Kajubi Richard, Huang Liusheng, Were Moses, Kiconco Sylvia, Li Fangyong, Marzan Florence, Gingrich David, Nyunt Myaing M, Ssebuliba Joshua, Mwebaza Norah, Aweeka Francesca T, Parikh Sunil
Infectious Disease Research Collaboration, Kampala, Uganda.
University of California-San Francisco, San Francisco General Hospital.
Open Forum Infect Dis. 2016 Dec 15;3(4):ofw217. doi: 10.1093/ofid/ofw217. eCollection 2016 Oct.
Artemisinins are primarily responsible for initial parasite clearance. Antimalarial pharmacokinetics (PK), human immunodeficiency virus (HIV) infection, and antiretroviral therapy have been shown to impact treatment outcomes, although their impact on early parasite clearance in children has not been well characterized.
Parasite clearance parameters were generated from twice-daily blood smears in HIV-infected and HIV-uninfected Ugandan children treated with artemether-lumefantrine (AL). Artemether and dihydroartemisinin (DHA) area-under-the-curve from 0-8 hours (AUC) after the 1st AL dose was compared with AUC after the last (6th) dose in a concurrently enrolled cohort. The association between post-1st dose artemisinin AUC and parasite clearance was assessed.
Parasite clearance was longer in HIV-infected versus HIV-uninfected children (median, 3.5 vs 2.8 hours; = .003). Artemether AUC was 3- to 4-fold lower after the 6th dose versus the 1st dose of AL in HIV-infected children on nevirapine- or lopinavir/ritionavir-based regimens and in HIV-uninfected children ( ≤ .002, 1st vs 6th-dose comparisons). Children on efavirenz exhibited combined post-1st dose artemether/DHA exposure that was significantly lower than those on lopinavir/ritonavir and HIV-uninfected children. Multiple regression analysis supported that the effect of artemether/DHA exposure on parasite clearance was significantly moderated by HIV status.
Parasite clearance rates remain rapid in Uganda and were not found to associate with PK exposure. However, significant decreases in artemisinin PK with repeated dosing in nearly all children, coupled with small, but significant increase in parasite clearance half-life in those with HIV, may have important implications for AL efficacy, particularly because reports of artemisinin resistance are increasing.
青蒿素主要负责初始寄生虫清除。抗疟药的药代动力学（PK）、人类免疫缺陷病毒（HIV）感染及抗逆转录病毒疗法已被证明会影响治疗效果，尽管它们对儿童早期寄生虫清除的影响尚未得到充分描述。
对接受蒿甲醚-本芴醇（AL）治疗的乌干达HIV感染和未感染儿童，通过每日两次血涂片来得出寄生虫清除参数。在一个同期入组队列中，比较了第1剂AL给药后0至8小时蒿甲醚和双氢青蒿素（DHA）的曲线下面积（AUC）与最后一剂（第6剂）后的AUC。评估了第1剂给药后青蒿素AUC与寄生虫清除之间的关联。
HIV感染儿童的寄生虫清除时间比未感染儿童更长（中位数分别为3.5小时和2.8小时；P = 0.003）。在接受基于奈韦拉平或洛匹那韦/利托那韦方案治疗的HIV感染儿童以及未感染儿童中，第6剂AL后的蒿甲醚AUC比第1剂低3至4倍（P≤0.002，第1剂与第6剂比较）。接受依非韦伦治疗的儿童在第1剂给药后蒿甲醚/DHA的综合暴露量显著低于接受洛匹那韦/利托那韦治疗的儿童和未感染儿童。多元回归分析支持HIV状态对蒿甲醚/DHA暴露对寄生虫清除的影响有显著调节作用。
乌干达的寄生虫清除率仍然很快，且未发现与PK暴露有关。然而，几乎所有儿童重复给药后青蒿素PK显著下降，以及HIV感染者的寄生虫清除半衰期虽小幅但显著增加，可能对AL疗效有重要影响，特别是鉴于青蒿素耐药性报告不断增加。
