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

疟疾是一种由按蚊属蚊子传播的寄生虫病。这种寄生虫在人类宿主中有两种形式，无性和有性。后者不引起疾病，但负责将感染从人类宿主传播给病媒蚊子。因此，减少寄生虫性形式（又称配子体）从人向蚊子转移的干预措施可能对疟疾传播产生重大影响，从而对疾病负担产生重大影响。针对配子体的唯一可用治疗方法是伯氨喹，这是一种在撒哈拉以南非洲地区尚未广泛使用的老药，因为它会导致患有葡萄糖-6-磷酸脱氢酶缺乏症的人的reb血细胞被破坏，有时会导致终身贫血。然而，贫血的风险是剂量依赖性的，即风险随着剂量的增加而增加。消除配子体所需的伯氨喹量已在60年代在少数受实验挑战的志愿者中确定。目前尚不清楚较低剂量的伯氨喹（可能与较低的贫血风险有关）是否会产生与推荐剂量相同的效果。使用较低剂量的伯氨喹将使其有可能在撒哈拉以南非洲大规模使用，那里葡萄糖-6-磷酸脱氢酶缺乏症的患病率可高达15%。本提案的总体目标是确定伯氨喹的最低可能剂量，其对配子体的活性与推荐剂量相似。这将通过在冈比亚的两个农村地点进行临床试验来实现。在研究地区，将对人口进行疟疾感染筛查。那些呈阳性的人，即感染疟疾但没有症状的人，将接受青蒿素类复方治疗（双氢青蒿素-哌喹），并随机接受仅这种治疗或另外接受推荐剂量或两种较低剂量的伯氨喹。治疗将在3天内进行，需要时，伯氨喹与最后一剂双氢青蒿素-哌喹联合给药。将对研究受试者进行一个月以上的主动随访，定期采集血样。采集的血液将用于确定不同给药组之间配子体携带的差异。将用比显微镜更敏感的分子方法搜索配子细胞。在一个研究受试者亚组中，我们将检查接受不同治疗的个体之间在传播给蚊子方面的实际差异。我们将在治疗开始后一周收集血液样本，我们将喂养实验室饲养的蚊子，一周后将其解剖，以检查是否已被感染。这项研究的结果将用于确定在疟疾负担最重的撒哈拉以南非洲大规模部署伯氨喹的可行性，并可能有助于推动该大陆实现疟疾预消除/消除。

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.