Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency.
Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency.
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DOI：
10.1186/s12916-015-0441-1
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发表时间：
2015-08-25
期刊：
影响因子：
9.3
通讯作者：
Christophel E
中科院分区：
文献类型：
--
作者：
Kheng S;Muth S;Taylor WR;Tops N;Kosal K;Sothea K;Souy P;Kim S;Char CM;Vanna C;Ly P;Ringwald P;Khieu V;Kerleguer A;Tor P;Baird JK;Bjorge S;Menard D;Christophel E
伯氨喹用于预防间日疟原虫复发，但在包括柬埔寨在内的许多疟疾流行国家没有使用，因为担心在葡萄糖-6-磷酸脱氢酶缺乏症（G6 PDd）患者中引发伯氨喹诱发的急性溶血性贫血。由于缺乏质量安全数据，人们更不愿意使用伯氨喹。本研究的目的是评估伯氨喹方案在柬埔寨严重缺乏G6 PD变体中的耐受性，以确定是否可以在不进行G6 PDd检测的情况下每周给予伯氨喹。从2013年1月至2014年1月，患有急性间日疟的埃塞俄比亚人在第0、1和2天（D）接受双氢青蒿素/哌喹治疗，伯氨喹每周剂量为0.75 mg/kg，持续8周（从D 0开始，D49末次给药），并随访至D56。受试者的G6 PD状态通过G6 PD基因型和测量G6 PD活性来确认。主要结局是治疗完成，无伯氨喹毒性，定义为以下任一项：（1）严重贫血（血红蛋白[Hb] <7 g/dL），（2）Hb从D 0下降> 25%，（3）需要输血，（4）血红蛋白尿，（5）急性肾损伤（基线血清肌酐增加> 50%）或（6）高铁血红蛋白血症> 20%。我们招募了75名患者，中位年龄为24岁（范围5-63岁）; 63名患者（84%）为男性。18例患者为G6 PD d（17/18例具有维昂占变体），D 0 G6 PD活性范围为0.1 - 1.5 U/g Hb（中位数为0.85 U/g Hb）。在57名G6 PD（G6 PDn）正常的患者中，D 0 G6 PD活性范围为6.9至18.5 U/g Hb（中位数12 U/g Hb）。G6 PDd（13 g/dL，范围9.6-16）和G6 PDn（13.5 g/dL，范围9-16.3）之间的中位D 0 Hb浓度相似（P = 0.46），两组均在D2达到最低值：分别为10.8 g/dL（8.2-15.3）和12.4 g/dL（8.8-15.2）（P = 0.006）。到D 7时，5名G6 PDd患者（27.7%）的Hb下降> 25%，而G6 PDn患者为0（P = 0.00049）。其中1例G6 PDd患者需要输血（D 0-D5 Hb，10.0-7.2 g/dL）。没有患者发生严重贫血、血红蛋白尿、高铁血红蛋白浓度> 4.9%或急性肾损伤。Vivax感染的G6 PDd柬埔寨患者表现出显着的，大多数是短暂的，福尔斯下降，在Hb和一个接受输血。每周伯氨喹在G6 PDd患者的要求医疗监督和治疗前筛查G6 PD状态。应探讨实施一套G6 PDd检测和监督伯氨喹的可行性。该试验于2013年3月1日注册，注册号为ACTRN 12613000003774。本文的在线版本（doi：10.1186/s12916-015-0441-1）包含补充材料，可供授权用户使用。
Primaquine is used to prevent Plasmodium vivax relapse; however, it is not implemented in many malaria-endemic countries, including Cambodia, for fear of precipitating primaquine-induced acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Reluctance to use primaquine is reinforced by a lack of quality safety data. This study was conducted to assess the tolerability of a primaquine regimen in Cambodian severely deficient G6PD variants to ascertain whether a weekly primaquine could be given without testing for G6PDd. From January 2013 to January 2014, Cambodians with acute vivax malaria were treated with dihydroartemisinin/piperaquine on days (D) 0, 1 and 2 with weekly doses of primaquine 0.75 mg/kg for 8 weeks (starting on D0, last dose on D49), and followed until D56. Participants’ G6PD status was confirmed by G6PD genotype and measured G6PD activity. The primary outcome was treatment completion without primaquine toxicity defined as any one of: (1) severe anaemia (haemoglobin [Hb] <7 g/dL), (2) a >25 % fractional fall in Hb from D0, (3) the need for a blood transfusion, (4) haemoglobinuria, (5) acute kidney injury (an increase in baseline serum creatinine >50 %) or (6) methaemoglobinaemia >20 %. We enrolled 75 patients with a median age of 24 years (range 5–63); 63 patients (84 %) were male. Eighteen patients were G6PDd (17/18 had the Viangchan variant) and had D0 G6PD activity ranging from 0.1 to 1.5 U/g Hb (median 0.85 U/g Hb). In the 57 patients with normal G6PD (G6PDn), D0 G6PD activity ranged from 6.9 to 18.5 U/g Hb (median 12 U/g Hb). Median D0 Hb concentrations were similar (P = 0.46) between G6PDd (13 g/dL, range 9.6–16) and G6PDn (13.5 g/dL, range 9–16.3) and reached a nadir on D2 in both groups: 10.8 g/dL (8.2–15.3) versus 12.4 g/dL (8.8–15.2) (P = 0.006), respectively. By D7, five G6PDd patients (27.7 %) had a >25 % fall in Hb, compared to 0 G6PDn patients (P = 0.00049). One of these G6PDd patients required a blood transfusion (D0–D5 Hb, 10.0–7.2 g/dL). No patients developed severe anaemia, haemoglobinuria, a methaemoglobin concentration >4.9 %, or acute kidney injury. Vivax-infected G6PDd Cambodian patients demonstrated significant, mostly transient, falls in Hb and one received a blood transfusion. Weekly primaquine in G6PDd patients mandates medical supervision and pre-treatment screening for G6PD status. The feasibility of implementing a package of G6PDd testing and supervised primaquine should be explored. The trial was registered on 3/1/2013 and the registration number is ACTRN12613000003774. The online version of this article (doi:10.1186/s12916-015-0441-1) contains supplementary material, which is available to authorized users.