Trypanosoma cruzi DTU diversity, benznidazole response, and clinical manifestations of Chagas disease: a seventeen-year systematic review and meta-analysis.

Chagas disease (CD) typically progresses through an often-asymptomatic acute phase, followed by a chronic phase where patients may evolve to the asymptomatic, cardiac, digestive, or cardiodigestive manifestations. The first-line treatment, benznidazole (BZN), is more effective in the acute phase but often causes severe side effects. One major obstacle to treatment success is the high genetic diversity of the Trypanosoma cruzi population, its etiological agent, which is classified into six discrete typing units (DTUs). Over the years, several attempts to predict the evolution of CD have unsuccessfully sought a relationship between DTUs, BZN response, and the clinical outcome of CD. We conducted a comprehensive 17-year literature review and meta-analysis, successfully mapping the BZN in vitro susceptibility across the parasite's life-cycle stages and the distribution of DTUs among CD clinical forms. Ninety-four articles were analyzed for the first question and 46 for the second, comprising 462 and 1,328 samples, respectively. Analysis of the parasite's life-cycle stages of each DTU showed distinct patterns of in vitro susceptibility to BZN. A non-random pattern of DTUs distribution across clinical forms was found. Furthermore, a lack of standardization among drug screening parameters was observed, and guidelines to allow comparisons among assays are provided. The study highlights the critical need for further research into the fundamental biology of T. cruzi, to better understand disease outcomes and, in doing so, lead to more effective and safer therapeutic schemes for CD.