Nguyen Tran Dang, Tran Thu Nguyen-Anh, Parker Daniel M, White Nicholas J, Boni Maciej F
Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, PA, United States of America.
Department of Population Health and Disease Prevention, Department of Epidemiology and Biostatistics, University of California, Irvine, Irvine, CA, United States of America.
PLOS Glob Public Health. 2023 Jul 26;3(7):e0002200. doi: 10.1371/journal.pgph.0002200. eCollection 2023.
Mass drug administration (MDA) with antimalarials has been shown to reduce prevalence and interrupt transmission in small populations, in populations with reliable access to antimalarial drugs, and in populations where sustained improvements in diagnosis and treatment are possible. In addition, when MDA is effective it eliminates both drug-resistant parasites and drug-sensitive parasites, which has the long-term benefit of extending the useful therapeutic life of first-line therapies for all populations, not just the focal population where MDA was carried out. However, in order to plan elimination measures effectively, it is necessary to characterize the conditions under which failed MDA could exacerbate resistance. We use an individual-based stochastic model of Plasmodium falciparum transmission to evaluate this risk for MDA using dihydroartemisinin-piperaquine (DHA-PPQ), in populations where access to antimalarial treatments may not be uniformly high and where re-importation of drug-resistant parasites may be common. We find that artemisinin-resistance evolution at the kelch13 locus can be accelerated by MDA when all three of the following conditions are met: (1) strong genetic bottlenecking that falls short of elimination, (2) re-importation of artemisinin-resistant genotypes, and (3) continued selection pressure during routine case management post-MDA. Accelerated resistance levels are not immediate but follow the rebound of malaria cases post-MDA, if this is allowed to occur. Crucially, resistance is driven by the selection pressure during routine case management post-MDA and not the selection pressure exerted during the MDA itself. Second, we find that increasing treatment coverage post-MDA increases the probability of local elimination in low-transmission regions (prevalence < 2%) in scenarios with both low and high levels of drug-resistance importation. This emphasizes the importance of planning for and supporting high coverage of diagnosis and treatment post-MDA.
事实证明，使用抗疟药物进行大规模药物给药（MDA）可降低小规模人群、能够可靠获取抗疟药物的人群以及诊断和治疗有望持续改善的人群中的疟疾流行率并阻断传播。此外，当MDA有效时，它既能消除耐药寄生虫，也能消除药物敏感寄生虫，这具有长期益处，即延长一线治疗药物对所有人群（而不仅仅是实施MDA的重点人群）的有效治疗期限。然而，为了有效规划消除措施，有必要明确MDA失败可能加剧耐药性的条件。我们使用基于个体的恶性疟原虫传播随机模型，在抗疟治疗获取率可能不统一高且耐药寄生虫重新输入可能常见的人群中，评估使用双氢青蒿素哌喹（DHA-PPQ）进行MDA的这种风险。我们发现，当满足以下所有三个条件时，MDA可加速kelch13位点的青蒿素耐药性进化：（1）强烈的基因瓶颈效应但未达到消除程度，（2）青蒿素耐药基因型的重新输入，以及（3）MDA后常规病例管理期间持续的选择压力。如果允许MDA后疟疾病例反弹，加速的耐药水平不会立即出现，而是跟随其后。至关重要的是，耐药性是由MDA后常规病例管理期间的选择压力驱动的，而不是MDA本身施加的选择压力。其次，我们发现，在耐药性输入水平低和高的情况下，MDA后提高治疗覆盖率会增加低传播地区（流行率<2%）局部消除的可能性。这强调了规划并支持MDA后高覆盖率诊断和治疗的重要性。
