Efficacy of Sulphadoxine/Pyrimethamine and Chlorproguanil/Dapsone in 6-59 Month Old Children With Uncomplicated Malaria and in 2-10 Month Old Asymptomatic Infants.

Introduction and Rational

This is part of a multicentre trial looking into antimalarial resistance within a series of Intermittent Preventive Treatment of malaria in Infants (IPTi) studies. IPTi is a promising intervention to reduce malaria in infants in malaria endemic countries. 3 doses of antimalarial drugs are given in the first year of life to asymptomatic infants at the time of 2nd and 3rd Diptheria, Tetanus and Pertusus immunisation and again at 9 months of age at time of measles immunisation. In the current Kilimanjaro IPTi study we are comparing 3 antimalarials (Mefloquine MQ, sulfadoxine/pyremethamine SP and chlorproguanil/dapsone CD) against placebo for IPTi in 2 transmission zones. Two published studies using SP for IPTi have shown different efficacies for this intervention. The first study (Schellenberg et al 2001) showed a 62% reduction in clinical cases of malaria and the second (Chandramohan et al, 2005) showed only a 25% reduction in clinical cases of malaria. The two sites differ in several ways, the first was carried out in an area of moderate to low transmission with a moderate rate of SP resistance in Tanzania and the latter was carried out in an area of intense but seasonal malaria with a low rate of SP resistance in Ghana. The current IPTi study is being carried out in a site of high transmission with expected high rates of SP resistance. Data from a site 100km away indicates SP efficacy to be 55% (Mutabingwa et al, 2001). There is no data on SP or other study drugs at the ongoing study sites.

In addition there is evidence (Personal communication Chandramohan 2005) that the outcome (Adequate Parasite Response (APR)) of asymptomatic parasitaemia in infants is better than that in symptomatic 6-59 month old children when using SP. For this reason we plan a novel study examining the efficacy of SP in asymptomatic 2-10 month old infants, the target age group for IPTi.

The main objective of this component of the drug resistance study is to understand the relationship between the efficacy of antimalarial drugs used for IPTi and the long term effect of IPTi on incidence of clinical malaria. Schellenberg et al (2005). observed a 36% reduction in the incidence of clinical malaria in the second year of life in the SP IPTi group compared to the placebo group even though the last course of SP IPTi was given at 9 months of age (Schellenberg et al, 2005). This suggests that SP IPTi in an area with moderate malaria transmission and moderate levels of resistance to SP (+/-25%) IPTi may enhance the development of immunity against malaria. In contrast, a study in Ghana in area with very high and seasonal malaria transmission and very low resistance to SP (<10%) showed a 20% increase in the incidence of clinical malaria with high parasite density (>5000 parasites/ml) in SP IPTi group compared to placebo group. The nature of the relationship between drug resistance and the long term effect of IPTi on malaria remains unclear.

Parasite clearance rate depends on the efficacy of antimalarial drug and host immunity. Host immunity depends on age - immunity in infants is likely to be lower than the immunity in 1-4 year old children. Parasite clearance rate depends on parasite density, multiplicity of infection, and the type of host response - these factors differ between clinical episodes of malaria and asymptomatic parasitaemia. The interaction between antimalarial drug and host response during a clinical episode of malaria is likely to be different from that during asymptomatic malaria parasitaemia. Although infants with mild illness will not be excluded from IPTi administration at routine EPI clinics, the majority of infants will be asymptomatic when they receive IPTi. Thus results of the standard WHO in vivo drug sensitivity studies conducted in 6-59 month-old symptomatic children are unlikely to be applicable to 2-10 month old mostly asymptomatic infants receiving IPTi. However, there is no empirical evidence to support or refute this assertion.