Biomarker-Based Test of Cure for Chagas Disease

Project Summary Chagas disease, caused by infection with Trypanosoma cruzi, is the most prevalent parasitic disease in the western hemisphere, infecting 8-11 million individuals and with over 70 million at risk. The infection is transmitted by an insect vector, but can also be acquired through blood transfusion, organ transplant, or congenitally. Following a brief acute phase, the parasite persists for years as a chronic, but often asymptomatic infection, which may progress to cardiomyopathy and other pathological conditions leading to severe morbidity and mortality. In the U.S., the prevalence of T. cruzi infection in immigrant populations has led to the implementation of blood screening assays to prevent transfusion transmission. Autochthonous transmission can be expected based on the gradual encroachment of the insect vector into the southernmost regions of the U.S. Treatment for Chagas disease currently relies on two drugs, benznidazole and nifurtimox. While these drugs are highly effective if used during the acute phase, their efficacy in the chronic phase varies, decreasing with increasing duration of infection. Moreover, due to their known toxicity, both drugs are known to have frequent adverse effects, which intensify with patient age. Benznidazole has been approved by FDA only for use on children aged 2-12, while nifurtimox has been approved for children up to age 18; adults are currently treated off-label. A variety of efforts are underway to develop new drugs to treat Chagas disease, supported by public health organizations and pharmaceutical companies. However, a major limitation is the lack of a reliable, standardized and validated test to measure the efficacy of Chagas drugs and to establish whether treatment is successfully eliminating an individual patient’s infection for purposes of clinical management. The aim of this project is the development of a test that measures the response to treatment in Chagas disease patients that will address these needs. Of the methodologies that have been evaluated for measuring effects of drug treatment on T. cruzi infection, serology has been the mainstay. A decrease in antibody titer to T. cruzi over time following treatment has been used as a de facto test for treatment response, but no commercial assay has been designed and validated for this use, and available assays only show changes in antibody titer over a period of many years. In Phase I, we identified T. cruzi peptide antigens to which IgG antibody titers declined rapidly in treated patients, providing a sensitive means to measure treatment response within a year. Prototype assays based on these peptides have been developed in both ELISA and lateral flow formats to enable testing in both laboratory and point-of-care settings. In Phase II, the performance of the assays as indicators of treatment response will be evaluated in comparison with conventional serological tests and PCR on well-characterized retrospective serum samples obtained at serial post-treatment time points, and on prospectively acquired samples from patients newly diagnosed and in the course of treatment. Validation of the ELISA and lateral flow assays will lead to introduction of the first commercially available tests of treatment response for Chagas disease.