Theseus in the Labyrinth and the Cure for Chagas Disease

In Greek mythology, Theseus was a hero who entered the Minotaur’s labyrinth using Ariadne’s thread as his guide. After freeing Crete from the monster that had taken so many lives, he found his way out of the labyrinth by retracing his steps, following the thread.

If the minotaur represents Chagas disease, the thread is the network of people united in the fight against this ailment. The TESEO project—whose name happens to be the Spanish form of Theseus—is contributing to the struggle against the disease by testing new treatment regimens in Bolivian patients. By spinning this thread, we hope to find our way through the labyrinth of Chagas. Our network consists of ISGlobal, the University of Texas at El Paso (UTEP) in the United States, CEADES in Bolivia, the López Neyra Institute of Parasitology and Biomedicine (IPBLN) in Spain, the US Food and Drug Administration (FDA) and the Mundo Sano Foundation, with financial support from the US National Institutes of Health (NIH).

If the minotaur represents Chagas disease, the thread is the network of people united in the fight against this ailment. The TESEO project—whose name happens to be the Spanish form of Theseus—is contributing to the struggle against the disease by testing new treatment regimens in Bolivian patients

TESEO, which stands for the original name of the study (New chemoThErapy regimens and biomarkerS for Chagas Inf EctiOn), took up this challenge in late 2019, although since then the project has suffered some delays due to the pandemic. We expect to have our first results by May 2024, on completion of patient follow-up.

The currently approved treatments for Chagas disease—benznidazole (BNZ) and nifurtimox (NFX)—were developed in the 1970s. The efficacy of both drugs in Chagas patients is variable and depends on the stage of the disease, the drug dose, the age of the patient and the infecting strain of Trypanosoma cruzi, the parasite that causes Chagas disease.

The word “cure” always generates controversy when used in reference to Chagas disease, since we do not have biomarkers to prove once and for all the full efficacy of the current drugs. We say this as a formality, because the treatment is undoubtedly effective. We know this because, among other approaches, we have a molecular biology technique called qPCR that allows us to observe the presence, absence or decrease in the number of parasites in the blood.

Photo: Cristina Alonso-Vega. Recruitment of patients at the TESEO Project. Cochabamba, Bolivia.

The two current drugs, benznidazole and nifurtimox, work quite well. But there are still three problems we need to solve: the possible side effects that occur in some cases, the duration of the current treatment regimen (60 days), and the lack of biomarkers that would allow us to quickly find out whether the treatment has eliminated the parasite and be able to say, confidently, that a patient has been cured. These problems are compounded by those intrinsic to a disease that has multiple routes of transmission and additional neglect-related issues, which can make outlining a comprehensive care strategy a labyrinthine challenge.

The two current drugs, benznidazole and nifurtimox, work quite well. But there are still three problems we need to solve: the possible side effects that occur in some cases, the duration of the current treatment regimen (60 days), and the lack of biomarkers

Studies currently underway are testing treatment regimens of different durations with lower doses of drugs. The study design of TESEO includes six treatment arms, two of which are standard 60-day treatment with benznidazole or nifurtimox, and four of which are experimental arms: short 30-day treatment with benznidazole or nifurtimox and 90-day treatment with benznidazole or nifurtimox. In three of the four experimental arms, the dosage and frequency of the drug are halved.

Will this result in fewer side effects? In all likelihood, yes, since the dosage is lowered in all treatment regimens being studied. But how can we demonstrate the true efficacy of these regimens?

To answer that question, we will have to go deep into the labyrinth of time and extend our patient follow-up for three years. Ours will be one of only a few studies with patients on drug treatment that have gone beyond 12 months of follow-up. In addition to conventional serology and qPCR tests, we will test new host-derived and parasite-derived biomarkers, which showed promising results in previous studies, to measure early response to treatment.

Photo: Ana Ferreira. Treatment regimen of a patient with Chagas. Bolivia.

For this study, we are counting on the collaboration of 450 people with asymptomatic chronic Chagas disease and mild cardiac involvement in Cochabamba, Tarija and Sucre. These patients are treated at centres belonging to the Platform for the Comprehensive Care of Patients With Chagas Disease, which is currently integrated into the Bolivian health system, and coordinated by ISGlobal and CEADES.

Population pharmacokinetics of both drugs will also be studied, and these data will be correlated with both the incidence of adverse events and parasitic load clearance as measured by qPCR. Parasite genotyping will also be performed in all patients before treatment and in patients with positive qPCR results at the end of the treatment period or during follow-up. This will give us information about the types of parasites circulating in the region and their relationship to treatment response.

Thanks to the scope of the TESEO project, its lengthy follow-up period and the parameters studied, we hope to lay the groundwork for new approaches to the treatment of Chagas disease

Thanks to the scope of the TESEO project, its lengthy follow-up period and the parameters studied, we hope to lay the groundwork for new approaches to the treatment of Chagas disease. The use of biomarkers for early assessment of therapeutic response and eventual parasitological cure compared to qPCR and conventional serology, in addition to the genotyping of T cruzi, will, in the event of promising results, provide us with new tools. These tools will facilitate the treatment and follow-up of patients in everyday clinical practice and the assessment of new drugs or new treatment regimens with existing drugs, so that we can finally say—unequivocally—that Chagas disease can be cured.