop than expected. We describe lessons learned which could be useful for future mHealth projects.

Diagnostic performance of a Recombinant Polymerase Amplification Test-Lateral Flow (RPA-LF) for cutaneous leishmaniasis in an endemic setting of Colombia.

BACKGROUND: Control of cutaneous leishmaniasis by public health systems in the Americas relies on case identification and treatment. Point-of-care diagnostics that can be performed by health workers within or near affected communities could effectively bring the health system to the resource-limited sites providing early diagnosis and treatment, reducing morbidity and the burden of disease. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was undertaken to evaluate the diagnostic test performance of Isothermal Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, coupled with a lateral flow (LF) immunochromatographic strip, in a field setting and a laboratory reference center. Minimally invasive swab and FTA filter paper samples were obtained by community health workers and highly trained technicians from ulcerated lesions of > 2 weeks' evolution from 118 patients' ≥ 2 years of age in the municipality of Tumaco, Nariño. Extracted DNA was processed by RPA-LF at a reference center or in a primary health facility in the field. Evaluation was based on a composite "gold standard" that included microscopy, culture, biopsy and real-time polymerase chain reaction detection of Leishmania 18S rDNA. Standard of care routine diagnostic tests were explored as comparators. Sensitivity and specificity of RPA-LF in the reference lab scenario were 87% (95%CI 74-94) and 86% (95%CI 74-97), respectively. In the field scenario, the sensitivity was 75% (95%CI 65-84) and specificity 89% (95%CI 78-99). Positive likelihood ratios in both scenarios were higher than 6 while negative likelihood ratios ranged to 0.2-0.3 supporting the usefulness of RPA-LF to rule-in and potentially to rule-out infection. CONCLUSIONS/SIGNIFICANCE: The low complexity requirements of RPA-LF combined with non-invasive sampling support the feasibility of its utilization by community health workers with the goal of strengthening the diagnostic capacity for cutaneous leishmaniasis in Colombia. TRIAL REGISTRATION: ClinicalTrials.gov NCT04500873.

Anaerobic digestion in wastewater reactors of separated organic fractions from wholesale markets waste. Compositional and batch characterization. Energy and environmental feasibility.

The food industry is one of the major industrial sectors in Europe and Spain, and therefore one of the major waste emitters, especially organic ones that can be classified into three different fractions (fruit and vegetables, meat and fish). One way to treat this waste environmentally responsible, energy-sustainable and economically cost-effective is anaerobic digestion. The generated biogas can be used as fuel and renewable energy source (providing a solution to the energy problem from an environmental point of view). As there must be a sewage treatment plant with anaerobic digesters in the wholesale markets, and if waste is treated on it, these facilities can be converted into power generators. It has been studied that, when treated along with sludge from a UASB reactor, the residue of fruit and vegetables produces about 900 ml per 100 g of residue with a stable and robust process; the meat residue generates 1300 ml of biogas per 100 g with a process that is slightly affected by the accumulation of acidic elements, internally reversed by the buffer effect of ammonia released; and the fish residue generates 700 ml of biogas, but with very low novels of methane since the process is inhibited early by excessive accumulation of ammonia. The proposed solution is positive, and the methods used to determine it are novel and robust, such as the use of hydrogen as an indicator of process stability. A deep characterization of the development of the process is provided, and feasibility for its application at the industrial level is studied. It is thus proven that wholesale markets can be converted into power generating plants up to 600 kW, assuming a reduction of up to 70 tons of CO2 equivalent (50%) if the generated biogas is used, replacing a conventional source such as natural gas.

Profiles of Local and Systemic Inflammation in the Outcome of Treatment of Human Cutaneous Leishmaniasis Caused by Leishmania (Viannia).

The immune mechanisms that contribute to the efficacy of treatment of cutaneous leishmaniasis (CL) are not fully understood. The aim of this study was to define immune correlates of the outcome of treatment of CL caused by Leishmania (Viannia) species during standard of care treatment with pentavalent antimonials. We conducted a comparative expression profiling of immune response genes in peripheral blood mononuclear cells (PBMCs) and lesion biopsy specimens obtained from CL patients before and at the end of treatment (EoT) with meglumine antimoniate. The ex vivo response of PBMCs to L (V) panamensis partially reflected that of lesion microenvironments. Significant downregulation of gene expression profiles consistent with local innate immune responses (monocyte and neutrophil activation and chemoattractant molecules) was observed at EoT in biopsy specimens of patients who cured (n = 8), compared to those from patients with treatment failure (n = 8). Among differentially expressed genes, pretreatment expression of CCL2 was significantly predictive of the therapeutic response (receiver operating characteristic [ROC] curve, area under the curve [AUC] = 0.82, P = 0.02). Polymorphisms in regulatory regions of the CCL2 promoter were analyzed in a pilot cohort of DNA samples from CL patients (cures, n = 20, and treatment failure, n = 20), showing putative association of polymorphisms rs13900(C/T) and rs2857656(G/C) with treatment outcome. Our data indicate that dampening gene expression profiles of monocyte and neutrophil activation characterize clinical cure after treatment of CL, supporting participation of parasite-sustained inflammation or deregulated innate immune responses in treatment failure.

Eligibility for Local Therapies in Adolescents and Adults with Cutaneous Leishmaniasis from Southwestern Colombia: A Cross-Sectional Study.

Local therapies have been proposed as safe and effective alternatives to systemic drugs in cutaneous leishmaniasis (CL), especially among less severe cases. However, they are not widely available and used in endemic places, including Colombia, which has a high burden of disease. Further complicating the uptake of local therapies is that different treatment guidelines have been established by the World Health Organization (WHO) and Pan American Health Organization (PAHO). Using data from a large referral center in Colombia, we determined the proportion of patients who would be eligible for and potentially benefit from local therapies according to both international guidelines. The sample included 1,891 confirmed cases of CL aged ≥ 12 years, mostly infected with Leishmania Viannia panamensis (91%, n = 601/660), between 2004 and 2014. Overall, 57% of the sample had one lesion, whereas another 31% had two to three lesions. For 74% of patients, all lesions were in an area other than head or neck. The maximum lesion size was ≤ 3 cm for 58% and < 5 cm for 88% of the sample. Based on our data, up to 56% of patients could have been eligible for local therapies according to the WHO criteria. By contrast, only 23% were eligible according to the more restrictive PAHO criteria. Regardless, these data suggest that a substantial proportion of CL patients in Colombia may benefit from local therapies given their relatively mild presentation of disease and low risk of complications. Individualized risk-benefit assessment and guideline adjustments may increase local therapy eligibility and benefit a large number of patients.

Interventions to treat cutaneous leishmaniasis in children: A systematic review.

BACKGROUND: Case management in children with cutaneous leishmaniasis (CL) is mainly based on studies performed in adults. We aimed to determine the efficacy and harms of interventions to treat CL in children. METHODS: We conducted a systematic review of clinical trials and cohort studies, assessing treatments of CL in children (≤12 years old). We performed structured searches in PubMed, CENTRAL, LILACS, SciELO, Scopus, the International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and Google Scholar. No restrictions regarding ethnicity, country, sex or year of publication were applied. Languages were limited to English, Spanish and Portuguese. Two reviewers screened articles, completed the data extraction and assessment of risk of bias. A qualitative summary of the included studies was performed. RESULTS: We identified 1092 records, and included 8 manuscripts (6 Randomized Clinical Trials [RCT] and 2 non-randomized studies). Most of the articles excluded in full-text review did not report outcomes separately for children. In American CL (ACL), 5 studies evaluated miltefosine and/or meglumine antimoniate (MA). Their efficacy varied from 68-83% and 17-69%, respectively. In Old-World CL (OWCL), two studies evaluated systemic therapies: rifampicin and MA; and one study assessed efficacy of cryotherapy (42%, Per Protocol [PP]) vs intralesional MA (72%, PP). Few studies (4) provided information on adverse events (AEs) for children, and no serious AEs were reported in participants. Risk of bias was generally low to unclear in ACL studies, and unclear to high in OWCL studies. CONCLUSION: Information on efficacy of treatment for CL in children is scarce. There is an unmet need to develop specific formulations, surveillance of AEs, and guidelines both for the management of CL and clinical trials involving the pediatric population. REGISTRATION: The protocol of this review was registered in the PROSPERO International register of systematic reviews, number CRD42017062164.

Simultaneous population pharmacokinetic modelling of plasma and intracellular PBMC miltefosine concentrations in New World cutaneous leishmaniasis and exploration of exposure-response relationships.

Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days. Results: A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. Conclusions: The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.

Cost-effectiveness of meglumine antimoniate versus miltefosine caregiver DOT for the treatment of pediatric cutaneous leishmaniasis.

BACKGROUND: Oral miltefosine has been shown to be non-inferior to first-line, injectable meglumine antimoniate (MA) for the treatment of cutaneous leishmaniasis (CL) in children. Miltefosine may be administered via in-home caregiver Directly Observed Therapy (cDOT), while patients must travel to clinics to receive MA. We performed a cost-effectiveness analysis comparing miltefosine by cDOT versus MA for pediatric CL in southwest Colombia. METHODOLOGY/PRINCIPLE FINDINGS: We developed a Monte Carlo model comparing the cost-per-cure of miltefosine by cDOT compared to MA from patient, government payer, and societal perspectives (societal = sum of patient and government payer perspective costs). Drug effectiveness and adverse events were estimated from clinical trials. Healthcare utilization and costs of travel were obtained from surveys of providers and published sources. The primary outcome was cost-per-cure reported in 2015 USD. Treatment efficacy, costs, and adherence were varied in sensitivity analysis to assess robustness of results. Treatment with miltefosine resulted in substantially lower cost-per-cure from a societal and patient perspective, and slightly higher cost-per-cure from a government payer perspective compared to MA. Mean societal cost-per-cure were $531 (SD±$239) for MA and $188 (SD±$100) for miltefosine, a mean cost-per-cure difference of +$343. Mean cost-per-cure from a patient perspective were $442 (SD ±$233) for MA and $30 (SD±$16) for miltefosine, a mean difference of +$412. Mean cost-per-cure from a government perspective were $89 (SD±$55) for MA and $158 (SD±$98) for miltefosine, with a mean difference of -$69. Results were robust across a variety of assumptions in univariate and multi-way analysis. CONCLUSIONS/SIGNIFICANCE: Treatment of pediatric cutaneous leishmaniasis with miltefosine via cDOT is cost saving from patient and societal perspectives, and moderately more costly from the government payer perspective compared to treatment with MA. Results were robust over a range of sensitivity analyses. Lower drug price for miltefosine could result in cost saving from a government perspective.

Risk factors for therapeutic failure to meglumine antimoniate and miltefosine in adults and children with cutaneous leishmaniasis in Colombia: A cohort study.

INTRODUCTION: Reports of therapeutic failure to meglumine antimoniate (MA) and miltefosine in cutaneous leishmaniasis (CL) varies between species, populations and geographic regions. This study aimed to determine the clinical, drug-related factors, and Leishmania species associated with treatment failure in children and adults with cutaneous leishmaniasis. METHODS: A cohort study was performed with children (2-12 years old) and adults (18-65 years old) with CL, who have participated in clinical studies at CIDEIM Cali, Tumaco and Chaparral. Incidence of therapeutic failure was estimated by treatment and age groups. Descriptive, bivariate, and multiple logistic regression analyses were performed for the complete cohort and pediatric patients. RESULTS: Two hundred and thirty patients were included (miltefosine: 112; MA: 118), of which 60.4% were children and 83.9% were infected with L.V. panamensis. Overall incidence of therapeutic failure was 15.65% (95%CI: 10.92-20.38), and was lower for miltefosine than for MA (8.92%, 95%CI: 3.59-14.26 versus 22.03%, 95%CI:14.48-29.58, p = 0.006). Treatment failure was associated with age ≤8 years (OR: 3.29; 95%CI: 1.37-7.89), disease duration ≤1 month (OR: 3.29; 95%CI: 1.37-7.89), regional lymphadenopathy (OR: 2.72; 95%CI: 1.10-6.70), treatment with MA (OR: 3.98; 95%CI: 1.66-9.50), and adherence <90% (OR: 3.59; 95%CI: 1.06-12.11). In children, higher Z-score of height/age was a protective factor (OR: 0.58; 95%CI: 0.36-0.93), while treatment with MA was a risk factor (OR: 40.82; 95%CI: 2.45-677.85), demonstrating significant interaction with age (p = 0.03). CONCLUSIONS: Clinical and drug-related factors determine therapeutic failure in CL. High risk of failure in children treated with MA indicates the need to reconsider this drug as first line treatment in this population. TRIAL REGISTRATION: Clinical trial registration: NCT00487253 Clinical trial registration: NCT01462500 Clinical trial registration: NCT01464242.