New chemotherapy regimens and biomarkers for Chagas disease

摘要 恰加斯病是由寄生虫克氏锥虫引起的，影响着拉丁美洲数百万人。 近年来，由于全球化，恰加斯病已成为一个新出现的世界性公共卫生问题。恰加斯 疾病有两个阶段：最初的急性期，通常有非特异性症状或无症状， 终身慢性期，在60-70%的患者中临床上无症状或不确定。然而，30-40%的 慢性病患者最终会出现心脏和/或消化系统并发症。目前，唯一获得批准的 治疗南美锥虫病的药物是苄硝唑（BZN）和硝呋莫司（NFX）。这些药物的功效是 可变的并且取决于疾病阶段、药物剂量、患者年龄和感染T. cruzi菌株。 在急性期的治疗是有效的两种药物。然而，这些药物在成人中的疗效 慢性、长期感染的发病率明显较低，且变化不定。此外，不良率高， 这些药物的事件阻碍了它们的常规临床使用，因此<1%的患者正在接受治疗。在这 项目，我们建议测试四种新的BZN和NFX给药方案。我们的第一个假设是， BZN和NFX给药频率，标准或延长治疗持续时间，可能具有相同或 比这些药物的标准治疗方案更好的疗效，不良事件更少。这里我们 计划分析目前和新的宿主和寄生虫衍生的BMK，这些BMK在试验中显示出有希望的结果， 完整的临床试验或动物研究，提供疾病状态和治疗的措施。因此，我们的第二个 假设在对BZN或NFX治疗有反应的那些患者中， 建议的BMK将在治疗后三年内显著减少或变为阴性。测试 根据这两个假设，我们提出了两个具体目标：具体目标1：确定 延长苯并咪唑或硝呋替莫治疗方案，降低给药频率。具体目标2： 评估宿主和寄生虫衍生的生物标志物，用于查加斯病化疗的随访。的 在这个项目中获得的信息也将允许更好地设计临床试验， 药物组合，其中BZN和NFX将发挥核心作用。

ABSTRACT Chagas disease is caused by the parasite, Trypanosoma cruzi, and affects millions of people in Latin America. Lately, Chagas disease has become an emerging worldwide public health issue due to globalization. Chagas disease has two phases: an initial acute phase, usually with nonspecific symptoms or asymptomatic, and a lifelong chronic phase, which is clinically silent or indeterminate in 60-70% of patients. However, 30-40% of chronic patients will eventually develop heart and/or digestive complications. Currently, the only approved drugs for treating Chagas disease are benznidazole (BZN) and nifurtimox (NFX). The efficacy of these drugs is variable and depends on the disease stage, drug dose, age of patients, and infecting T. cruzi strain(s). Treatment in the acute phase is effective with both drugs. However, the efficacy of these drugs in adults with chronic, long-established infections is significantly lower and variable. Moreover, the high rate of adverse events of these drugs has hampered their regular clinical use, thus <1% of patients are being treated. In this project, we propose to test four new dosing regimens of BZN and NFX. Our first hypothesis is that a lower frequency of BZN and NFX dosing, with standard or extended treatment duration, might have the same or better efficacy than the standard treatment regimens with these drugs, with fewer adverse events. Here, we plan to analyze current and novel host- and parasite-derived BMKs that have shown promising results in pilot, full clinical trials or in animal studies, providing a measure of disease state and cure. Thus, our second hypothesis is that in those patients that respond to BZN or NFX treatment the serum levels of one or more proposed BMKs will be significantly reduced or become negative within three years post-treatment. To test these two hypotheses, we propose two specific aims: Specific Aim 1: To determine the safety and efficacy of extended benznidazole or nifurtimox treatment regimens with lower dosing frequency. Specific Aim 2: To evaluate host- and parasite-derived biomarkers for the follow-up of Chagas disease chemotherapy. The information gained in this project would also allow for better-designed clinical trials with previously proposed drug combinations, in which BZN and NFX would play a central role.