Mass drug administration of ivermectin and dihydroartemisinin-piperaquine as an additional intervention for malaria elimination

自2000年以来，撒哈拉以南非洲的疟疾负担大幅减少，原因是长期驱虫蚊帐和室内滞留喷洒等病媒控制干预措施的规模扩大，以及采用青蒿素类联合疗法对病例进行了更好的管理。虽然冈比亚和塞内加尔等一些非洲国家的标准控制干预措施覆盖率很高，但疟疾传播并未中断。这可能是由于两个主要因素造成的，即(i)巨大而隐蔽的人类感染库，即没有任何症状但感染了疟疾的个体，因此能够感染蚊子媒介，以及（ii）与媒介相关的因素，例如媒介行为和杀虫剂耐药性，使媒介逃脱了诸如LLIN和IRS等标准控制干预措施。维持传播的这两个因素需要专门针对它们采取额外的干预措施。大规模药物管理（MDA）包括定期向全体人口提供全面的抗疟疾治疗。这一干预措施已被确定为在病媒控制活动覆盖率已经很高的地区进一步减少传播的潜在工具，因为它将清除无症状携带者的疟疾感染，从而减少人类感染库。对全体人口实施联合治疗应能减少疟疾感染者的人数，从而可能对传播产生影响。伊维菌素（IVM）是一种灭蚊剂，对人类是安全的，但对以最近用它治疗过的个体为食的按蚊是有毒的。联合联合以青蒿素为基础的联合药物与体外抑制药物可能具有协同效应，因为前者将减少人类感染库，而后者将杀死逃脱标准病媒控制干预措施的蚊子。此外，联合以青蒿素为基础的联合药物与综合药物管理相结合，还将减少大规模预防措施为对传播产生影响所需的最低覆盖范围。传输模型表明，将IVM添加到MDA干预中可能会中断传输，而标准MDA是不够的。然而，这从未在精心设计的集群随机试验中得到严格评估。这项以社区为基础的集群随机试验将在冈比亚上游河区进行。32个相距至少3-4公里、居民200-600人的村庄（组）将被随机分为干预组或对照组。将在16个干预村和干预村周围缓冲地带（2公里）内的任何其他人类住区实施以IVM和双氢青蒿素-哌喹（DP）为基础的大规模预防用药。在疟疾传播季节，每年将进行为期两年的3个月轮次的预防疟疾方案。比较干预组和控制组各传播高峰期疟疾流行情况和蚊虫年龄结构。我们还将收集关于覆盖率、干预的潜在瓶颈、依从性和可接受性的定性社会科学数据；一项卫生经济学研究将确定干预措施在预防疟疾感染和疟疾患者方面的成本。

Since 2000, there has been a substantial decrease of the malaria burden in sub-Saharan Africa due to the scale up of vector control interventions such as long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), and better case management with artemisinin-based combination therapy (ACT). Though some African countries such as The Gambia and Senegal have achieved excellent coverage of standard control interventions, malaria transmission has not been interrupted. This is probably due to two major factors, namely (i) the large and hidden human reservoir of infection, meaning individuals without any symptom but infected with malaria and thus able to infect the mosquito vector, and (ii) vector-related factors, e.g. vector behaviour and insecticide resistance, allowing vectors to escape standard control interventions such as LLIN and IRS. These two factors maintaining transmission require additional interventions specifically targeting them. Mass Drug Administration (MDA) consists in administering at regular intervals a full antimalarial treatment to the whole population. This intervention has been identified as a potential tool to further reduce transmission where coverage of vector control activities is already high as it would clear malaria infection from asymptomatic carriers and thus reduce the human reservoir of infection. An ACT administered to the whole population should decrease the number of malaria-infected individuals and thus may have an effect on transmission. Ivermectin (IVM) is a mosquitocidal agent that is safe for humans but toxic to Anopheles mosquitoes when feeding on individuals recently treated with it. Combining an ACT with an IVM may have a synergistic effect because the former would reduce the human reservoir of infection while the latter would kill mosquitoes that have escaped standard vector control interventions. In addition, combining an ACT with IVM would also reduce the minimal coverage required by MDA to have an effect on transmission. Transmission models suggest that adding IVM to a MDA intervention may interrupt transmission where standard MDA would be insufficient. However, this has never been rigorously evaluated in a well-designed cluster-randomized trial. This community-based, cluster-randomized trial will be carried out in the Upper River Region of The Gambia. Thirty two villages (clusters) at least 3-4km apart and with 200-600 inhabitants will be randomized to either the intervention or the control arm. MDA with IVM and dihydroartemisinin-piperaquine (DP) will be implemented in 16 intervention villages and any other human settlement in the buffer zone around intervention villages (2km). MDA will consist of 3-monthly rounds per year during the malaria transmission season for two years. Malaria prevalence at the peak of each transmission season and the mosquito population age structure will be compared between intervention and control arms. We will also collect qualitative social science data on coverage, potential bottlenecks for the intervention, adherence and acceptability; a health economics study will determine the cost of the intervention in relation to malaria infections and malaria patients prevented.