A trial of the benefit of including azithromycin in the drug combination used for seasonal malaria chemoprevention in African children

非洲在控制疟疾方面正在取得良好进展，但只取得了部分成功。在一些国家，疟疾发病率仅略有下降，尽管广泛部署了经杀虫剂处理的蚊帐，在房屋内部喷洒杀虫剂，并使用以青蒿属植物化合物为基础的高效药物组合治疗临床病例。需要作出更多努力来扩大这些干预措施，但还需要更多的控制工具。一个潜在的新工具是季节性疟疾化学预防(SMC)。SMC涉及在感染风险最大的时期向所有有风险的儿童提供有效的抗疟疾药物组合的治疗剂量。这种控制疟疾的方法专门针对气候因素将疟疾传播限制在一年中只有几个月的地区，这样就不必给药超过三到四次。小岛屿发展中国家将是适当干预措施的地区包括萨赫勒大部分地区和萨赫勒以南地区(人口约2亿)。在疟疾季节性传播地区进行的研究表明，SMC与磺胺/乙胺嘧啶(SP)和阿莫地喹(AQ)相结合，将严重和无并发症疟疾的发病率降低了70%以上，并可能减少死亡人数。这种干预是安全的，耐受性良好，而且成本效益很高。村志愿者成功、安全地给出了抗疟疾药物。世界卫生组织的一个政策咨询委员会最近审查了SMC的试验结果，并可能建议将其作为季节性疟疾高度传播地区的疟疾控制干预措施。尽管SMC与SP和AQ在减少疟疾方面取得了成功，但这种干预措施试验中的儿童仍多次患上传染病，有些是严重的，有些是致命的。这些严重疾病中的大多数很可能是由细菌感染引起的。因此，有可能在用于SMC的治疗方案中添加抗生素，通过预防严重的细菌感染，从而减少严重疾病和可能的死亡，从而提供额外的好处。以这种方式使用的最合适的抗生素是阿奇霉素(AZ)。AZ已作为集体治疗用于数百万健康儿童，以控制沙眼(一种可能导致失明的细菌性眼睛感染)，并被证明是安全和耐受性良好的。令人惊讶的是，当AZ被部署在埃塞俄比亚的沙眼消除计划中时，总体儿童死亡率下降了约65%。如果AZ确实防止了幼儿死亡，很可能是通过预防细菌感染，特别是肺炎球菌引起的感染，肺炎球菌是非洲幼儿死亡和严重疾病的重要原因。因此，在SMC方案中加入AZ可能会带来额外的益处，这在生物学上是合理的。为了验证这一假设，将在疟疾传播率较高的布基纳法索和马里地区对大约16,000名儿童进行试验。儿童将被随机分配接受SP+AQ的SMC，无论是否添加AZ。在整个2013年疟疾传播季节(7月至10月)，将对儿童进行仔细跟踪。将记录所有死亡或住院情况，并记录因发烧疾病就诊的情况。在传播季节结束时，将随机抽取4000名儿童进行疟疾和贫血检查和测试。此时将测试疟疾寄生虫对SP和从鼻部获得的肺炎球菌的敏感性，以及它们对AZ的敏感性。将确定在SMC方案中加入AZ的成本及其可接受性。这项试验的结果应该清楚地确定，在用于SMC的SP+AQ方案中加入AZ是否有额外的好处，如果有，这是否安全和成本效益高。

Good progress is being made in controlling malaria in Africa but success has been only partial. In some countries there has been only a modest decline in the incidence of malaria despite the widespread deployment of insecticide treated bed nets , spraying of the inside of houses with insecticide and treatment of clinical cases with highly effective drug combinations based on compounds derived from the plant Artemisia annua . More efforts need to be made to scale up these interventions but additional control tools are needed. One potential new tool is seasonal malaria chemoprevention (SMC). SMC involves the administration of a treatment dose of an effective antimalarial drug combination to all children at risk during a period of maximum risk of infection. This approach to malaria control is targeted specifically at areas where malaria transmission is limited by climatic factors to only a few months of the year so that drugs do not have to be given on more than three or four occasions. Areas where SMC would be an appropriate intervention include most of the Sahel and sub-Sahel (population approximately 200 million). Studies conducted in areas of seasonal malaria transmission have shown that SMC with the combination of sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) reduced the incidence of severe and uncomplicated malaria by over 70% and probably reduced deaths. The intervention was safe, well tolerated and highly cost effective. Anti-malaria drugs were given successfully and safely by village volunteers. A WHO Policy Advisory Committee has recently reviewed the results of trials of SMC and is likely to recommend this as a malaria control intervention for areas with highly seasonal malaria transmission.Despite the success of SMC with SP and AQ in reducing malaria, children in the trials of this intervention still suffered many episodes of infectious diseases, some severe and some fatal. It is likely that the majority of these severe illnesses were caused by bacterial infections. Thus, it is possible that adding an antibiotic to the treatment regimen used for SMC could provide added benefit by preventing severe bacterial infections and hence reducing severe illnesses and perhaps deaths. The most suitable antibiotic to be used in this way is azithromycin (AZ). AZ has been given as mass treatment to millions of healthy children to control trachoma (a bacterial eye infection that can lead to blindness) and shown to be safe and well tolerated. Surprisingly, when AZ was deployed in a trachoma elimination programme in Ethiopia, overall child mortality fell by approximately 65%. If AZ really does prevent deaths in young children, it is likely that it does so by preventing bacterial infections, particularly those caused by the pneumococcus, an important cause of death and severe illnesses in young African children. Thus, it is biologically plausible that adding AZ to SMC regimens might provide additional benefit. To test this hypothesis, a trial will be conducted in approximately 16,000 children in areas of Burkina Faso and Mali where malaria transmission is highly. Children will be randomly allocated to receive SMC with SP+AQ either with or without the addition of AZ. Children will be followed carefully throughout the 2013 malaria transmission season (July-October). All deaths or hospital admissions will be recorded and clinic attendances with a febrile illness will be noted. At the end of the transmission season, a random sample of 4,000 children will be examined and tested for malaria and anaemia. Malaria parasites will be tested at this time for their sensitivity to SP and pneumococci, obtained from the nose, for their sensitivity to AZ. The costs of adding AZ to the SMC regimen and its acceptability will be determined.The results of this trial should establish clearly whether adding AZ to the regimen of SP+AQ used for SMC provides added benefit and, if it does, whether this is safe and cost effective.