Table 1. Definitions used to develop the TPP for a test for the early assessment of treatment efficacy in Chagas disease patients.

Concept	Definition	Current diagnostic
Acute Chagas disease	The first phase of T. cruzi infection is characterized by a high number of parasites circulating in the blood that can be detected by direct methods (e.g., microscopy). In most cases, symptoms are absent or mild and unspecific. Acute Chagas disease occurs after a short incubation time (5–15 days on average, longer for cases of transmission by blood transfusion) and can last for 2 months. Infection may occur by vectorial transmission when T. cruzi parasites enter the body via a skin break caused by a bug bite, by skin breaching after scratching the bite site, or via mucosal entry (e.g., oral transmission through contaminated food). Vector-independent transmission routes include: congenital infection; blood transfusion; cell, blood, or tissue transplantation; and needle sharing. Infection can also occur accidentally after the manipulation of infected triatomines and/or infected animals or laboratory samples. Immunocompromised patients with chronic T. cruzi infection are at risk of the disease being reactivated and then undergoing an acute presentation with a high mortality rate.	During the acute phase, T. cruzi infection is diagnosed by direct detection of the parasite or parasite DNA circulating in the bloodstream or the detection of specific IgM and IgG antibodies.
Chronic Chagas disease	After a variable period (4–8 months) of infection or after unsuccessful treatment, the chronic phase is established during which T. cruzi parasites mainly persist in a variety of tissues. Patients in the chronic phase of the disease can be clinically divided into two groups:     •Asymptomatic patients without demonstrable disease, who are characterized by the absence of damage or organ alterations following evaluation through “classic” diagnostic tools (electrocardiogram, plain thoracic X-rays, echocardiogram, Rezende technique). These patients’ clinical status is also known as the chronic indeterminate form.     •Symptomatic patients with demonstrable disease (around 30%–40% of those chronically infected), who show a variable degree of cardiac disorder and/or digestive clinical manifestations. They suffer from the chronic determinate form. Chronic Chagas disease patients can also be classified based on the level of tissue damage (e.g., Kuschnir´s modified classification for cardiac damage or Ximenes and Rezende classifications for digestive damage) [24].	Patients in the chronic phase are diagnosed via the detection of T. cruzi antibodies which, according to WHO recommendations, entails obtaining concordant positivity in two tests based on different sets of T. cruzi antigens [4].
Chagas disease treatment	According to current guidelines [25], treatment should be offered to all patients except those with advanced Chagas disease (e.g., Kuschnir grade III), where it is not recommended.     • In patients with Kuschnir grade II, age can be taken into consideration when evaluating treatment administration.     • Treatment of patients with digestive damage is dependent on the degree of involvement, similar to the approach for cardiac patients (not an evidence-based recommendation). Arguments in favor of excluding advanced cases from treatment are based on the rationale that in the late stages of the disease, parasite load and activity may no longer be relevant in determining disease evolution. This was concluded by the BENEFIT trial (ClinicalTrials.gov Identifier: NCT00123916) in relation to cardiac pathology [12].
Cure in Chagas disease patients	Elimination of T. cruzi parasites from the patient’s body following treatment.
Treatment efficacy	Treatment success: elimination of T. cruzi parasites from the patient’s body, independently of whether the infection is asymptomatic or symptomatic, after specific treatment. Treatment failure: the detection of T. cruzi parasites in the patient’s body after specific treatment.	Markers of T. cruzi elimination (treatment success):     • Indirect: seroconversion (from positive to negative) in terms of reactivity against T. cruzi antigens. Markers of T. cruzi presence (treatment failure):     • Direct: positive parasitemia measured by T. cruzi DNA amplification reaction.     • Indirect: persistence of reactivity against T. cruzi antigens.

IgG, immunoglobulin G; IgM, immunoglobulin M; TPP, target product profile; WHO, World Health Organization