单剂量低剂量伯氨喹在葡萄糖-6-磷酸脱氢酶缺乏的恶性疟原虫感染非洲男性中的安全性：两项开放标签、随机、安全性试验。

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

作者信息

Bastiaens Guido J H, Tiono Alfred B, Okebe Joseph, Pett Helmi E, Coulibaly Sam A, Gonçalves Bronner P, Affara Muna, Ouédraogo Alphonse, Bougouma Edith C, Sanou Guillaume S, Nébié Issa, Bradley John, Lanke Kjerstin H W, Niemi Mikko, Sirima Sodiomon B, d'Alessandro Umberto, Bousema Teun, Drakeley Chris

机构信息

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.

Department of Biomedical Sciences, Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.

出版信息

PLoS One. 2018 Jan 11;13(1):e0190272. doi: 10.1371/journal.pone.0190272. eCollection 2018.

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.

TRIAL REGISTRATION

Clinicaltrials.gov NCT02174900 Clinicaltrials.gov NCT02654730.

背景

伯氨喹（PQ）可有效清除成熟的恶性疟原虫配子体，但在葡萄糖-6-磷酸脱氢酶缺乏（G6PDd）个体中可导致溶血。我们评估了低剂量PQ联合蒿甲醚-本芴醇（AL）或双氢青蒿素-哌喹（DP）用于无症状恶性疟原虫疟疾的G6PDd非洲男性的安全性。

方法与结果

在布基纳法索，G6PDd成年男性被随机分为单独接受AL治疗（n = 10）或接受剂量为0.25（n = 20）或0.40 mg/kg（n = 20）的PQ治疗；G6PD正常男性接受AL加0.25（n = 10）或0.40 mg/kg（n = 10）的PQ。在冈比亚，G6PDd成年男性和男孩单独接受DP治疗（n = 10）或接受0.25 mg/kg的PQ治疗（n = 20）；G6PD正常男性接受DP加0.25（n = 10）或0.40 mg/kg（n = 10）的PQ。主要研究终点是28天随访期间血红蛋白浓度的变化。还测定了细胞色素P-[450]同工酶2D6（CYP2D6）代谢状态、配子体携带情况、触珠蛋白、乳酸脱氢酶水平和网织红细胞计数。在布基纳法索，随机接受0.25 mg/kg PQ的G6PDd个体血红蛋白的平均最大绝对变化为-2.13 g/dL（95%置信区间[CI]，-2.78，-1.49），接受0.40 mg/kg PQ的个体为-2.29 g/dL（95%CI，-2.79，-1.79）。在冈比亚，接受0.25 mg/kg PQ的G6PDd个体血红蛋白浓度的平均最大绝对变化为-1.83 g/dL（95%CI，-2.19，-1.47）。在调整基线浓度后，布基纳法索G6PDd个体血红蛋白的降低比接受相同PQ剂量的G6PD正常个体更明显（分别为P = 0.062和P = 0.022）。随访期间血红蛋白水平恢复正常。异常的触珠蛋白和乳酸脱氢酶水平提供了PQ后轻度短暂溶血的额外证据。