Combination interventions for controlling malaria transmitted by pyrethroid resistant mosquitoes: A novel bed net with synergist and IRS formulation.

大规模扩大病媒控制措施已导致许多撒哈拉以南非洲国家的疟疾负担大幅减少(最高可达50%)。这使人们有理由乐观地认为，疟疾有朝一日将不再是非洲的一个主要公共卫生问题。主要的疟疾预防和病媒控制工具是长效杀虫蚊帐和室内滞留喷洒。这两种杀虫剂都依靠拟除虫菊酯类杀虫剂在人类和蚊子之间提供驱避屏障，或者在蚊子传播疟疾之前杀死蚊子。由于正在做出巨大努力向高危人群提供LLIN的普遍覆盖，不幸的是，蚊子面临着巨大的选择压力，需要对拟除虫菊酯产生抗药性。现在许多地方都出现了抗药性，有些形式似乎如此强大，以至于媒介蚊子在接触中存活下来，并继续传播疟疾。世卫组织和制造业正在通过开发新型LLIN来应对，在某些情况下，这种LLIN包括一种化学增效剂，它可以消除耐药性机制，从而使LLIN继续受到保护。其他制造商的回应是生产长效非拟除虫菊酯杀虫剂，这种杀虫剂可以喷洒在墙上，并提供近一年的防治。通过将这两种工具结合起来，希望疟疾将继续控制在不断下降的水平，对拟除虫菊酯具有抗性的蚊子将继续被杀死，并防止进一步选择对拟除虫菊酯具有抗性。这两种产品都进行了第二阶段试验，都获得了世卫组织的人类使用批准。当务之急是在拟除虫菊酯耐药性变得更加严重、阻碍控制或破坏我们消除疟疾的信心之前部署这种新一代工具，但首先需要对这些工具进行适当的试验。LSHTM与其非洲伙伴机构KCMC和NIMR在坦桑尼亚进行蚊媒和疟疾控制试验有很长的历史，最近在五大湖边境地区(乌干达和卢旺达之间)进行了一项整群随机试验，结果表明，拟除虫菊酯抗药性现在很常见，尽管几年来一直试图使用拟除虫菊酯IRS来控制疟疾，但疟疾传播率仍然很高。因此，我们建议在湖区的48个村庄进行四臂CRT，比较a)目前普遍覆盖LLIN的做法，b)新LLIN加增效剂的全覆盖，c)长效IRS，d)新LLIN加长效IRS。这项试验将提供影响的流行病学、昆虫学、经济和社会证据，因为我们将衡量疟疾流行率和疟疾传播率EIR的下降，以及耐药性频率、蚊子种类比率和经济成本效益的变化。拟议的试验将证明新的LLIN和长效IRS配方是否对控制冈比亚按蚊更有效。与目前使用传统LLIN的做法相比，降低疟疾流行率。人们对进行这项试验非常感兴趣。可替代的媒介控制产品有限，而且大多数新杀虫剂不适合用于LLIN或作为IRS。疟疾控制的主要国际资助者--全球基金和总统疟疾倡议--都在支持该地区的疟疾控制。两国都认识到需要引入新的更好的工具，但都没有进行疟疾控制试验的授权或专业知识。这两个机构都将利用这次试验的结果来就未来的战略做出业务决策。由于将单独评估这两种干预措施的流行病学效果和成本效益，这将有助于今后根据情况分配疟疾控制资源。它不会把我们限制在未来使用这两种干预措施；相反，这项试验将刺激其他制造商生产新型LLIN和IRS。

The massive scale-up of vector control measures has led to a major reduction in malaria burden (up to 50%) in many sub-Saharan African countries. This is giving grounds for optimism that malaria will one day cease to be a major public health problem in Africa. The main malaria prevention and vector control tools are long lasting insecticidal nets (LLINs) and indoor residual spraying (IRS). Both rely on pyrethroid insecticides either to provide a repellent barrier between humans and mosquitoes or to kill mosquitoes before they can transmit malaria. With the huge efforts being taken to provide universal coverage of LLINs to those at risk there is, unfortunately, enormous selection pressure on mosquitoes to develop resistance to pyrethroids. Resistance is now occurring in many places and some forms appear to be so strong that vector mosquitoes survive contact and continue to transmit malaria. WHO and manufacturing industry are responding by developing new types of LLIN that, in some cases, incorporate a chemical synergist that knocks out the resistance mechanism so the LLIN continues to protect. Other manufacturers are responding by producing long-lasting non-pyrethroid insecticides that can be sprayed on walls and provide control for almost a year. By combining the two tools it is hoped that malaria shall continue to be controlled to ever decreasing levels, pyrethroid resistant mosquitoes shall continue to be killed, and further selection of pyrethroid resistance shall be prevented. Both products have undergone Phase II trials and both are approved by WHO for human use. There is great urgency to deploy this new generation of tools before pyrethroid resistance grows much worse, sets back control, or undermines our confidence to eliminate malaria, but first the tools need to be properly trialled. LSHTM together with its African partner institutions, KCMC and NIMR, have a long history of conducting mosquito vector and malaria control trials in Tanzania and have recently undertaken a cluster randomised trial in the Great Lakes border region (between Uganda and Rwanda) which showed that pyrethroid resistance is now commonplace and malaria transmission remains high despite several years of attempted control with pyrethroid IRS. We therefore propose to conduct a four-arm CRT in 48 villages in the Lakes region comparing a) current practice of universal coverage of LLINs, b) full coverage of the novel LLIN plus synergist, c) the long lasting IRS, d) the novel LLIN plus the long lasting IRS. The trial will provide epidemiological, entomological, economic and social evidence of impact, as we shall be measuring the reductions in malaria prevalence and malaria transmission rates EIR, and changes in the frequency of resistance, mosquito species ratios and economic cost effectiveness. The proposed trial will demonstrate whether the novel LLIN and long lasting IRS formulation will be more effective for controlling An.gambiae s.s. and reducing malaria prevalence than current practice with the conventional LLIN. There is great interest in conducting this trial. Alternative vector control products are limited and most new insecticides are not suitable for use on LLINs or as IRS. The main international funders of malaria control, the Global Fund and President's Malaria Initiative, are both supporting malaria control in the region. Both recognise the need to introduce new and better tools but neither has the mandate nor expertise to conduct malaria control trials. Both agencies would use the findings of this trial to make operational decisions on future strategy. Because epidemiological effectiveness and cost effectiveness of the two interventions will be evaluated alone and together this will facilitate future allocation of malaria control resources according to situation. It would not tie us down to using these two interventions in the future; rather the trial would act as a stimulus for other manufacturers to produce new types of LLIN and IRS.