System-based insights into parasitological and clinical treatment failure in Chagas disease

Abstract

Infectious disease treatment success requires symptom resolution (clinical treatment success), which often but not always involves pathogen clearance. Both of these treatment goals face disease-specific and general challenges. In this review, we summarize the current state of knowledge in mechanisms of clinical and parasitological treatment failure in the context of Chagas disease, a neglected tropical disease causing cardiac and gastrointestinal symptoms. Parasite drug resistance and persistence, drug pharmacokinetics and dynamics, as well as persistently altered host immune responses and tissue damage are the most common reasons for Chagas disease treatment failure. We discuss the therapeutics that failed before regulatory approval, limitations of current therapeutic options and new treatment strategies to overcome persistent parasites, inflammatory responses, and metabolic alterations. Large-scale omics analyses were critical in generating these insights and will continue to play a prominent role in addressing the challenges still facing Chagas disease drug treatment.

Keywords: Chagas disease; Trypanosoma cruzi; antiparasitic treatment; drug development; drug resistance; genomics; metabolomics; pathogen persistence; treatment failure.

Fig 1

Causes of parasitological and clinical treatment failure and examples of current approaches to mitigate them. Clinical treatment failure can be observed with or without parasite clearance (blue arrows). ADME, absorption, distribution, metabolism, and excretion. Arrows show the direction of impact. Dashed lines represent new treatment approaches.

Fig 2

CD treatments in clinical usage worldwide, selected experimental treatments discussed in the text, and selected Bz metabolites.