White N J, Chotivanich K
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Clin Microbiol Rev. 2024 Dec 10;37(4):e0010924. doi: 10.1128/cmr.00109-24. Epub 2024 Oct 15.
SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the Kelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.
青蒿素类抗疟药是当前疟疾治疗的基石。青蒿素耐药性的出现对疟疾控制和消除构成了重大威胁。近20年前在东南亚大湄公河次区域首次发现青蒿素耐药性，目前在南美洲的圭亚那、巴布亚新几内亚均有记录，最近在东非（卢旺达、乌干达、南苏丹、坦桑尼亚、埃塞俄比亚、厄立特里亚和刚果民主共和国东部）也已出现且已牢固确立。青蒿素耐药性与 Kelch 基因螺旋桨区域的突变有关，这些突变起因果作用，尽管寄生虫的遗传背景也对表型有重要影响。临床上，青蒿素耐药性表现为杀寄生虫活性降低和寄生虫清除速度减慢，因此基于青蒿素的联合疗法（ACT）治疗失败的风险增加。这是由于青蒿素对较年轻的循环环状阶段寄生虫失去活性所致。这种活性丧失可能会削弱青蒿琥酯在治疗严重恶性疟中的救命优势。配子体杀灭作用以及因此的传播阻断活性也会降低。在当前的耐药水平下，青蒿素耐药性寄生虫在无性发育的滋养体阶段仍保持敏感，因此，青蒿素仍有助于治疗反应。由于ACT是世界上使用最广泛的抗疟药物，从疟疾控制的角度来看，ACT治愈率保持在高位至关重要。需要更好的方法来识别单纯性高疟原虫血症（ACT治疗失败的主要原因），以便能为这些高危患者提供更长疗程的治疗。减少青蒿素单药疗法的使用将减少持续的选择压力，这可能潜在导致更高水平的青蒿素耐药性。应尽快采用三联青蒿素联合疗法，以保护ACT中的伙伴药物，从而延缓更高水平耐药性的出现。由于新的可负担得起的抗疟药物仍需数年时间才能问世，青蒿素耐药性的控制必须依赖于更好地利用现有工具。
