Data from: Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: two open-label, randomized, safety trials

Background: Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria. Methods and findings: In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined. In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ. Conclusions: Single low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy.

背景：伯氨喹（Primaquine, PQ）可主动清除成熟恶性疟原虫（Plasmodium falciparum）配子体，但在葡萄糖-6-磷酸脱氢酶缺乏症（glucose-6-phosphate dehydrogenase deficient, G6PDd）个体中可引发溶血反应。本研究旨在评估低剂量伯氨喹联合蒿甲醚-苯芴醇（artemether-lumefantrine, AL）或双氢青蒿素-哌喹（dihydroartemisinin-piperaquine, DP）用于伴无症状恶性疟感染的G6PDd非洲男性人群的安全性。
方法与结果：在布基纳法索，将G6PDd成年男性随机分为三组：单纯蒿甲醚-苯芴醇治疗组（n=10）、0.25mg/kg伯氨喹联合蒿甲醚-苯芴醇治疗组（n=20）及0.40mg/kg伯氨喹联合蒿甲醚-苯芴醇治疗组（n=20）；G6PD正常男性则接受蒿甲醚-苯芴醇联合0.25mg/kg（n=10）或0.40mg/kg（n=10）伯氨喹治疗。在冈比亚，G6PDd成年男性及男童分为两组：单纯双氢青蒿素-哌喹治疗组（n=10）、0.25mg/kg伯氨喹联合双氢青蒿素-哌喹治疗组（n=20）；G6PD正常男性则接受双氢青蒿素-哌喹联合0.25mg/kg（n=10）或0.40mg/kg（n=10）伯氨喹治疗。本研究的主要终点为28天随访期间的血红蛋白浓度变化。同时检测了细胞色素P450同工酶2D6（Cytochrome P-450 isoenzyme 2D6, CYP2D6）代谢型、配子体携带率、结合珠蛋白、乳酸脱氢酶水平及网织红细胞计数。在布基纳法索，接受0.25mg/kg伯氨喹治疗的G6PDd人群的血红蛋白平均最大绝对变化值为-2.13g/dL（95%置信区间[CI]：-2.78，-1.49），接受0.40mg/kg伯氨喹治疗者为-2.29g/dL（95% CI：-2.79，-1.79）。在冈比亚，接受0.25mg/kg伯氨喹治疗的G6PDd人群的血红蛋白平均最大绝对变化值为-1.83g/dL（95% CI：-2.19，-1.47）。在校正基线浓度后，布基纳法索的G6PDd人群的血红蛋白降幅较接受相同伯氨喹剂量的G6PD正常人群更为显著（分别为P=0.062和P=0.022）。随访期间血红蛋白水平可恢复至正常范围。异常的结合珠蛋白及乳酸脱氢酶水平为伯氨喹给药后轻度一过性溶血提供了额外佐证。
结论：单剂低剂量伯氨喹联合蒿甲醚-苯芴醇或双氢青蒿素-哌喹治疗，可导致轻度、一过性的血红蛋白降低。所有研究受试者均未出现中度或重度贫血，亦无严重不良事件发生。这表明，单剂低剂量伯氨喹联合青蒿素类复方疗法用于G6PDd非洲男性人群具有安全性。