How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?
How Robust Are Malaria Parasite Clearance Rates as Indicators of Drug Effectiveness and Resistance?
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DOI：
10.1128/aac.00481-15
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发表时间：
2015-10-01
影响因子：
4.9
通讯作者：
Hodel, Eva Maria
中科院分区：
文献类型：
--
作者：
Hastings, Ian M.;Kay, Katherine;Hodel, Eva Maria
基于青蒿素的联合疗法（ACT）目前是治疗无并发症的恶性疟疾（人类最致命的疟疾）的一线药物。根据 ACT 治疗后患者血液估算的疟疾寄生虫清除率已被广泛采用作为药物有效性的衡量标准以及检测是否存在潜在青蒿素耐药性的监测工具。该指标尚未经过详细研究，也尚未确定其属性或潜在缺点。在此，将药物治疗的药理学、寄生虫生物学和人体免疫相结合，研究 ACT 后寄生虫清除的动态。这种方法简单地恢复了主要的临床特征和清除动态。人类免疫力是清除率的主要决定因素，除非或直到青蒿素的杀灭作用已降至接近无效的水平。因此，清除率是非常不敏感的监测指标，可能会导致过度自信，因为即使药物敏感性大幅降低，也可能不会被检测为较低的清除率。同样严重的是使用清除率来量化 ACT 治疗方案变化的影响，因为这种策略可能会错过药物有效性的大幅提高。特别是，疟疾界可能错过了通过改变治疗方案（特别是通过改用每日两次治疗方案和/或增加青蒿素剂量水平）来大幅提高 ACT 有效性的机会。因此，疟疾界似乎过度依赖单一的药物有效性指标，即寄生虫清除率，该指标存在重大且严重的缺陷。
Artemisinin-based combination therapies (ACTs) are currently the first-line drugs for treating uncomplicated falciparum malaria, the most deadly of the human malarias. Malaria parasite clearance rates estimated from patients' blood following ACT treatment have been widely adopted as a measure of drug effectiveness and as surveillance tools for detecting the presence of potential artemisinin resistance. This metric has not been investigated in detail, nor have its properties or potential shortcomings been identified. Herein, the pharmacology of drug treatment, parasite biology, and human immunity are combined to investigate the dynamics of parasite clearance following ACT. This approach parsimoniously recovers the principal clinical features and dynamics of clearance. Human immunity is the primary determinant of clearance rates, unless or until artemisinin killing has fallen to near-ineffective levels. Clearance rates are therefore highly insensitive metrics for surveillance that may lead to overconfidence, as even quite substantial reductions in drug sensitivity may not be detected as lower clearance rates. Equally serious is the use of clearance rates to quantify the impact of ACT regimen changes, as this strategy will plausibly miss even very substantial increases in drug effectiveness. In particular, the malaria community may be missing the opportunity to dramatically increase ACT effectiveness through regimen changes, particularly through a switch to twice-daily regimens and/or increases in artemisinin dosing levels. The malaria community therefore appears overreliant on a single metric of drug effectiveness, the parasite clearance rate, that has significant and serious shortcomings.