A Parasite Biomarker Set for Evaluating Benznidazole Treatment Efficacy in Patients with Chronic Asymptomatic Trypanosoma cruzi Infection

Abstract

One of the current greatest challenges of Chagas disease is the establishment of biomarkers to assess the efficacy of drugs in a short period of time. In this context, the reactivity of sera from 66 adults with chronic indeterminate Chagas disease (IND) for a set of four Trypanosoma cruzi antigens (KMP11, PFR2, HSP70, and 3973 d ) was analyzed before and after benznidazole treatment. The results showed that the reactivity against these antigens decreased at 9, 24, and 48 months after treatment. Moreover, the 42.4% and 68.75% of IND patients met the established standard criteria of therapeutic efficacy (STEC) at 24 and 48 months posttreatment, respectively. Meeting the STEC implied that there was a continuous decrease in the reactivity of the patient sera against the four antigens after treatment and that there was a substantial decrease in the reactivity for at least two of the antigens. This important decrease in reactivity may be associated with a drastic reduction in the parasite load, but it is not necessarily associated with a parasitological cure. After treatment, a positive PCR result was only obtained in patients who did not meet the STEC. The percentage of granzyme B ϩ /perforin ϩ CD8 ϩ T cells was significantly higher in patients who met the STEC than in those who did not meet the STEC (35.2% versus 2.2%; P Ͻ 0.05). Furthermore, the patients who met the STEC exhibited an increased quality of the multifunctional response of the antigen-specific CD8 ϩ T cells compared with that in the patients who did not meet the STEC.

Target product profile for a test for the early assessment of treatment efficacy in Chagas disease patients: An expert consensus

“…A test allowing the early assessment of antiparasitic treatment efficacy in Chagas disease patients has been recognized as a priority for a long time [16,17,19,27]. However, despite some recent advances [28,29], these tests are currently only available for research use.…”

“…This TPP should guide the development of tests to rapidly evaluate Chagas disease antiparasitic treatment efficacy. These tests might be based on biomarkers derived from the parasite, such as PFR2, KMP11, HSP70, the peptide 3973, F29, αGal-containing antigens, and the list of epitope-based antigens provided by Granjon and colleagues [28][29][30][31][32][33][34]; biomarkers derived from the host, such as hypercoagulability markers F1+2 and ETP [35], and the APOA1 and FN fragments [36]; or a combination of both. At present, preliminary results using Infinity antigen 3 (AG 3; derived from the parasite) and the SaMi-Trop cohort from Brazil show promise, but further insight is required to ensure that the 40% parasite clearance reported upon treatment persists over time [28].…”

T Cell Specificity: A Great Challenge in Chagas Disease

“…Although different outcomes for memory phenotype, senescence and antigen experience were found depending on the peptide analyzed, CD8 + T cells specific to all the peptides showed a high percentage of these cells at an advanced stage of differentiation (CD45RA + CD127 - ) both before and after treatment ( 40 ). In a prior report, the same group had characterized the functional capacity of antigen-specific CD8 + T cells (based on the expression of IFN-γ, IL-2, TNF-α, granzyme B and perforin) before and after drug treatment but, in this case, they used recombinant proteins instead of peptides from those T. cruzi antigens ( 75 ). Patients showing therapeutic efficacy (based on serological response) presented polyfunctional antigen-specific CD8 + T cells whereas cells from patients with therapeutic failure were monofunctional ( 75 ).…”

The senseless orphanage of Chagas disease

“…The aim of several ongoing studies is to identify and validate markers to early address disease prognosis and/or therapeutic response. These studies have evaluated both parasite-derived markers [83][84][85], as well as host-derived ones [86][87][88][89]. The latter could be classified into three main groups: (i) immunological markers (cytokines) elicited by the host cellular response to the infection; (ii) biochemical biomarkers, such as hypercoagulability markers, fragments of apolipoprotein A1 (ApoA1), or transforming growth factor beta (TGFβ); and (iii) inflammatory markers of cardiac damage (e.g.…”

“…Very recently, the use of cytokine IL17A as biomarker of treatment response has generated expectation [91], but further studies should be implemented to better characterize and validate them, especially in chronically infected adult population. On the other hand, expectations have been as well deposited on a promising group of parasitederived biomarkers, which mostly encompass parasite surface molecules [83][84][85]92]. The future availability of different types of long-awaited early response-to-treatment biomarkers, and the corresponding tests based on them will be crucial to "un-orphan" Chagas disease.…”