Introduction
Despite increased attention to malaria control by donors, researchers, clinicians, and communities, malaria continues to exact an intolerable toll, particularly in sub-Saharan Africa. The development of new tools such as combination of drug therapies and insecticide treated nets (ITNs) have offered hope, but their impact has been limited by low implementation and logistical and financial constraints. No single tool currently exists that can drastically reduce the malaria burden. Given this reality, and while awaiting new technologies, the malaria community must reexamine available data and interventions to look for creative and synergistic control strategies.
It is well documented and accepted that the burden of malaria falls greatly on young children and infants [
1]. Even in low/moderate malaria transmission settings, where older children suffer the most malaria episodes, infants have the highest fatality rate [
2]. Finding cost-effective and affordable approaches to deliver malaria control interventions to infants is a public heath priority, especially since adequate control may be followed by important reductions in mortality for infants as well as young children [
3]. The Expanded Program on Immunization (EPI) is the only available scheme that involves regular contact between the population at risk and the health system, even in places with very limited access to services. The intermittent preventive treatment in infants (IPTi) consists of administering a treatment dose of an antimalarial drug at predetermined intervals regardless of the presence of parasitaemia or symptoms. Through the EPI, it has the potential to become a cost-effective strategy.
IPTi with sulphadoxine-pyrimethamine (SP) has been shown to significantly reduce malaria episodes in randomized trials carried out in Tanzania, and more recently in Ghana and Mozambique [
4‐
6]. The effect of one treatment dose of SP can last as long as 60 days [
7]. Thus, the administration of SP coinciding with immunizations through the EPI scheme could provide a period of suppressive prophylaxis that retains some beneficial effects of regular chemoprophylaxis without compromising the development of malaria immunity [
8].
Despite the positive results for efficacy and safety, the determinants and underlying protection mechanisms of IPTi are not yet clear. The analysis of differences between clinical trials that use similar designs could provide insight into the potential determinants and possible underlying protection mechanisms, as well as facilitate planning for future policy recommendations. We had the unique opportunity to compare two very similar IPTi trials in two malaria endemic countries in Eastern and Southern Africa. We present results from a comparative analysis of the protective efficacy of IPTi, and examine the factors that may explain the different protection levels achieved [
4,
6]. The goal is that this information will help garner future research and guide decision making about the most appropriate role of IPTI in malaria control.
Discussion
Intermittent preventive treatment with SP had different protective efficacies in reducing malaria and anemia incidence in these two malaria endemic settings in sub-Saharan Africa. The two trials were very similar in most aspects. Randomization, intervention, follow-up and assessment of outcome procedures were close to identical. The active drug and placebo were manufactured by the same pharmaceutical company. Intensity of malaria transmission during the course of both studies was comparable, not only in the comparable EIR, but also in the rates of malaria episodes in the placebo groups during the first year of life (Table
1). At the time of the trials, parasitological resistance and clinical response to SP were similar, and information obtained shortly before the trials started showed that the drug had an adequate level of efficacy in both settings [
12‐
15]. Moreover, the analysis during the month after each dose (Table
2) shows that SP efficacy was above 50% in both sites. Therefore, it is unlikely that a reduced parasitological efficacy of SP in Manhiça could solely account for the observed difference in clinical protection.
The overall incidence of severe anaemia up to 1 year of age was not significantly affected by the SP intervention in Manhiça [
6]. Prophylactic iron supplements were not given to study infants in the Mozambican study since this is not part of the standard of care. In Ifakara, on the other hand, prophylactic ferrous sulphate was given for 4 months to all study participants. The discrepancy in anemia prevention between the two trials could be because malaria is less important than other causes of anaemia in infants in the Manhiça area. An alternative explanation is that protection against malaria needs to be sustained to have a significant impact on associated anaemia. This would also explain the significant effect of IPTi on anaemia in Ifakara where the intervention was given in the context of high ITN's coverage. Moreover, another study in this same setting found a significant reduction in the risk of anaemia in infancy by weekly malaria chemoprophylaxis for 10 months [
8].
The administration of the IPTi regimen differed slightly in the two trials because of the different EPI immunization schedules. Consequently, in Ifakara the first two doses were given at 2 and 3 months, while in Manhiça they were administered at 3 and 4 months of age. It is unlikely that this variation in the intervention regimen would explain the difference found in the efficacy; particularly since the time between administration of the second and third dose was shorter in Mozambique. The risk of malaria is greater between age 5 and 9 months than during the first 3 months of life, and thus implies a theoretical advantage to the infants in the Manhiça study, which was not observed [
21].
HIV infection during pregnancy has been associated with increased susceptibility to malaria and lower efficacy of IPT with SP [
22]. In contrast, no information exists on the impact of the co-infection in children [
23]. The HIV infection status was not recorded for children participating in either trial. However, HIV seroprevalence at antenatal clinics differed between the two sites, and it is expected that slightly more enrolled infants in Manhiça would have been infected than in Ifakara. Although specific studies are needed to look at this interaction in children, it is unlikely that HIV associated immunosuppression played an important role in reducing the impact of the intervention in the Manhiça study at the magnitude observed.
The analysis presented in this paper shows that, as expected, the risk of malaria was greatly reduced for 1 month in children who received a stat dose of a moderately effective antimalarial. However, the different protection levels between the two trials is mainly explained by the difference in risk of malaria outside the window of time when the drug is efficacious. There are no obvious reasons that explain these findings. In a previous report we have hypothesized that this reduced risk is a function of the accelerated acquisition of immunity in children receiving IPTi in the first year of life [
18]. The question arises why this accelerated acquisition of immunity did not occur in Manhiça. The only remarkable difference between the two sites that could explain this difference refers to the wide-scale use of ITNs in Ifakara. It points to a possible synergistic effect between IPTi and ITNs that reduces the dose of infection from the mosquito and allows an improved acquisition of immunity. This would explain why there is no rebound effect after stopping IPTi in Ifakara, and there is even a sustained reduction of the risk of clinical malaria extending beyond the pharmacological effect of the drug [
18]. This additive protection of drugs and ITNs is supported by the results of a study in The Gambia, where the combination of weekly chemoprophylaxis and ITNs provided substantial additional protection against malaria infection and clinical malaria attacks [
3].
Acknowledgements
We are in debt to the parents and children that participated in the studies. We are grateful to the staff of the Ifakara Health Research and Development Center and Saint Francis Designated Hospital in Tanzania, as well as to the staff of the Manhiça Health Research Center and Manhiça Health Center in Mozambique. We acknowledge Hoffman-La Roche for providing the sulphadoxine-pyrimethamine (Fansidar®) and placebo.
Research and ethical clearances for both trials were provided by the local and national IRBs in Mozambique and Tanzania as well as from the IRBs of all institutions involved in the trials.
The Manhiça study received financial support from the Banco de Bilbao, Vizcaya, Argentaria Foundation (grant number BBVA 02-0) and the Bill and Melinda Gates Foundation (BMGF) (grant number IPTi103-0). The CISM receives core support from the Spanish Agency for International Cooperation (AECI).
The Ifakara study received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), the Spanish Agency for International Cooperation (AECI) and the Fondo de Investigaciones Sanitarias (FIS number 00/0803). The IHRDC receives core support from the Swiss Agency for Development and Cooperation.
Authors' contributions
CM. I declare that I have participated in the conception, design and conduction of the studies, and writing up of the manuscript, and have seen and approved the final version of the manuscript.
DS. I declare that I have participated in the conception, design and conduction of the study (Ifakara), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
EM. I declare that I have participated in the conduction and analysis of the study (Manhiça), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
PA. I declare that I have participated in the conduction of the study (Manhiça), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
EK. I declare that I have participated in the conduction of the study (Ifakara), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
SS. I declare that I have participated in the analysis of the study (Manhiça), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
JJA. I declare that I have participated in the conception, design, and analysis of the studies, and writing up of the manuscript, and have seen and approved the final version of the manuscript.
JS. I declare that I have participated in the conduction of the study (Manhiça), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
HM. I declare that I have participated in the conception, and design of the study (Ifakara), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
MT. I declare that I have participated in the conception, and design of the study (Ifakara), and writing up of the manuscript, and have seen and approved the final version of the manuscript.
PLA. I declare that I have participated in the conception, and design of the studies, and writing up of the manuscript, and have seen and approved the final version of the manuscript