Deconstructing Combination Therapies and Drug Repurposing for Cutaneous Leishmaniasis via Component Network Meta-Analysis

Abstract

INTRODUCTION: Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by Leishmania parasites, with approximately one million new cases reported annually. Current treatments, primarily pentavalent antimonials, face challenges including toxicity, prolonged administration, and emerging resistance. Consequently, alternative strategies like drug repurposing and combination therapies are increasingly sought. The objective of this study was to apply a component network meta-analysis (cNMA) to deconstruct combination therapies into individual elements, estimating their independent effects to identify optimal treatment regimens.  

​METHOD: This study followed a systematic review and cNMA framework, adhering to PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses) guidelines. A systematic search identified randomised controlled trials (RCTs) evaluating multi-component therapies for Old World CL. The primary outcome was the clinical cure rate. Statistical analysis used a frequentist additive component model in R to isolate the incremental Risk Ratio (iRR) of 27 active components. Heterogeneity and certainty of evidence were assessed using I² statistics and the CINeMA (Confidence In Network Meta-Analysis) framework.  

​RESULTS: The analysis included 38 RCTs involving 33 regimens. Among pharmacological components, dapsone demonstrated the highest efficacy (iRR = 2.31; p = 0.0011). Carbon dioxide (CO2) laser and radiofrequency induced heat therapy (RFHT) were the most effective physical modalities. Combination therapies significantly outperformed monotherapy; notably, antimonials combined with pentoxifylline (RR = 2.31) or cryotherapy (RR = 2.15) showed superior cure rates. CINeMA analysis revealed varying confidence levels, with high confidence for modern combinations like paromomycin plus gentamycin, but lower confidence for older repurposed drugs due to within-study bias.  

​CONCLUSION: Combination therapies and drug repurposing offer superior clinical outcomes for CL compared to standard monotherapy. Dapsone and CO2 laser emerged as highly potent therapeutic elements. The cNMA framework provides a data-driven approach for species-specific, optimised treatment selection, facilitating more agile clinical responses in both endemic and emerging non-endemic settings.  

​Keywords: Combination therapies, Cutaneous leishmaniasis, Drug repurposing, Network meta-analysis, Old World