Shorter Once-Daily Benznidazole Course Matches Standard Chagas Treatment With Fewer Side Effects

A shorter and simpler drug regimen could reshape the way chronic Chagas infection is treated around the world. The TESEO trial, a large randomized clinical study co-led by the Barcelona Institute for Global Health (ISGlobal), a center supported by the “la Caixa” Foundation, together with the University of Texas at El Paso and the Bolivian health organization CEADES, has found that benznidazole taken once a day for 30 days is as effective as the current standard of care while producing markedly fewer side effects. The findings, published in The Lancet Infectious Diseases, suggest that a treatment first established more than half a century ago can be safely and effectively shortened, potentially removing one of the biggest obstacles that keeps most infected people from ever being cured.

Trypanosoma cruzi, the parasite that causes Chagas disease, infects more than seven million people worldwide, with the heaviest burden concentrated in Latin America. In recent decades, migration and travel have turned the infection into a public health concern well beyond its traditional geographic boundaries, with cases now identified in the United States, Europe and Japan. Although the parasite often remains silent for years, roughly 30 to 40 percent of infected individuals eventually develop Chagas disease, which can lead to serious and potentially life-threatening heart or digestive complications. Despite the scale of the problem, fewer than one percent of infected people are ever diagnosed and treated, a gap driven by weak screening programs, stigma, and the poor tolerability of the drugs that exist.

Only two medicines are available against T. cruzi: benznidazole and nifurtimox. Both were developed in the 1960s and 1970s, and both are still administered according to dosing schedules that have barely changed since then. The standard benznidazole course requires patients to take the drug twice a day for 60 days, a demanding commitment for people who may live far from clinics or have jobs that make midday dosing difficult. More importantly, these prolonged regimens frequently cause adverse reactions ranging from skin rashes and digestive complaints to neurological symptoms, and up to 31 percent of patients abandon treatment before finishing it. Because treatment completion is essential for curing the infection, side effects and pill burden translate directly into treatment failure at the population level.

TESEO was designed to test whether alternative durations and dosing schedules could improve that equation. According to Igor Almeida of the University of Texas at El Paso, corresponding author and co-senior author of the study alongside Faustino Torrico of CEADES and Joaquim Gascón of ISGlobal, the trial was the first randomized clinical study to evaluate benznidazole and nifurtimox head-to-head under identical conditions, with sustained follow-up designed to detect parasites in the blood by PCR for three years. This long observation window matters because the parasite can persist at very low levels after treatment, and confirming sustained clearance requires patient monitoring that many earlier studies simply could not provide.

The phase 2b trial enrolled 450 adults at three centers in Bolivia, a country where Chagas infection remains highly endemic and where the research team has decades of clinical experience. Participants were randomly assigned to one of six treatment groups. Three groups received benznidazole, either as the 60-day standard regimen or as shortened 30-day and extended 90-day courses, while three parallel groups received nifurtimox on the same three schedules. Throughout the study, investigators recorded every drug-related adverse event and periodically tested participants’ blood for parasite DNA using quantitative PCR, a molecular technique sensitive enough to detect residual infection that microscopic or serological methods would miss. The statistical design and analysis were led by the ISGlobal Biostatistics Unit, which also supported an independent board responsible for monitoring patient safety throughout the trial.

The safety results pointed clearly in one direction. Only the 30-day benznidazole regimen significantly reduced side effects: 37 percent of participants on that schedule experienced a drug-related adverse event, compared with 60 percent of those on the standard 60-day course, a reduction of nearly 40 percent. Tolerability translated directly into adherence. On the shorter regimen, 83 percent of patients completed treatment without interruption, versus 60 percent on the standard schedule. An additional practical advantage is that the 30-day course requires only one dose per day rather than two, simplifying life for patients and health systems alike. The researchers also observed that most side effects appeared within the first two weeks of treatment regardless of how long the drug was continued, and that almost all of these reactions resolved, suggesting that the later weeks of the standard course add toxicity without adding early-warning signals.

Crucially, the shorter course did not sacrifice efficacy. Three years after treatment ended, the parasite remained undetectable in the blood of 94 percent of participants in the 30-day benznidazole group, compared with 95 percent in the standard 60-day group. Because the trial was designed as a non-inferiority study, this narrow difference met the prespecified statistical criterion, meaning the shorter regimen could be considered as effective as the established one. Among the six strategies tested, the 30-day benznidazole course therefore offered the best overall balance between benefits and harms. The nifurtimox arms performed less well across the board, with parasite clearance rates ranging from 81 to 90 percent, reinforcing benznidazole’s position as the preferred first-line option where it is available and tolerated.

The implications extend beyond individual patients to the economics and logistics of public health programs. Because the 30-day regimen uses a quarter of the total drug required by the standard course, the same supply of benznidazole can treat four times as many people. Torrico highlighted this point directly, noting that four patients can now be treated with the amount of drug previously needed for one. Gascón added that the improved safety profile, combined with once-daily dosing, has the potential to substantially increase the proportion of patients who complete treatment, which is precisely the bottleneck that has limited the impact of Chagas therapy for decades. For national control programs in Latin America and for growing patient populations in the United States and Europe, a shorter, cheaper and better-tolerated cure could make routine treatment far more feasible.

The authors caution that larger phase 3 trials are needed to confirm the results before the 30-day regimen can be written into official treatment guidelines, and they emphasize that people currently receiving therapy for Chagas disease should continue the regimen prescribed by their doctor. Even so, the trial represents a milestone for a disease long classified as neglected. By demonstrating that a 50-year-old drug can be given more briefly, more conveniently and more safely without losing efficacy, TESEO provides the strongest evidence yet that the barriers keeping millions of people from a cure can be substantially lowered. The study was funded by the National Institute of Allergy and Infectious Diseases, part of the US National Institutes of Health, and is registered as ClinicalTrials.gov NCT03981523. The authors declare no competing interests.

Subject of Research: A randomized phase 2b trial comparing alternative benznidazole and nifurtimox regimens for chronic Trypanosoma cruzi infection

Article Title: A shorter, better-tolerated treatment for chagas disease is possible

Article References: A shorter, better-tolerated treatment for chagas disease is possible. (n.d.). Original publication

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DOI: Not provided

Keywords: Chagas disease, Trypanosoma cruzi, benznidazole, nifurtimox, TESEO trial, randomized clinical trial, neglected tropical diseases, ISGlobal, treatment adherence, parasitology, Bolivia, The Lancet Infectious Diseases