New chemotherapy regimens and biomarkers for Chagas disease

摘要 恰加斯病是由克氏锥虫寄生虫引起的，在拉丁美洲影响着数百万人。 最近，由于全球化，恰加斯病已经成为一个新兴的世界性公共卫生问题。查加斯 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，以及 终生慢性期，60%-70%的患者临床上无症状或不确定。然而，30%-40%的 慢性患者最终会出现心脏和/或消化并发症。目前，唯一获批的 治疗恰加斯病的药物是苯硝唑(BZN)和硝呋莫司(NFX)。这些药物的疗效是 可变的，取决于疾病阶段、药物剂量、患者年龄和感染克鲁兹旋毛虫菌株(S)。 急性期的治疗对这两种药物都有效。然而，这些药物在成年人中的疗效 长期存在的慢性感染率明显较低且多变。此外，较高的不良反应发生率 这些药物的事件阻碍了它们的正常临床使用，因此1%的患者正在接受治疗。在这 在该项目中，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较低的 标准疗程或延长疗程的BZN和NFX剂量的频率可能相同或 与使用这些药物的标准治疗方案相比，疗效更好，不良事件更少。在这里，我们 计划分析当前和新的宿主和寄生虫来源的BMK，这些BMK在试点中显示出有希望的结果， 完整的临床试验或动物研究，提供疾病状态和治愈的衡量标准。因此，我们的第二个 假说是，在那些对BZN或NFX治疗有反应的患者中，血清中一种或多种 建议的BMK将在治疗后三年内显著减少或转为阴性。为了测试 这两个假设，我们提出了两个具体目标：具体目标1：确定的安全性和有效性 扩大的苯硝唑或硝呋莫司治疗方案的剂量频率较低。具体目标2： 评估宿主和寄生虫来源的生物标记物用于查加斯病化疗的随访。这个 从这个项目中获得的信息还将使先前提议的更好地设计临床试验成为可能 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.