Duration of protection against malaria and anaemia provided by intermittent preventive treatment in infants in Navrongo, Ghana

Abstract

Background: Intermittent preventive treatment for malaria in Infants (IPTi) has been shown to give effective and safe protection against malaria. It has been suggested that IPTi might have long-lasting beneficial effects but, in most settings, the protection provided by IPTi appears to be short-lived. Knowledge of the duration of protection given by IPTi would help interpret the results of existing trials and suggest optimal delivery schedules for IPTi. This study investigated how the protective efficacy of IPTi against malaria and anaemia changes over time.

Methods and findings: A secondary analysis of data from a cluster-randomised, placebo-controlled trial of IPTi using sulfadoxine-pyrimethamine (SP) in Ghana was conducted. In this trial IPTi was given to 2485 infants at 3, 4, 9 and 12 months of age; children remained in follow-up until two years of age. Poisson regression with a random effect to adjust for the cluster-randomised design was used to determine protective efficacy of IPTi against clinical malaria and anaemia in defined time strata following administration of IPTi. Analysis of first-or-only clinical malaria episode following the individual IPTi doses showed that some protection against malaria lasted between 4 to 6 weeks. A similar pattern was seen when the incidence of all malaria episodes up to 2 years of age was analysed in relation to the most recent IPT, by pooling the incidence of malaria after the individual IPTi doses. Protective efficacy within four weeks of IPTi was 75.2% (95% CI: 66-82) against malaria, 78.9% (95% CI: 69-86) against high parasite density malaria, and 93.8% (95% CI: 73-99) against anaemia. Protection against these outcomes was short-lived, with evidence of any effect lasting for only 6, 6 and 4 weeks respectively. Protection in children who were parasitaemic when receiving IPTi appeared to be of shorter duration than in uninfected children. There was no evidence of any benefit of IPTi after the immediate period following the IPTi doses.

Conclusions: Intermittent preventive treatment provides considerable protection against malaria and anaemia for short periods, even in an area of intense seasonal transmission. Due to the relatively short duration of protection provided by each dose of IPTi, this treatment will be of most benefit when delivered at the time of peak malaria incidence.

Figure 1. Kaplan-Meier failure plots for individual IPT doses.

Kaplan-Meier plots showing cumulative proportion of children with a malaria episode following IPT doses 1–4. Numbers below x-axis labels indicate number of children remaining in follow-up at that time point.

Figure 2. Protective efficacy of individual IPT doses against clinical malaria.

Protective efficacy against first-or-only episode of clinical malaria (history of fever or temperature ≥37.5°C plus malaria parasites detected on a blood smear) by week since treatment for IPTi doses 2, 3 & 4. Error bars indicate 95% confidence intervals. The y-axis is truncated at −100 for IPT2 and IPT3, and at −150 for IPT4. No children given SP had malaria during week 2 after IPT4.

Figure 3. Protective efficacy of IPT against clinical malaria.

Protective efficacy of IPTi by week since treatment against clinical malaria (history of fever or temperature ≥37.5°C plus malaria parasites detected on a blood smear). Error bars indicate 95% confidence intervals. PE estimates are for all IPT doses combined; all episodes that occurred before two years of age were included in the analysis. No long term protection was observed; for brevity estimates are presented up to twenty weeks following treatment. Incidence in weeks 13–16 and 17–20 was aggregated; data points are shown at the midpoint of each interval.

Figure 4. Protective efficacy of IPT against high parasite density malaria.

Protective efficacy of IPTi by week since treatment against high parasite density malaria (clinical malaria with parasite density ≥5000/µl). Error bars indicate 95% confidence intervals. PE estimates are for all IPT doses combined; all episodes that occurred before two years of age were included in the analysis. No long term protection was observed; for brevity estimates are presented up to twenty weeks following treatment. Incidence in weeks 13–16 and 17–20 was aggregated; data points are shown at the midpoint of each interval.

Figure 5. Protective efficacy of IPT against anaemia.

Protective efficacy of IPTi by week since treatment against anaemia (packed cell volume <24%). Error bars indicate 95% confidence intervals. PE estimates are for all IPT doses combined; all episodes that occurred before two years of age were included in the analysis. No long term protection was observed; for brevity estimates are presented up to twenty weeks following treatment. Weeks were aggregated as 1–2, 3–4, 5–6, 7–8, 9–10, 11–12, 13–16 & 17–20 weeks since treatment; data points are shown at the midpoint of each interval. The y-axis is truncated at −100, for full data see table 2.

Figure 6. Effect of parasitaemia on protective efficacy following IPT.

Protective efficacy against clinical malaria (history of fever or temperature ≥37.5°C plus malaria parasites detected on a blood smear) with time in children aparasitaemic (A) and parasitaemic (B) at time of IPT. Error bars indicate 95% CIs. PE estimates are for all IPT doses combined; all episodes that occurred before two years of age after an IPT dose at which a blood slide was taken were included. No long term protection was observed; for brevity estimates are presented up to twenty weeks following treatment. Incidence in weeks 13–16 and 17–20 was aggregated; data points are shown at the midpoint of each interval. For clarity of presentation the y-axis is truncated at −100%.