The lack of clear and early biological markers that can indicate parasitological outcome following treatment and, ultimately, definitive cure is a major problem in drug development for Chagas disease. To date, the only measurable outcomes are clinical benefit and seroconversion, but the latter can take several decades.
The initial focus has been on optimizing blood sampling procedures and validation of DNA quantification through polymerase chain reaction (PCR). The TRAENA and BENEFIT projects, two placebo-controlled clinical studies of benznidazole in adult patients with chronic Chagas disease, offer the opportunity to correlate serological response and PCR outcomes with long follow-up after treatment. In the longer-term, DNDi is working towards identifying new biological markers including those identified through proteomic platforms, lytic antibodies, T-cell assays, multiplex serodiagnostic assays and gene expression profiling. Continued follow-up evaluation of lytic antibodies and PCR is underway, together with an analysis of the landscape of known biological markers.
A project with the University Hospitals of Geneva and McGill University to assess the use of proteomic signatures in serum samples of nifurtimox-treated Chagas patients identified biological markers of potential for early assessment of therapeutic response, and preliminary results from children treated with benznidazole have now been obtained.
DNDi is collaborating with the University of Georgia and the Texas Biomedical Research Institute in a Wellcome Trust funded, non-human primate study in naturally infected animals with chronic Chagas disease, to further determine PCR and other markers as sensitive tools to consistently differentiate parasitological cure from treatment failure. The dosing period of this study has now been concluded and a 12-month follow-up assessment is to be completed in August 2015. DNDi is a member of the NHEPACHA network of investigators created for the long-term cohort evaluation of potential biomarkers.