中越地区二氢青蒿素/哌喹与青蒿琥酯单药治疗无并发症恶性疟原虫疟疾的疗效。
Efficacy of dihydroartemisinin/piperaquine and artesunate monotherapy for the treatment of uncomplicated Plasmodium falciparum malaria in Central Vietnam.
机构信息
Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.
出版信息
J Antimicrob Chemother. 2020 Aug 1;75(8):2272-2281. doi: 10.1093/jac/dkaa172.
BACKGROUND
Artemisinin-based combination therapies (ACTs) have significantly contributed to reduce Plasmodium falciparum malaria burden in Vietnam, but their efficacy is challenged by treatment failure of dihydroartemisinin/piperaquine ACT in Southern provinces.
OBJECTIVES
To assess the efficacy of dihydroartemisinin/piperaquine for uncomplicated P. falciparum malaria in Gia Lai, Central Vietnam, and determine parasite resistance to artemisinin (ClinicalTrials.gov identifier NCT02604966).
METHODS
Sixty patients received either dihydroartemisinin/piperaquine (4 mg/kg/day, 3 days; n = 33) or artesunate monotherapy (4 mg/kg/day, 3 days; n = 27) followed by dihydroartemisinin/piperaquine (AS + DHA/PPQ). Clinical phenotypes were determined during a 42 day follow-up and analysed together with ex vivo susceptibility to antimalarials and molecular markers of drug resistance.
RESULTS
Day 3 positivity rate was significantly higher in the AS + DHA/PPQ arm compared with dihydroartemisinin/piperaquine (70.4% versus 39.4%, P = 0.016). Parasite clearance time was 95.2 h (AS + DHA/PPQ) versus 71.9 h (dihydroartemisinin/piperaquine, P = 0.063) and parasite clearance half-life was 7.4 h (AS + DHA/PPQ) versus 7.0 h (dihydroartemisinin/piperaquine, P = 0.140). Adequate clinical and parasitological response at Day 42 was 100% in both arms. By RT-qPCR, 36% (19/53) patients remained positive until Day 7. No recurrences were detected. kelch13 artemisinin resistance mutations were found in 87% (39/45) of isolates and 50% (20/40) were KEL1/C580Y. The piperaquine resistance marker plasmepsin-2 was duplicated in 10.4% (5/48). Isolates from Day 3-positive patients (n = 18) had higher ex vivo survival rates to artemisinin compounds (P < 0.048) and prevalence of kelch13 mutations (P = 0.005) than Day 3-negative patients (n = 5). The WHO definition of artemisinin resistance was fulfilled in 60% (24/40) of cases.
CONCLUSIONS
Although dihydroartemisinin/piperaquine remained effective to treat P. falciparum, the high Day 3 positivity rate and prevalence of KEL1 strains calls for continuous monitoring of dihydroartemisinin/piperaquine efficacy in Central Vietnam.
背景
青蒿素类复方疗法（ACTs）在降低越南恶性疟原虫疟疾负担方面发挥了重要作用，但在南部省份，二氢青蒿素/哌喹 ACT 的治疗失败对其疗效构成了挑战。
目的
评估二氢青蒿素/哌喹治疗越南北部嘉莱省无并发症恶性疟原虫疟疾的疗效，并确定对青蒿素的寄生虫耐药性（ClinicalTrials.gov 标识符 NCT02604966）。
方法
60 名患者分别接受二氢青蒿素/哌喹（4mg/kg/天，3 天；n=33）或青蒿琥酯单药治疗（4mg/kg/天，3 天；n=27），然后给予二氢青蒿素/哌喹（AS+DHA/PPQ）。在 42 天的随访期间确定临床表型，并与抗疟药物的体外敏感性和耐药性分子标志物一起进行分析。
结果
与二氢青蒿素/哌喹组相比，AS+DHA/PPQ 组第 3 天阳性率显著升高（70.4%比 39.4%，P=0.016）。寄生虫清除时间为 95.2 小时（AS+DHA/PPQ）与 71.9 小时（二氢青蒿素/哌喹，P=0.063），寄生虫清除半衰期为 7.4 小时（AS+DHA/PPQ）与 7.0 小时（二氢青蒿素/哌喹，P=0.140）。第 42 天，两组均有 100%的患者获得良好的临床和寄生虫学反应。通过 RT-qPCR，36%（19/53）的患者在第 7 天仍呈阳性。未发现复发。kelch13 青蒿素耐药突变在 87%（39/45）的分离株中发现，50%（20/40）为 KEL1/C580Y。在 10.4%（5/48）的分离株中发现了双倍的哌喹耐药标记物质膜蛋白酶-2。来自第 3 天阳性患者（n=18）的分离株对青蒿素化合物的体外存活率更高（P<0.048），kelch13 突变的发生率更高（P=0.005），而第 3 天阴性患者（n=5）则更低。60%（24/40）的病例符合世界卫生组织对青蒿素耐药性的定义。
结论
尽管二氢青蒿素/哌喹仍能有效治疗恶性疟原虫，但第 3 天阳性率较高和 KEL1 株的流行，需要持续监测越南北部二氢青蒿素/哌喹的疗效。
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