Chagas Disease Treatment Efficacy Biomarkers: Myths and Realities

Abstract

Chagas disease (CD), caused by Trypanosoma cruzi, affects millions of people worldwide. Although CD R&D has made progress during the last decade, clinicians and general practitioners are still facing the same challenge, i.e., the lack of adequate markers of clinical cure, hindering assessment of new drug efficacy in clinical trials and counseling of patients about treatment outcome. To date, no new markers have been validated as surrogates of seroreversion-the only marker of parasitological cure which is itself considered to be a surrogate of clinical benefit. T. cruzi DNA detected using PCR cannot currently be considered as a surrogate of seroconversion. Much emphasis has been placed on different T. cruzi antigens but no definite proof of correlation between titers, as determined by serology at a given timepoint, and seroreversion has been shown. Thanks to the improvement of analytical methods and the application of new methodologies, the identification of potential new markers is being facilitated, and some of these are progressing. However, there is a long journey from the identification of a potential biomarker to its clinical validation and acceptance by the regulatory authorities that requires a common effort from the entire Chagas community.

Chagas disease diagnosis and cure assessment: Getting formally hierarchical about a naturally hierarchical problem

“…This reflects the general problem of imperfect test specificity. In what follows, I will focus on target availability and test sensitivity by temporarily assuming 100% specificity; although hard to ensure even under best sampling and laboratory practices, specificity may be close to 100% for direct ascertainment of pathogen presence (e.g., through microscopy-, culture-, or xenodiagnosis-based parasitological methods) and for some DNA-based tests (e.g., using PCR or isothermal amplification) (see [ 2 , 3 , 6 ] and, for an example on T . cruzi detection in its vectors, [ 8 ]).…”

A Rapid Review on the Efficacy and Safety of Pharmacological Treatments for Chagas Disease

“…The only method to define a parasitological cure at this stage is sero-reversion, which can take several years to decades to occur or may never happen. This obvious limitation makes the determination of the curative action of trypanocidals with the current serological tools available extremely difficult, if not impossible; for that reason sero-reversion should not be used as an endpoint in clinical trials [ 38 ]. The detection of parasites in the peripheral blood is a useful tool for determining if treatment was unsuccessful, but is not useful for determining a cure, as parasites may disappear in the peripheral blood and remain in the amastigote form within tissue pseudocysts [ 20 ].…”

Monoclonal Antibodies for Protozoan Infections: A Future Reality or a Utopic Idea?

“…In this stage, the protozoa reach the target organs and in 10–40% of infected subjects can generate cardiomyopathy or mega viscera such as hepatomegaly or splenomegaly ( 63 – 65 ). Despite the efforts to discover novel and safe drugs, anti- T. cruzi chemotherapy for both newborns and adults still relies on nifurtimox (NFX) and benznidazole (BZN), two drugs discovered in the '60s with known adverse side effects ( 64 , 66 ). To improve CD treatment, strategies based on combinations of existing drugs or re-dosing regimens are currently being evaluated ( 67 ).…”