The BENEFIT Trial: Where Do We Go from Here?

In the next five years, we can now project that 200,000 people living with Chagas disease will die from heart disease and related complications. We urgently need to redouble our efforts to identify and treat young people who are still in the early stages of their illness, but ultimately we need to find better treatments and new cures. According to recent estimates, there are 5.7–9.4 million people living with Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi), a neglected tropical disease and leading cause of heart disease and cardiomyopathy, especially in Latin America and the United States [1,2]. Today, less than 1% of people infected with T. cruzi have access to diagnosis and treatment [3], a consequence of the fact that Chagas disease mostly affects those living in extreme poverty and in marginal surroundings. This finding is especially sad given new information by the World Health Organization (WHO) stating that more than one-half of Chagas disease sufferers live in Latin America’s three wealthiest countries—Argentina, Brazil, and Mexico [1]. Moreover, there are hundreds of thousands of infected people living in the US, with emerging evidence for significant T. cruzi transmission in Texas [4,5]. In this sense, Chagas disease represents one of the Western Hemisphere’s greatest health disparities. Moreover, in recent years we also have seen the globalization of Chagas disease to Spain and elsewhere in Europe and worldwide [6]. For years, the community of scientists, physicians, and other health care providers and Chagas disease patients has been awaiting the results of the Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial, which was designed to evaluate the safety and efficacy of benznidazole in patients with Chagasic cardiomyopathy [7]. Approximately 20%–30% of T. cruzi-infected individuals progress to Chagasic cardiomyopathy, a debilitating heart condition associated with conduction disturbances, heart failure, and sudden death. While it is established that benznidazole is effective in curing Chagas disease patients during their early acute phase [8–11], very few individuals are diagnosed at this stage of the disease. The BENEFIT trial aimed to determine if the 1.17 million people now living with Chagasic cardiomyopathy (WHO estimate [1]) might also experience improved clinical outcomes or even cures with benzimidazole treatment. Unfortunately, the answer appears to be “no.” Compared to a placebo control, benznidazole did not result in a statistically significant improvement in cardiac clinical outcomes. Although the study was not sufficiently powered to show incremental benefits in cardiac outcome (on the order of 5%–15%), it is clear that our current strategies for antiparasitic chemotherapy need to be revisited for patients with evidence of Chagasic heart disease. But there is additional bad news—the BENEFIT trial found that in both treated and placebo arms (comprising almost three thousand patients), 17%–18% died over a five-year time frame, most from cardiac complications [7]. If we extrapolate from the WHO estimate, this means that roughly 200,000 people will die from Chagasic cardiomyopathy over the next five years. To put this number in perspective, it is almost identical to the number of women living in the US who will die from breast cancer over the same period [12]. Whereas breast cancer is now linked with a highly successfully and accomplished advocacy and awareness campaign that promotes early detection and treatment, as well as research and development (R&D) into an exciting portfolio of new and innovative therapies, we are now facing almost the opposite situation with Chagas disease and cardiomyopathy. Today, there are few advocates for the millions of Chagas disease sufferers mostly living in poor and marginalized conditions. As a result, the vast majority have no access to diagnosis and treatment, and far too little is invested into R&D for new drugs, vaccines, and other tools (including tests for cure). From our perspective, the BENEFIT trial is a wake-up call to aggressively pursue a global initiative of diagnosis, treatment, and research, emphasizing the following specific points: