Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study.
Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study.
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DOI：
10.1016/s1473-3099(12)70181-0
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发表时间：
2012-11
影响因子：
56.3
通讯作者：
Fairhurst, Rick M.
中科院分区：
文献类型：
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作者：
Amaratunga, Chanaki;Sreng, Sokunthea;Suon, Seila;Phelps, Erika S.;Stepniewska, Kasia;Lim, Pharath;Zhou, Chongjun;Mao, Sivanna;Anderson, Jennifer M.;Lindegardh, Niklas;Jiang, Hongying;Song, Jianping;Su, Xin-zhuan;White, Nicholas J.;Dondorp, Arjen M.;Anderson, Tim J. C.;Fay, Michael P.;Mu, Jianbing;Duong, Socheat;Fairhurst, Rick M.
据报道，柬埔寨西部拜林地区发现了抗青蒿素恶性疟原虫，其体内寄生虫清除率缓慢。这种表型在泰国西部和其他地方的出现可能会损害所有基于青蒿素的联合疗法的有效性。寄生虫遗传学与寄生虫清除率相关，但不能解释所有变异。我们研究了柬埔寨西部菩萨地区寄生虫遗传学和宿主因素对青蒿素抗性表型的贡献。 2009年6月19日至11月28日以及2010年6月26日至12月6日期间，我们招募了10岁或以上的无并发症的恶性疟疾患者，无性寄生虫密度至少为每微升全血10 000个，没有严重疟疾的症状或体征，没有其他原因引起的发热性疾病，也没有慢性疾病。我们在 0、24 和 48 小时给予参与者 4 mg/kg 青蒿酯，在 72 小时给予 15 mg/kg 甲氟喹，在 96 小时给予 10 mg/kg 甲氟喹。我们每 6 小时评估厚血膜上的寄生虫密度，直到检测不到。根据寄生虫清除曲线计算寄生虫清除半衰期。我们使用 18 个微卫星标记对寄生虫和患者进行了血红蛋白 E、α-地中海贫血和 G6PD 突变（编码葡萄糖-6-磷酸脱氢酶）的基因分型。为了解释获得性免疫对半衰期可能产生的影响，我们使用了三个替代因素来衡量接触恶性疟原虫的可能性增加：年龄、性别和居住地。本研究已在 ClinicalTrials.gov 注册，编号 NCT00341003。我们评估了菩萨省所有六个地区的 3504 名寻求疟疾症状治疗的人。我们招募了 168 名符合纳入标准的恶性疟疾患者。菩萨中的几何平均半衰期为 5.85 小时（95% CI 5.54-6.18），与拜林中报道的相似（p=0.109）。我们鉴定了两个遗传上不同的寄生虫克隆群：寄生虫群 1 (PG1) 和寄生虫群 2 (PG2)。在血红蛋白 E 患者（0.55 小时；p=0.078）、男性患者（0.96 小时；p=0.064）和 2010 年患者（0.68 小时；p=0.068）中，寄生虫清除半衰期没有显着增加； PG1 与显着增加相关（0.79 小时；p=0.033）。半衰期的平均寄生虫遗传力为 0.40 (SD 0.17)。柬埔寨第二个省份出现了遗传性青蒿素耐药性。为了准确识别对青蒿素本质敏感或耐药的寄生虫，未来的研究应探讨红细胞多态性和特异性免疫反应对半衰期变化的影响。美国国立卫生研究院国家过敏和传染病研究所校内研究部。
Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD, which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum: age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5.85 h (95% CI 5.54–6.18) in Pursat, similar to that reported in Pailin (p=0.109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0.55 h; p=0.078), those of male sex (0.96 h; p=0.064), and in 2010 (0.68 h; p=0.068); PG1 was associated with a significant increase (0.79 h; p=0.033). The mean parasite heritability of half-life was 0.40 (SD 0.17). Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.