Human Trypanosoma cruzi chronic infection leads to individual level steady-state parasitemia: Implications for drug-trial optimization in Chagas disease

Currently available drugs against Trypanosoma cruzi infection, which causes 12000 deaths annually, have limitations in their efficacy, safety and tolerability. The evaluation of therapeutic responses to available and new compounds is based on parasite detection in the bloodstream but remains challenging because a substantial proportion of infected individuals have undetectable parasitemia even when using diagnostic tools with the highest accuracy. We characterize parasite dynamics which might impact drug efficacy assessments in chronic Chagas by analyzing pre- and post-treatment quantitative-PCR data obtained from blood samples collected regularly over a year. We show that parasitemia remains at a steady-state independently of the diagnostic sensitivity. This steady-state can be probabilistically quantified and robustly predicted at an individual level. Furthermore, individuals can be assigned to categories with distinct parasitological status, allowing a more detailed evaluation of the efficacy outcomes and adjustment for potential biases. Our analysis improves understanding of parasite dynamics and provides a novel background for optimizing future drug efficacy trials in Chagas disease.Trial Registration: original trial registered with ClinicalTrials.gov, number NCT01489228.Author summary: Better understanding of the Trypanosma cruzi parasite dynamics in the bloodstream of chronically infected individuals is critical to improving existing treatments against Chagas disease, as well as to support the development of new therapeutics. Here, we characterize the dynamics of parasitemia over time in two cohorts of individuals suffering from chronic Chagas disease based on quantitative molecular methods and using statistical modeling. We found evidence that parasitemia remains at a steady-state in untreated individuals for long periods of time. The steady-state can be quantified and predicted at an individual level. This novel analysis framework in chronically infected individuals allows improving the evaluation of outcomes in clinical trials, and provides a new background to further understanding the clinical impact of T. cruzi infection.