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. Author summary: Mucosal leishmaniasis (ML) is a deforming leishmaniasis clinical form related to functional damage and stigmatization. This disease is caused mainly by L. braziliensis and predominates in neglected populations in the Americas, where approximately 2000 cases occur per year. There are few ML clinical trials, which makes the current treatment supported by fragile scientific evidence. In this study, we carried out an extensive literature search to gather the accumulated evidence for ML treatment. Twenty-seven studies with different designs were included with a total of 1,666 patients with ML treated. The results confirmed that antimony is still the main drug used for ML treatment, with only a moderate cure rate, an efficacy possibly increased by pentoxifylline combination. Miltefosine was found to be an alternative, with a cure rate similar to antimonials standard doses. In turn, the high toxicity of amphotericin B deoxycholate was clearly demonstrated, generating low cure rates due to early interruption of treatment. Other alternatives such as pentamidine, imidazoles, and aminosidine, were evaluated in a small number of cases and presented variable cure rates. The quality of the studies is low, and there is great heterogeneity in the definitions of cure, which limits a global analysis of the data. More and well-designed studies are needed to guide ML treatment recommendations. [ABSTRACT FROM AUTHOR]