Primaquine's gametocytocidal efficacy in malaria asymptomatic carriers treated with dihydroartemisinin-piperaquine

疟疾是一种由按蚊传播的寄生虫病。这种寄生虫在人类宿主中有两种形式，无性和有性。后者不会引起疾病，但负责将感染从人类宿主传播给媒介蚊子。因此，减少寄生虫性形式(也称为配子体)从人到蚊子的转移的干预措施可能会对疟疾传播产生重大影响，从而降低疾病负担。唯一可用的针对配子细胞的治疗方法是伯喹，这是一种古老的药物，在撒哈拉以南非洲地区尚未广泛使用，因为它会导致患有葡萄糖-6-磷酸脱氢酶缺乏症的人的REB血细胞遭到破坏，有时会导致危及生命的贫血。然而，贫血的风险是剂量依赖的，即风险随着剂量的增加而增加。消除配子体所需的伯喹的数量在60年代已经在一小部分接受实验挑战的志愿者身上得到了确定。目前尚不清楚较低剂量的伯喹是否会产生与推荐剂量相同的效果，这可能与贫血风险较低有关。低剂量伯喹的使用将开启在撒哈拉以南非洲大规模使用它的可能性，那里葡萄糖-6-磷酸脱氢酶缺乏症的流行率可能高达15%。这项建议的总体目标是确定具有与推荐剂量相似的抗配子细胞活性的可能最低剂量的伯喹。这将通过在冈比亚的两个农村地区进行临床试验来实现。在研究地区，将对人群进行疟疾感染筛查。那些阳性者，即感染了疟疾但没有症状的人，将接受青蒿素为基础的联合治疗(双氢青蒿素-哌喹)，并随机只接受这种治疗或再接受推荐剂量或两个较低剂量的伯喹。治疗将持续3天以上，必要时在最后一剂双氢青蒿素-哌喹的同时给予伯喹。对研究对象进行为期一个多月的积极跟踪，定期采血。采集的血液将被用来确定不同治疗组之间配子体携带的差异。将用比显微镜更灵敏的分子方法来寻找配子体。在研究对象的一个子组中，我们将检查接受不同治疗的个体在传播给蚊子方面的实际差异是什么。我们将在治疗开始后一周采集血液样本，并喂食实验室饲养的蚊子，一周后将解剖这些蚊子，以检查这些蚊子是否已被感染。这项研究的结果将被用来确定在疟疾负担最高的撒哈拉以南非洲大规模使用伯氨喹的可行性，并可能有助于推动在该大陆实现预先消除/消除疟疾。

Malaria is a parasitic disease transmitted by mosquitoes of the species Anopheles. The parasite can be found in the human host in two forms, asexual and sexual. The latter does not cause disease but is responsible for the transmission of the infection from the human host to the vector mosquito. Therefore, interventions reducing the transfer of parasite sexual forms, called also gametocytes, from man to mosquito may have a major impact on malaria transmission and hence on the burden of disease. The only available treatment against gametocytes is primaquine, an old drug that has not been extensively used in sub-Saharan Africa because it can cause the destruction of reb blood cells in people with a genetic conditions called glucose-6-phosphate dehydrogenase deficiency, resulting sometimes in life-threathening anemia. However, the risk for anaemia is dose-dependent, i.e. the risk increases with increasing dose. The amount of primaquine needed to eliminate gametocyte has been established in the 60s in a small number of experimentally challenged volunteers. It is unknown if lower dosages of primaquine, which are probably associated with a lower risk for anaemia, could have the same effect than the recommended one. The use of primaquine at lower dosages would open the possibility of using it on a large scale in sub-Saharan Africa, where the prevalence of glucose-6-phosphate dehydrogenase deficiency can be as high as 15%. The general objective of this proposal is to determine the lowest possible dose of primaquine having similar activity against gametocytes than the recommended one. This will be done by carring out a clinical trial in two rural sites in The Gambia. In the study area, the population will be screened for malaria infection. Those positive, i.e. with a malaria infection but without symptoms, will be given an artemisinin-based combination treatment (dihydroartemisinin-piperaquine) and randomized to receive only this treatment or to have in addition the recommended or two lower dosages of primaquine. The treatment will be given over 3 days, with primaquine given, when required, in association with the last dose of dihydroartemisinin-piperaquine. Study subject will be actively followed up for more than a month, with blood sampling at regular intervals. The blood collected will be used to determine the difference in gametocyte carriage between the different treatment groups. Gametocytes will be searched with molecular methods, which are more sensitive than microscopy. In a subgroup of study subject we will check what is the actual difference in transmission to mosquitoes between individuals having received different treatments. We will collect a blood sample one week after the beginning of the treatment and we will feed laboratory-reared mosquitoes that will be dissected one week after, to check if the have become infected. The results of this study will be used to determine the feasibility of deploying primaquine on a large scale in sub-Saharan Africa, where the malaria burden is the highest, and may contribute to the drive towards malaria pre-elimination/elimination in this continent.