Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.
Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens.
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DOI：
10.1371/journal.pmed.1002224
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发表时间：
2017-02
期刊：
影响因子：
15.8
通讯作者：
White NJ
中科院分区：
文献类型：
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作者：
Chu CS;Bancone G;Moore KA;Win HH;Thitipanawan N;Po C;Chowwiwat N;Raksapraidee R;Wilairisak P;Phyo AP;Keereecharoen L;Proux S;Charunwatthana P;Nosten F;White NJ
在葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症患者中，用8-氨基喹啉(伯氨喹或他苯喹)根治间日疟合并溶血。G6PD杂合子女性，由于红系细胞中X染色体失活(里昂化)模式的个体差异，其大部分红细胞中的G6PD活性可能较低，但目前的表型筛查试验通常报告为G6PD“正常”。它们在用8-氨基喹啉类药物治疗时的溶血风险尚未得到很好的表征。在一项随机临床试验中嵌套的一项队列研究比较了不同的间日疟治疗方案，标准NADPH荧光斑点试验结果正常的患者(≳为正常G6PD活性的30%-40%)被随机分成三组，分别接受氯喹或双氢青蒿素哌喹与伯喹的联合治疗，标准大剂量为0.5mgbase/kg/d，疗程为14d，或更高剂量为1mgbase/kg/d，疗程为7d。对G6PD野生型和G6PD杂合子女性参与者的溶血模式进行了比较。2012年2月21日至2014年7月4日期间，241名女性参与者入选，其中34人为G6PD Mahidol变异杂合子。与服用标准高剂量(14天)的G6PD杂合子(2/16[13%])相比，服用较高(7天)伯喹剂量(9/17[53%])的G6PD杂合子患者的溶血显著增加，且更大比例的参与者达到临床显著溶血的阈值(红细胞压积降低分数和GT；25%；p=0.022)。在杂合子中，与标准高剂量(14天)的−13.1%(95%CI−17.6%至−8.6%)(低谷6天)相比，较高剂量(7天方案)的平均红细胞压积降低程度相应地更大：−20.4%(95%CI−26.0%至−14.8%)(第5天)。两名杂合子服用较高剂量(7天)的伯喹需要输血。在野生型参与者中，平均红细胞压积降低在临床上并不显著，并且在两种剂量下相似：−5.8(95%CI−7.2%至−4.4%)(最低值第3天)与−5.5%(95%CI−7.4%至−3.7%)(最低值第4天)。这项嵌套队列研究的局限性在于，试验的主要目标是评估疗效，而不是与G6PD基因有关的溶血，而且杂合子组很小。在G6PD杂合子女性中，较高的日剂量伯氨喹有可能导致临床上显着的溶血，这些女性在目前的护理点测试中被报告为表型正常。临床试验.gov NCT01640574。在一项根治疟疾的临床试验的队列研究中，Cindy S.Chu和他的同事评估了在葡萄糖-6-磷酸脱氢酶缺乏症杂合子女性中与伯氨喹治疗相关的溶血风险。伯氨喹是唯一广泛可用的治疗方法，可以消除间日疟原虫潜伏的肝脏阶段，从而防止复发(根治)。伯喹可导致葡萄糖-6-磷酸脱氢酶(G6PD)缺陷患者潜在的严重溶血。半合子男性和纯合子女性通过目前的表型试验被可靠地鉴定为G6PD缺乏；然而，杂合子女性在G6PD快速诊断表型试验中可能有正常或缺陷的结果。G6PD表型试验正常的G6PD杂合子女性仍易患伯氨喹引起的临床重要溶血。本研究旨在描述和量化G6PD表型正常的G6PD Mahidol杂合子女性在服用伯氨喹根治间日疟时的红细胞压积变化。研究人员对感染间日疟原虫的参与者进行了标准的高剂量伯喹方案(0.5毫克/公斤/天，14天)或替代的高剂量伯喹方案(1毫克/公斤/天，7天)，这些参与者经G6PD荧光斑点试验检测为G6PD正常。观察2wk的红细胞压积水平，并与G6PD基因、定量G6PD酶活性和初始寄生虫血症进行比较。在Mahidol变异型G6PD缺乏症杂合子的女性参与者中，较高的日剂量伯氨喹(1 mg base/kg/d)与显著的溶血有关。在所有G6PD表型试验正常的女性受试者中，标准大剂量伯氨喹(0.5mgbase/kg/d，14d)耐受性良好。在没有密切监测的情况下，对于G6PD突变类似于或比Mahidol变异更严重的杂合子女性，不应使用高于标准高剂量伯喹(大于0.5 mg base/kg/d)的每日剂量。需要更多关于G6PD杂合子妇女和具有不同G6PD酶活性水平的女孩的溶血风险的信息。新的G6PD缺乏症快速诊断测试应该是定量的，并包括评估血红蛋白水平。对于G6PD缺乏的患者，需要更安全的伯氨喹治疗方案。
Radical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythroid cells, may have low G6PD activity in the majority of their erythrocytes, yet are usually reported as G6PD “normal” by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. In a cohort study nested within a randomised clinical trial that compared different treatment regimens for P. vivax malaria, patients with a normal standard NADPH fluorescent spot test result (≳30%–40% of normal G6PD activity) were randomised to receive 3 d of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5 mg base/kg/day for 14 d or a higher dose of 1 mg base/kg/d for 7 d. Patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous female participants. Between 21 February 2012 and 04 July 2014, 241 female participants were enrolled, of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis was substantially greater and a larger proportion of participants reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 d) primaquine dose (9/17 [53%]) compared with G6PD heterozygotes taking the standard high (14 d) dose (2/16 [13%]; p = 0.022). In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7-d regimen): −20.4% (95% CI −26.0% to −14.8%) (nadir on day 5) compared with the standard high (14 d) dose: −13.1% (95% CI −17.6% to −8.6%) (nadir day 6). Two heterozygotes taking the higher (7 d) primaquine dose required blood transfusion. In wild-type participants, mean haematocrit reductions were clinically insignificant and similar with both doses: −5.8 (95% CI −7.2% to −4.4%) (nadir day 3) compared with −5.5% (95% CI −7.4% to −3.7%) (nadir day 4), respectively. Limitations to this nested cohort study are that the primary objective of the trial was designed to measure efficacy and not haemolysis in relation to G6PD genotype and that the heterozygote groups were small. Higher daily doses of primaquine have the potential to cause clinically significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests. ClinicalTrials.gov NCT01640574. In a cohort study within a clinical trial of radical cure regimens for malaria, Cindy S. Chu and colleagues assess the haemolytic risk associated with primaquine treatment among women heterozygous for glucose-6-phosphate dehydrogenase deficiency. Primaquine is the only widely available treatment to eliminate latent liver stages of P. vivax malaria and thereby prevent relapse (radical cure). Primaquine can cause potentially severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient patients. Hemizygous males and homozygous females are identified reliably as G6PD deficient by current phenotypic testing; however, heterozygous females may have a normal or deficient result on G6PD rapid diagnostic phenotypic tests. G6PD heterozygous females who have a normal G6PD phenotypic test are still susceptible to clinically important haemolysis caused by primaquine. This study was designed to describe and quantify the haematocrit changes in G6PD Mahidol heterozygous females with a normal G6PD phenotype when taking primaquine for the radical cure of P. vivax malaria. The researchers administered a standard high-dose primaquine regimen (0.5 mg base/kg/d for 14 d) or an alternative higher-dose primaquine regimen (1 mg base/kg/d for 7 d) to participants infected with P. vivax malaria who tested as G6PD normal by the G6PD fluorescent spot test. Haematocrit levels were followed for 2 wk and compared with respect to the G6PD genotype, quantitative G6PD enzymatic activity, and initial parasitaemia. Higher daily doses of primaquine (1 mg base/kg/d) were associated with significant haemolysis in female participants who were heterozygous for Mahidol variant G6PD deficiency. The standard high dose primaquine (0.5 mg base/kg/d for 14 d) was well tolerated in all female participants who had a normal G6PD phenotypic test. In the absence of close monitoring, daily doses higher than standard high dose primaquine (greater than 0.5 mg base/kg/d) should not be used in females who are heterozygous for a G6PD mutation that is similar to or more severe than the Mahidol variant. More information is needed on the haemolytic risk in G6PD heterozygous women and girls with different G6PD enzymatic activity levels. New rapid diagnostic tests for G6PD deficiency should be quantitative and include assessment of haemoglobin levels. Safer regimens of primaquine are needed for G6PD-deficient patients.