Identifying sub-optimal responses to ivermectin in the treatment of River Blindness
Identifying sub-optimal responses to ivermectin in the treatment of River Blindness
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DOI：
10.1073/pnas.0906176106
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发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Basanaz, Maria-Gloria
中科院分区：
文献类型：
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作者：
Churcher, Thomas S.;Pion, Sebastien D. S.;Basanaz, Maria-Gloria
在耐药性成为公共卫生问题之前识别耐药性需要明确区分正常和次优治疗反应的构成。提出了一种分析人类蠕虫病药物疗效研究的新方法，并用于调查最近关于伊维菌素治疗河盲症的非典型反应的说法。使用基于个体的盘尾丝虫病数学模型对伊维菌素治疗后盘尾丝虫微丝蚴在宿主皮肤中重新生长的速率的变异性进行量化。该模型估计了每个采样宿主的单一皮肤再生率，从而可以将次优反应的报告与之前未接触过伊维菌素的人群的反应进行统计比较。据统计，尽管在未使用伊维菌素的人群中观察到的皮肤再生率存在很大差异，但在 3 个加纳村庄（治疗 12-17 次）观察到皮肤再生率更快。另一个先前被认为具有高皮肤再生率的村庄被证明与正常的治疗反应没有区别。该模型用于生成可检验的假设，以确定微丝蚴的非典型皮肤再生率是否可能仅由治疗覆盖率低引起，或者提供伊维菌素功效下降的证据。需要进一步研究将表型不良反应与寄生虫分子遗传学标记治疗联系起来，以确认耐药性。用于估计寄生虫负荷的皮肤剪断方法的局限性表明，微丝蚴繁殖率分布的变化，而不是其绝对值，可能是新出现的伊维菌素耐药性的更敏感指标。
Identification of drug resistance before it becomes a public health concern requires a clear distinction between what constitutes a normal and a suboptimal treatment response. A novel method of analyzing drug efficacy studies in human helminthiases is proposed and used to investigate recent claims of atypical responses to ivermectin in the treatment of River Blindness. The variability in the rate at which Onchocerca volvulus microfilariae repopulate host's skin following ivermectin treatment is quantified using an individual-based onchocerciasis mathematical model. The model estimates a single skin repopulation rate for every host sampled, allowing reports of suboptimal responses to be statistically compared with responses from populations with no prior exposure to ivermectin. Statistically faster rates of skin repopulation were observed in 3 Ghanaian villages (treated 12-17 times), despite the wide variability in repopulation rates observed in ivermectin-naive populations. Another village previously thought to have high rates of skin repopulation was shown to be indistinguishable from the normal treatment response. The model is used to generate testable hypotheses to identify whether atypical rates of skin repopulation by microfilariae could result from low treatment coverage alone or provide evidence of decreased ivermectin efficacy. Further work linking phenotypic poor responses to treatment with parasite molecular genetics markers will be required to confirm drug resistance. Limitations of the skin-snipping method for estimating parasite load indicates that changes in the distribution of microfilarial repopulation rates, rather than their absolute values, maybe a more sensitive indicator of emerging ivermectin resistance.