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

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.