Citation: Alonso-Padilla J, Abril M, Alarcón de Noya B, Almeida IC, Angheben A, Araujo Jorge T, et al. (2020) Target product profile for a test for the early assessment of treatment efficacy in Chagas disease patients: An expert consensus. PLoS Negl Trop Dis 14(4): e0008035. https://doi.org/10.1371/journal.pntd.0008035
Editor: Helton da Costa Santiago, Universidade Federal de Minas Gerais, BRAZIL
Published: April 23, 2020
Copyright: © 2020 Alonso-Padilla et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: ISGlobal work is supported by the Departament d’Universitats i Recerca de la Generalitat de Catalunya, Spain (AGAUR; 017SGR00924) and by the Instituto de Salud Carlos III (ISCIII) RICET Network for Cooperative Research in Tropical Diseases (ISCIII; RD16/0027/0004 - PI1290) and FEDER. MJP research is supported by the Ministry of Health, Government of Catalonia (PERIS 2016-2010 SLT008/18/00132). ICA, JG, and FT are supported by the grant number U01AI129783 from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). ICA is also partly supported by the grant number 5U54MD007592 from the National Institute on Minority Health and Health Disparities (NIMHD), NIH. MCL and MCT were supported by ISCIII RICET grant RD16/0027/0005 - PI1290 and FEDER and by grants SAF2016-81003-R and SAF2016-80998-R from the Spanish “Programa Estatal I+D+i (MINECO)”. AA's work was supported by the Italian Ministry of Health “Fondi Ricerca Corrente - Linea 3, progetto 9” to IRCCS Sacro Cuore Don Calabria Hospital. JR was supported by CONACyT Fossis grant #261006. The Drugs for Neglected Diseases initiative (DNDi) is grateful to its donors, public and private, who have provided funding to DNDi since its inception in 2003. A full list of DNDi's donors can be found at http://www.dndi.org/donate/donors/. FIND is grateful to its donors, public and private, who have helped bring innovative new diagnostics for diseases of poverty. A full list of FIND’s donors can be found at: https://www.finddx.org/partners-donors/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. IA, MCL, MCT, AMR, and MZ are involved in the development of serological assays based on parasite-derived biomarkers for the early assessment of treatment response in Chagas disease. No patents applications or other forms of intellectual properties will be considered in this development work.
Six to 7 million people are estimated to be infected by Trypanosoma cruzi, the parasite causing Chagas disease . Thirty to 40% of them, i.e., 1.8 to 2.4 million people, will suffer cardiac disorders and/or digestive clinical manifestations if they are not treated early during the course of the infection [1, 2]. However, only a small fraction of patients are properly diagnosed and treated . Current clinical guidelines recommend treating T. cruzi–infected people if they are asymptomatic or present early symptoms of the disease (Table 1) [4, 5]. Benznidazole (BNZ) and nifurtimox (NFX) are the first-line antiparasitic treatments currently available, both with long administration regimens (60 days) that can produce adverse side effects [6–8]. Despite the fact they are not 100% effective in patients with chronic disease [9–12], they are the only drugs currently registered, and the benefits of their administration have been confirmed in several clinical studies [9–14]. Currently, clinical trials with new compounds, using alternative regimens that aim to maintain efficacy whilst reducing toxicity, are ongoing and could lead to new therapeutic opportunities and/or policy change .
In any case, the absence of a test for the early assessment of treatment efficacy, often called a test of cure (ToC), is a major obstacle to Chagas disease control. Accurately monitoring treatment response would undoubtedly improve patient management and support the conduct of clinical trials. Although treatment efficacy and treatment response may be conceptually different, we are using these terms synonymously for the purpose of the current target product profile (TPP) [16, 17].
Unfortunately, there is no gold-standard test for the early determination of whether someone who has been treated for chronic Chagas disease has been cured or not. Current methods used for monitoring Chagas disease treatment efficacy are suboptimal due to the fact that: (1) clinical progression of the disease is silent and associated with complex and mostly unknown host–pathogen interactions; (2) once in the chronic stage, infected subjects remain seropositive for years, with very low and intermittent parasitemia counts; and (3) as a consequence, in the chronic phase, parasitological detection methods have very low sensitivity, whereas molecular detection can only be done in reference laboratories. Besides, clinical evaluation may not be specific to Chagas disease and cannot be used in cases where some structural tissue damage already exists. In addition, measuring seroconversion by conventional tests is not viable as it may take years or decades for a patient with chronic disease to revert serologically. Finally, the posttreatment detection of circulating parasites (through their DNA) by molecular amplification techniques, such as quantitative polymerase chain reaction (qPCR), may be useful for determining treatment failure, but a negative qPCR result cannot be considered a surrogate of cure .
Development of a test that can determine in a timely manner if a patient treated for Chagas disease has successfully responded to treatment has therefore been identified as a priority . As mentioned above, such a test could be used in two different scenarios or use cases: (1) the daily clinical management (DCM) of Chagas disease patients posttreatment to decide if and/or when a patient should be followed up after treatment completion and (2) in the context of clinical trials (CT), where the test would be used as the endpoint measurement for the evaluation of new anti–T. cruzi treatments.
The development of this test (or tests) should be guided by a TPP. TPPs for a test to assess treatment response in Chagas disease patients have been suggested previously [17, 19]. Building on them, we now present a TPP specifically describing the required technical and performance characteristics of a test to determine if a Chagas disease patient has been cured posttreatment. We have considered two use scenarios: day-to-day healthcare provision and clinical evaluation of new anti–T. cruzi drugs or alternative regimens of the drugs currently available.
As in previous TPPs [17, 19], we defined the test characteristics on the basis of Chagas disease expert opinion on the response to anti–T. cruzi treatment in Chagas disease patients. Discussions leading to this TPP document were coordinated and developed by the NHEPACHA (new tools for the diagnosis and evaluation of Chagas disease patients) network . Created in 2011 with the goal of identifying and validating the use of biomarkers for Chagas disease, the network currently consists of 14 groups, 11 of them from America and the remaining three from Europe. The network includes expert clinicians working with patients, researchers working in academia, and specialists in industry and product development partnerships (PDPs). All of them were first asked to come to a consensus on a series of definitions to be used in the TPP (Table 1). Then they were asked to agree on the parameters for each of the test characteristics. The categories used in the TPP were adapted from previously published TPPs for diagnostic tests [21–23] and included specific features such as number of samples or timing of sampling.
Several face-to-face meetings were organized (in March 2017, March 2018, and March 2019), and email surveys were sent around in preparation for the final consensus document. For each of the characteristics in the TPP, specialists were asked to take into consideration both use-case scenarios. Since the requirements for a test to be used as an endpoint in clinical trials for new drugs or new regimens (use case 1; CT) may be more stringent, such a test should meet, in general, “ideal” conditions. This does not apply to the “operational characteristics” in which “ideal” conditions are related to a test to improve daily clinical management of treated Chagas disease patients (use case 2; DCM).
The TPP for a test for early assessment of treatment response in Chagas disease patients is presented in Table 2. This takes into consideration the following parameters: scope, performance, and operational characteristics.
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.
The development and evaluation of such a test is challenging for multiple reasons, including the lack of a practical gold standard and consensus on the definition of a cure for Chagas disease patients (see Table 3). In this paper, we have tried to address these issues and built on the previous TPPs [17, 19] to develop a detailed description of the requirements of a ToC for two use cases: management of Chagas disease patients and development of new drugs or alternative regimens using currently available drugs.
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 [28–34]; biomarkers derived from the host, such as hypercoagulability markers F1+2 and ETP , and the APOA1 and FN fragments ; 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 . It also remains to be shown how this compares to trends in conventional serology reactivity and whether similar levels of response can be found with samples from other geographic origins . All the studies that evaluated host-derived markers were performed with a reduced number of samples, and therefore their potential will need to be assessed with larger collections.
The TPP can also help to evaluate the approaches currently used to assess treatment efficacy: serology and qPCR. The latter has been used in clinical studies as a test for treatment failure. Serial blood sampling and molecular amplification reactions have been implemented to assess the absence of circulating T. cruzi DNA in chronically infected patients during treatment follow-up . A major limitation of the use of qPCR to monitor treatment response is that it has not been assessed in long-term cohorts and studies; consequently, a negative molecular outcome at a specific time cannot exclude that a relapse may occur later on. As a result, there remains an urgent need for more reliable and straightforward tests to evaluate treatment efficacy, which we expect this TPP can help to streamline.
We have presented a new and complete TPP for the development of tests for the early assessment of Chagas disease treatment efficacy. In the context of this neglected infectious disease, this is mostly an underrepresented area of investigation, and the current lack of such tests greatly hampers the management of patients and control of the disease.
Today, the large majority of the 6 to 7 million people infected by T. cruzi remain untreated . Recent advances in diagnostics (e.g., use of rapid diagnostic tests)  and treatment (e.g., a shorter course—two weeks instead of eight weeks—of BNZ), as well as the implementation of new access strategies and an increasing availability of drugs, will hopefully result in a rapid increase in the number of patients treated in the next few years . A test for the early assessment of treatment efficacy will be fundamental to managing those patients, as well as to accelerating the evaluation of new drugs or regimens. The TPP described in this article can guide the development and uptake of these tests.
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