Facilitators and Barriers to Uptake of an Extended Seasonal Malaria Chemoprevention Programme in Ghana: A Qualitative Study of Caregivers and Community Health Workers

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Abstract

Background

Seasonal Malaria Chemoprevention (SMC) is currently recommended for children under five in areas where malaria transmission is highly seasonal. We explored children’s caregivers’ and community health workers’ (CHWs) responses to an extended 5-month SMC programme.

Methods

Thirteen in-depth interviews and eight focus group discussions explored optimal and suboptimal ‘uptake’ of SMC to examine facilitators and barriers to caregivers’ uptake.

Results

There did not appear to be major differences between caregivers of children with optimal and sub-optimal SMC uptake in terms of their knowledge of malaria, their perceptions of the effect of SMC on a child’s health, nor their understanding of chemoprevention. Caregivers experienced difficulty in prioritising SMC for well children, perceiving medication being for treatment rather than prevention. Prior to the study, caregivers had become accustomed to rapid diagnostic testing (RDT) for malaria, and therefore blood testing for malaria during the baseline survey at the start of the SMC programme may have positively influenced uptake. Facilitators of uptake included caregivers’ trust in and respect for administrators of SMC (including CHWs), access to medication and supportive (family) networks. Barriers to uptake related to poor communication of timings of community gatherings, travel distances, absence during SMC home deliveries, and limited demand for SMC due to lack of previous experience. Future delivery of SMC by trained CHWs would be acceptable to caregivers.

Conclusion

A combination of caregivers’ physical access to SMC medication, the drug regimen, trust in the medical profession and perceived norms around malaria prevention all likely influenced caregivers’ level of uptake. SMC programmes need to consider: 1) developing supportive, accessible and flexible modes of drug administration including home delivery and village community kiosks; 2) improving demand for preventive medication including the harnessing of learnt trust; and 3) developing community-based networks for users to support optimal uptake of SMC.

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Most cited references 15

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Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial.

Badara Cisse, Cheikh Sokhna, Denis Boulanger … (2006)

In the Sahel and sub-Sahelian regions of Africa, malaria transmission is highly seasonal. During a short period of high malaria transmission, mortality and morbidity are high in children under age 5 years. We assessed the efficacy of seasonal intermittent preventive treatment-a full dose of antimalarial treatment given at defined times without previous testing for malaria infection. We did a randomised, placebo-controlled, double-blind trial of the effect of intermittent preventive treatment on morbidity from malaria in three health-care centres in Niakhar, a rural area of Senegal. 1136 children aged 2-59 months received either one dose of artesunate plus one dose of sulfadoxine-pyrimethamine or two placebos on three occasions during the malaria transmission season. The primary outcome was a first or single episode of clinical malaria detected through active or passive case detection. Primary analysis was by intention-to-treat. This study is registered with , number NCT00132561. During 13 weeks of follow-up, the intervention led to an 86% (95% CI 80-90) reduction in the occurrence of clinical episodes of malaria. With passive case detection, protective efficacy against malaria was 86% (77-92), and when detected actively was 86% (78-91). The incidence of malaria in children on active drugs was 308 episodes per 1000 person-years at risk, whereas in those on placebo it was 2250 episodes per 1000 person-years at risk. 13 children were not included in the intention-to-treat analysis, which was restricted to children who received a first dose of antimalarial or placebo. There was an increase in vomiting in children who received the active drugs, but generally the intervention was well tolerated. Intermittent preventive treatment could be highly effective for prevention of malaria in children under 5 years of age living in areas of seasonal malaria infection.

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Estimating the potential public health impact of seasonal malaria chemoprevention in African children

Matthew Cairns, Arantxa Roca-Feltrer, Tini Garske … (2012)

Child mortality remains unacceptably high in many countries in sub-Saharan Africa, with malaria being a major contributor to this burden. Current estimates of malaria morbidity in Africa range from 174 million to 271 million clinical cases each year1 2, resulting in 600,000 to 1.1 million deaths1 3. Although there are uncertainties and limitations attached to each of these estimates, the burden of malaria is clearly unacceptably high and new malaria control measures are urgently needed, particularly for African children under 5 years of age. A series of studies conducted in Sahelian and sub-Sahelian Africa have shown that seasonal malaria chemoprevention (SMC), previously known as intermittent preventive treatment of malaria in children (IPTc), is a promising tool for the control of malaria in areas where transmission of malaria is highly seasonal. A meta-analysis of SMC studies in which a therapeutic course of sulphadoxine-pyrimethamine plus amodiaquine (SP-AQ) was given once per month to children under the age of 5 years during the peak malaria transmission season showed an 83% (95% CI: 72%, 89%) reduction in the incidence of clinical attacks of malaria and a similar reduction in the incidence of severe malaria (77%; 95% CI: 45%, 90%)4. Similar findings were obtained in a recent Cochrane review of IPTc studies5. The SP-AQ combination used in most trials was safe. Current evidence is consistent with a reduction in all-cause mortality due to SMC but the confidence intervals are wide (A.L.W., unpublished results)4 5. Similar results have been obtained with other antimalarial combinations given on a monthly basis. Administration every 2 months has also been tried but was less effective6. High levels of coverage have been achieved using community health workers to administer SMC, and the intervention is highly cost effective7 8. In the majority of studies, three monthly administrations have been employed and, although longer periods of administration may be considered, the evidence in relation to feasibility of delivery, safety and efficacy of SMC relates primarily to administration over a 3-month period. The World Health Organization (WHO) convened a meeting of a Technical Expert Group in May 2011 to consider whether sufficient data had been gathered to recommend incorporation of SMC into the malaria control programmes of areas with highly seasonal transmission of malaria. Their positive recommendation was reviewed by a newly constituted WHO Malaria Policy Advisory Committee in February 2012. If SMC with SP-AQ is formally recommended as policy by the Malaria Policy Advisory Committee, implementation may begin in certain countries of the Sahel and sub-Sahel sometime in 2012. Malaria control programme managers will need to consider whether regions of their country are suitable for the implementation of SMC on the basis of the incidence of malaria and its seasonality in those regions. To assist policy makers and programme managers in making such decisions, we have identified the geographical areas where SMC is likely to be an appropriate and cost-effective intervention using data on the overall incidence and seasonality of malaria in different parts of sub-Saharan Africa. In this study, we show that there are two large areas of Africa likely to have both sufficient seasonality and sufficient malaria incidence for SMC to be both effective and cost-effective. In particular, the Sahelian and sub-Sahelian regions of Africa have a large population of children under 5 years of age at risk in areas where SMC with current antimalarials is likely to be highly efficacious, and where millions of malaria cases and tens of thousands of childhood deaths could potentially be prevented each year. Results Defining areas suitable for the implementation of SMC Fifty-six sites where monthly malaria incidence had been measured for 12 consecutive months were identified in 22 sub-Saharan African countries (Supplementary Tables S1,2). Areas meeting seasonality definition B (60% of annual incidence within 4 consecutive months) were observed more frequently in the Sahel and sub-Sahel than in other parts of Africa. Definition B gave consistent results in sites where more than one type of malaria outcome had been recorded (for example, severe malaria and clinical malaria) or where information was available for several years. Definition C (50% of annual incidence in 4 months) was not stringent enough to identify SMC areas, as a large number of sites had this level of seasonality. Definition A (75% of annual incidence in 4 months) excluded several sites known to be highly seasonal, including sites in the Gambia and Senegal, suggesting that this definition is too strict. Definition B was, therefore, used for subsequent analyses. After inspection of site-specific rainfall patterns, the severe malaria data reported for one site were considered unreliable (seasonality in malaria incidence was much stronger than the seasonality in rainfall), and this site was excluded as an outlier; 55 sites were, therefore, available for analysis (Supplementary Tables S1,2). The best predictor of sufficient seasonality for SMC according to definition B was >60% of the total annual rainfall within three consecutive months; this cutoff identified areas with incidence patterns suitable for SMC with a sensitivity of 95.0% and a specificity of 73.5% (Fig. 1). Maps produced by rainfall seasonality alone, and by rainfall seasonality in areas endemic for Plasmodium falciparum, identified two broad areas as being potentially suitable for deployment of SMC (Fig. 2a,b). The first includes much of the Sahelian and sub-Sahelian regions of Africa, which matches well with the sites identified from the seasonality assessment of epidemiological data. The second area is in southern Africa, stretching from Namibia in the west to Mozambique and Southern Tanzania in the east. Estimating the population and burden in SMC areas The geographical area mapped by rainfall seasonality, as defined above, in malaria endemic areas led to an estimate of 39 million children under 5 years of age at risk of malaria in areas suitable for implementation of SMC, 24.9 million in the Sahel or sub-Sahel and 14.1 million in southern and eastern Africa. On the basis of this population at risk, the method used in the World Malaria Report 2008 (WMR)9 gave a total burden estimate of 33.7 million cases per year in children under 5 years of age in sites suitable for SMC, 24.1 million cases in the Sahel and sub-Sahel, and 9.6 million per year in the rest of Africa (Table 1). The burden estimate using a prevalence-incidence relationship derived by the Malaria Atlas Project (MAP)10 was 12 million malaria cases (see Methods), 8.5 million of these in the Sahel and sub-Sahel. Mortality estimates using a fixed case fatality rate were 151,552 (108,506 in the Sahel and sub-Sahel) for the WMR burden estimate and 53,953 (38,474 in the Sahel and sub-Sahel) for the MAP burden estimate. Use of a population-based mortality rate, as described by Rowe et al.11 gave an estimate of 314,283 deaths from malaria (221,811 in the Sahel and sub-Sahel). Applying a higher case fatality rate of 10 per 1,000 gave similar estimates to those produced using the method of Rowe et al.11 (data not shown). The burden in SMC areas above minimum incidence thresholds Applying lower prevalence thresholds to the map of areas suitable for SMC (Fig. 2c,d) produced smaller population estimates (Tables 2 and 3): 28.9 million children under 5 years of age at risk in areas with incidence greater than 0.1 episodes per child during the transmission peak (21 million in the Sahel and sub-Sahel) and 24.9 million children at risk in areas with 0.2 episodes per child during the transmission peak (18.9 million in the Sahel and sub-Sahel). Corresponding morbidity and mortality estimates were slightly lower but remained substantial, particularly in the Sahel and sub-Sahel. The most stringent incidence threshold of 0.2 episodes per child during the transmission peak resulted in an estimate of 25.7 million malaria cases and 115,704 deaths (18.9 million cases and 85,225 deaths in the Sahel and sub-Sahel). Estimating the potential public health impact of SMC Using the WMR estimate of 33.7 million malaria cases per year in children under 5 years of age in the areas mapped as suitable for SMC, and 151,552 deaths per year (applying the fixed case fatality rate (CFR) to the incidence estimate), SMC is predicted to have a considerable impact (Fig. 3). Restricting estimates to areas with incidence greater than 0.2 cases per child per year made only relatively minor changes. Even if our approach has resulted in a 50% overestimate of the malaria burden in SMC areas, the potential impact of SMC could still be substantial, with ~5 million cases and 20,000 deaths averted if the intervention was widely deployed (Table 4). Discussion We have defined the epidemiological settings where SMC is likely to be a suitable intervention and mapped the geographical areas where this epidemiology is likely to be found. Climate-based predictors identified the highly seasonal areas suitable for SMC with high sensitivity and good specificity. It is clear from our estimates that there is a large population of children under 5 years of age at risk from malaria in areas where SMC is likely to be appropriate. The burden of malaria in these areas, particularly in countries in the Sahel and sub-Sahel, is substantial and suggests that SMC deployed at scale could have a major public health impact. Most evidence on the efficacy of SMC relates to delivery over 3 months. We chose to focus on incidence during a period of 4 consecutive months as this is the longest period for which 3 monthly courses of SMC might be expected to provide a reasonably high level of protection. Our assumption of impact during a 4-month peak was conservative as this was based on estimates of protective efficacy obtained from a study of children sleeping under insecticide treated nets over a three-and-a-half month follow-up period, assuming no protection in the subsequent two weeks. Although a considerable number of studies were identified in the literature review, only a small proportion of these reported morbidity data in the required format to assess seasonality in malaria burden reliably. Nevertheless, enough data points were found to explore the utility of different cutoffs to define malaria incidence as sufficiently seasonal for SMC to be valuable. As previously reported12, in sites with 2 rainy seasons, the largest number of cases per month did not necessarily occur in 4 consecutive months (Supplementary Tables S1,2). Therefore, some situations where SMC may be appropriate, if directed at two seasonal peaks in transmission, may not have been identified by the approach used here. However, to date, SMC has not been used in such settings; whether this would be appropriate requires further investigation. Our approach focusses on epidemiological situations with a single peak in transmission, situations in which the efficacy of SMC has already been well characterized. Rainfall patterns delineated two distinct geographical areas where SMC could be considered. The estimates of populations of SMC areas defined in our analyses are consistent with the populations living in seasonal transmission areas determined by the Mapping Malaria Risk in Africa project13, but are more conservative (Supplementary Tables S3,4). The map incorporating malaria endemicity is more biologically plausible than one based on rainfall alone as it excludes areas where rainfall may be seasonal but very low, or where other conditions prohibit malaria transmission. Malaria control programmes operating in countries bordering the area identified as being suitable for SMC should undertake assessment of the seasonality of malaria in these areas, using local incidence data to guide decisions about whether deployment of SMC would be appropriate. For example, rainfall in most of northern Ghana did not meet the seasonality criterion and our estimate of the population at risk in Ghana is consequently relatively small. However, the epidemiology of malaria in Navrongo, Ghana suggests that the northern regions may be suitable for SMC (Supplementary Tables S1,2)14. Therefore, it is likely that a larger area could potentially benefit from SMC and a larger population could be protected than we have defined in this study. The continental maps showing areas suitable for SMC implementation covered primarily Sahelian and sub-Sahelian areas as expected a priori. Areas meeting the seasonality criterion were also found in southern and eastern Africa, where there is much less epidemiological information on the seasonality of malaria. In some of these areas, the incidence of malaria is low and unstable and therefore SMC is not likely to be a suitable intervention. Incidence thresholds, based on cost per case and per disability-adjusted life year averted, indicated that SMC might still be worthwhile in some areas, particularly in southern Tanzania, Malawi and northern Mozambique, but this needs further investigation. For SMC to be deployed in southern and eastern Africa, an alternative to the SP-AQ combination would be needed owing to high levels of SP resistance15. The difficulties in estimating the malaria burden in Africa accurately are well recognized3 9 11 16 17 18. Our emphasis was to derive a plausible and conservative estimate of the malaria burden using transparent methods, rather than aiming to produce an alternative estimate to those provided by others. However, burden estimates based on different approaches showed broadly consistent figures. The estimates using the MAP prevalence–incidence function were lowest, but it is clear from comparison with data from SMC sites that these are likely to be an underestimate as the function relates prevalence in children to all-age incidence rather than incidence in children under 5 years of age. Furthermore, the estimates produced using the WMR method were similar to those derived using a prevalence–incidence function fitted specifically to incidence data on children under 5 years of age (Griffin J., personal communication). Our estimate of the impact of SMC on mortality is simplistic, assuming that a reduction in malaria cases would be accompanied by a proportional reduction in malaria deaths. However, our estimates of impact do not include the reductions in indirect mortality that may result from better control of malaria. Some of the areas with the highest malaria burden in all of Africa lie within the parts of the Sahel and sub-Sahel, which we have identified as being suitable for SMC2. Deployment of SMC in these areas would be expected to be highly cost effective on the basis of the high malaria incidence per child each year. The coverage and efficacy that would be achieved, if SMC was to be implemented as a large-scale public health measure, is not yet known, but high coverage has been achieved by community-based health workers7, and efficacy should remain high where SP and AQ resistance levels remain low or moderate. Furthermore, our analysis suggests that even with moderate levels of coverage, the deployment of SMC could have a significant public health impact. The epidemiological and geographical situations in which SMC is likely to be useful can be defined on the basis of epidemiological data and surrogate measures of seasonality in malaria transmission. A simple algorithm could be developed to help policy makers to decide whether the malaria incidence in their country, or certain regions within their country, was sufficiently seasonal for the deployment of SMC. The algorithm could also indicate the potential impact of implementation of SMC with different levels of efficacy and coverage. Although the burden of malaria in the areas where SMC could be deployed is uncertain, it is likely to be considerable. Our analyses suggest that even where other effective malaria control tools, such as insecticide-treated nets (ITNs), indoor residual spraying of insecticides (IRS) and partially effective malaria vaccines are deployed, SMC could potentially avert a very large number of malaria episodes and many thousands of unnecessary deaths in several countries where malaria is currently not adequately controlled. Methods Defining SMC seasonality We performed a literature review to identify studies reporting incidence of parasitologically confirmed clinical malaria and/or severe malaria for 12 consecutive months. Sources of data used included published monthly malaria incidence data obtained from a systematic review conducted in 2005 (refs 12,19), surveillance data and an additional systematic review undertaken in 2010, including contact with authors. Search criteria and further details are included in Supplementary Methods, Supplementary Table S5 and Supplementary Fig. S1. Locations of the sites are shown in Supplementary Figs S2,3. A previous analysis indicated that ≥75% of malaria incidence occurring within 6 consecutive months provided a useful definition of 'marked seasonality'12. Most of the evidence for the efficacy and safety of SMC relates to monthly delivery over a 3-month period, which provided protection during a transmission peak of 3-to-4 months. We therefore explored different definitions of the degree of seasonality based on the maximum percentage of the total annual malaria burden occurring within any consecutive four-month period. Three definitions were considered: at least 75% (definition A), 60% (definition B) and 50% (definition C) of the total annual incidence of malaria within four consecutive months. Identifying spatial predictors of SMC areas To characterize seasonality in malaria incidence outside the areas, for which epidemiological data were available, we explored whether rainfall patterns, estimated from a combination of satellite imagery and rain gauge data20, could be used as a predictor of the degree of seasonality in incidence. Daily accumulated rainfall data were available for a grid of 0.1 degree×0.1 degree resolution, with data missing for only 2 days since November 2000. We used data from 2002 to 2009 and aggregated the daily time series to time series using 64 points per year. Fourier analyses were undertaken to capture the average seasonality over this time period. Each site identified by our review was geo-referenced and site-specific rainfall data obtained. For each location of interest, we selected the pixel closest to the given longitude/latitude. The percentage (in 5% intervals) of the annual total rainfall occurring in a range of different consecutive periods (ranging from 2 to 6 months) was then calculated to create a set of potential indicators of seasonality. The sensitivity and specificity of each indicator variable as a predictor of the degree of seasonality in malaria incidence was calculated to create receiver operating characteristic (ROC) curves using Stata 11 software (College Station, Texas, USA). The best predictor of seasonality in malaria incidence was then used to map areas suitable for SMC across Africa using the 0.1 degree×0.1 degree grid of rainfall data. For each pixel, the seasonality in rainfall was calculated by assessing the maximum percentage of the total annual rainfall occurring in a period of consecutive months. Pixels meeting the criterion specified by the best indicator variable were considered as potentially suitable for SMC. To further improve the biological plausibility of the spatial mapping of SMC areas, we merged the map produced by seasonality in rainfall with spatial malaria endemicity estimates produced by MAP for 2010 (ref. 21), restricting the area mapped by seasonality in rainfall to include only areas with stable P. falciparum transmission (annual incidence of P. falciparum infections >0.1 per 1,000 population per annum). Estimating the population and burden in SMC areas The total population at risk in the areas identified by the approach described above was derived from LandScan 2007 population estimates22. Population estimates were aggregated within first administrative level and then by country, and scaled to 2010 by applying national growth rates from UN projections23. We estimated the number of children under 5 years of age using UN demographic information for each country23 and the percentage living in urban/rural areas based on a population density threshold24. For full details, see Supplementary Methods. Malaria incidence in children under 5 years of age in SMC areas was estimated using two published methods (Table 5). The first follows the approach used in the 2008 WMR for countries where estimates of malaria incidence could not be made from routinely reported data9 25. Fixed age-specific incidence rates were used according to the level of malaria risk as defined by the Mapping Malaria Risk in Africa map, and in high-transmission areas, incidence estimates were halved for populations living in urban areas13. To retain transparency, incidence estimates were not reduced further to account for coverage of other malaria control tools; the possible impact of interventions such as ITNs and IRS are considered in a sensitivity analysis. The second method used a published function relating annual all-age incidence to prevalence of parasitaemia in children 2–10 years of age10. We applied the central estimate of this function to the MAP prevalence data to estimate incidence (Fig. 4). The effect of urban residence is incorporated in the prevalence estimates2 and is, therefore, implicitly accounted for. By comparison with observed incidence/prevalence observations made in SMC studies, this relationship is likely to result in a conservative estimate of the incidence of malaria in children under 5 years of age during the transmission peak for a given prevalence (Fig. 4). The mortality burden in SMC areas was also estimated by two approaches (Table 5). Method one assumes a fixed CFR of 4.5 deaths per 1,000 malaria cases (0.45%), the central estimate for areas where malaria morbidity is routinely reported9. This fixed CFR was applied to incidence estimates derived using both the WMR method and the MAP incidence–prevalence function. We also explored a higher case fatality rate of 10 per 1,000 (that is, 1% fatality rate). Method 2 uses the approach of Rowe et al., applying a fixed mortality rate to populations at risk rather than to malaria cases11. For simplicity, we did not amend our estimates to take account of the relative contribution of malaria to all-cause under 5 mortality, as performed in the WMR, but this would only be expected to reduce the estimates by ~10% (ref. 9). The burden in SMC areas above minimum incidence thresholds Analysis of the costs of SMC delivery undertaken by the IPTc Working Group suggests that, on the basis of both costs per case averted and cost per disability-adjusted life year averted, SMC is likely to be cost-effective where malaria incidence exceeds 0.2. episodes per child during the peak transmission season, but may not be cost effective where incidence is less than 0.1 episodes per child during the transmission peak (Pitt C, Milligan P, unpublished results). The MAP incidence–prevalence relationship suggests that incidence would be at least 0.1 episodes per child per season at a prevalence of parasitaemia >8.8%, and at least 0.2 episodes per child at a prevalence >17.3%. Using these cutoffs is likely to be highly conservative because incidence in children at a given prevalence is likely to be substantially higher than all age incidence, the prediction given by the MAP function (Fig. 4). These minimum prevalence thresholds were used to map a restricted SMC area, giving a conservative estimate of the population at risk and of morbidity and mortality in areas where SMC would be appropriate on the basis of sufficiently high incidence. Estimating the potential public health impact of SMC We considered the number of cases and deaths that could potentially be averted with different levels of SMC efficacy and coverage. In sites considered suitable for SMC, the median fraction of incidence occurring in the 4 consecutive months of peak transmission was 77% and the mean 75.7% (Supplementary Table S1,2). We therefore assumed that, on average, 75% of the annual burden occurred in the SMC period, but also explored the impact of SMC, if 60% and 90% of annual incidence occurred in the period when SMC was given. In recent studies of SMC in Burkina Faso and Mali, protective efficacy of 3, monthly courses over a period of three-and-a-half months from the date of the first course was 70% and 82% respectively26 27. On the basis of these figures, assuming no protective effect in the two weeks after the end of the follow-up, the protective efficacy over four months would be 61% (Burkina) and 72% (Mali), a mean of 67%. We therefore assumed that a protective efficacy of 65% would be a reasonable estimate of protection provided by three courses over a 4-month peak. Four monthly courses over 4 months might provide protective efficacy of ~80%. We explored the potential range in impact of SMC by allowing for a 25 or 50% underestimate or overestimate of the malaria burden without SMC. We accounted for a possible overestimate in this way to include the burden estimate that would be expected, had we additionally adjusted for coverage of other widely used malaria control tools. ITNs and IRS would be estimated to reduce incidence by ~50% and 60%, respectively, at 100% coverage9 28. However, actual coverage of these interventions is currently far less than 100% in most African countries29. Author contributions M.C. and A.R.F. designed the study and wrote the first draft of the manuscript. M.C., A.R.F. and T.G. analysed the data. A.R.F. and A.W. undertook the literature review. M.C. and T.G. calculated the burden estimates. D.D. provided data and contributed to the analysis of incidence data. A.G. developed the spatial modelling framework. P.M. undertook the cost-effectiveness analysis. P.M., A.G. and B.G. contributed to all stages of the design and analysis. B.G. led the study team. All authors contributed to interpretation of the analyses and revised the draft manuscript. Additional information How to cite this article: Cairns, M. et al. Estimating the potential public health impact of seasonal malaria chemoprevention in African children. Nat. Commun. 3:881 doi: 10.1038/ncomms1879 (2012). Supplementary Material Supplementary Information Supplementary Figures S1–S3, Supplementary Tables S1–S5, Supplementary Methods and Supplementary References

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Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial

Alassane Dicko, Abdoulbaki Diallo, Intimbeye Tembine … (2011)

Introduction An estimated 863 million people live in sub-Saharan Africa of whom 16.2% are under 5 y of age [1]. About 300 million people live in areas where malaria transmission is highly seasonal. Malaria remains a major cause of morbidity and mortality and is estimated to cause 881,000 deaths globally per year and sub-Saharan Africa is disproportionately affected, suffering 91% of global malaria deaths with 88% occurring in children under 5 y of age [2]. Thus, in the absence of a vaccine, simple and effective control strategies are urgently needed to reduce the malaria burden in sub-Saharan Africa. Vector control, using insecticide-treated bednets (ITNs), insecticide-treated curtains, or indoor residual spraying (IRS), can reduce mortality and morbidity from malaria substantially [3], but in high transmission settings, these interventions provide only partial protection and additional control measures are needed. Intermittent preventive treatment (IPT) is a new approach in the prevention of malaria in infants and older children. Several randomised controlled trials have demonstrated that IPT of malaria in infants (IPTi) with sulphadoxine pyrimethamine (SP) given during routine vaccinations at approximately 2, 3, and 9 mo of age, reduces the incidence of clinical malaria by 22% to 59% [4], and this strategy has been shown to be safe and cost effective. However, in many regions of Africa, the main burden of malaria falls not on infants but on older children [5]. In parts of Africa, such as much of the Sahel and sub-Sahel, where malaria transmission is very seasonal, the incidence of severe malaria currently peaks at 2 to 3 y of age. As the overall incidence of malaria decreases in Africa in response to enhanced control efforts, an effect already being seen in some countries, it can be anticipated that the mean age of cases of malaria will increase further. For these reasons, trials have been undertaken in areas of seasonal malaria transmission to determine whether IPT in children (IPTc) could be used as an effective malaria control tool in older children. In Mali, a 69% reduction in the incidence of clinical malaria was seen in children 0–5 y old when two doses of SP were given 8 wk apart during the malaria transmission season [6]. In Senegal, SP plus a single dose of artesunate (AS), administered on three occasions at monthly intervals during the peak malaria season, reduced the incidence of clinical malaria by 86% [7]. A subsequent trial of different drug regimens showed that IPT with SP and amodiaquine (AQ) was even more effective than SP+AS, providing approximately 95% protection [8]. A further study, conducted in an area of Ghana with more prolonged transmission, found that AS+AQ monthly was more effective than AS+AQ or SP alone given every 2 mo, suggesting that for drugs such as SP and AQ, monthly administration is needed to achieve effective IPTc [9]. Bednet coverage among young children was low at each of the sites where these trials were conducted and use of ITNs was very uncommon. Use of ITNs is now a favoured approach to the control of malaria in most parts of Africa and major efforts are being made to scale up their use. With international support, ITN coverage is increasing in many malaria endemic countries in sub-Saharan Africa [10] and it is expected that almost universal coverage with ITNs in high risk groups, as called for in the Global Malaria Action Plan [11], will be achieved in many malaria endemic countries. Thus, following on the initial encouraging results obtained with IPTc, an issue that needs to be addressed urgently is whether IPTc can provide significant added benefit to the protection against malaria provided by ITNs to warrant its use as a malaria control tool in areas with seasonal transmission of malaria and a high use of ITNs. It was initially planned to address this question simultaneously in each of the three countries Mali, Burkina Faso, and Ghana, using a similar design and methods. However, the site in Ghana had to be abandoned because of delays in obtaining regulatory approval for the use of SP+AQ, the drug combination chosen for the study on the basis of the results of previous trials and knowledge of the sensitivity of Plasmodium falciparum to these drugs in the proposed study areas. Very similar protocols were used for the studies conducted in Burkina Faso and Mali. Methods The protocol of the trial (Text S1), protocol amendment (Text S5), and CONSORT checklist (Text S2) are available as supporting information. Objectives The primary objective of the study was to determine the degree to which IPTc given during the malaria transmission season reduces the incidence of clinical malaria in children who sleep under a long-lasting insecticide-treated net (LLIN). Secondary objectives were determination of the impact of this strategy on severe malaria, all cause hospital admissions, anaemia, nutrition (wasting, stunting, and being underweight), malaria infection, and molecular markers of resistance to SP and AQ. Study Sites The study was conducted in two rural villages, Djoliba and Siby, and the small town of Ouelessebougou situated in the district of Kati in the savannah region of Mali. Djoliba and Siby are located 40 and 30 km south west of the capital city Bamako, respectively, and Ouelessebougou is located 80 km south of Bamako. In Djoliba and Siby, community health centres are staffed with a physician and nurses. In Ouelessebougou, the community health centre is staffed by an assistant physician and nurses, but located less than 100 m from a district health centre staffed by four physicians and six nurses. A research team composed of physicians and medical residents was established in each of the three sites to follow up and provide health care to the study participants. Malaria transmission in the study area is highly seasonal and 80%–90% of malaria cases occur between August and November. The entomological inoculation rate (EIR) was 9.4 and 6.6 infective bites per person per season, respectively, in Siby and in Ouelessebougou, two localities far from any river and 37.3 infective bites per person per season in Djoliba located on the bank of the Niger River (Text S3). The coverage of ITNs at baseline was 33.4% (312/935) in Siby, 84.7% (563/665) in Djoliba, and 89.8% (2,207/2,458) in Ouelessebougou. Study Design and Participants The study was designed as an individually randomised, placebo-controlled trial of IPTc with SP+AQ in children who received a LLIN. Children aged 3–59 mo were enumerated and given a census identification number including a house number to facilitate their identification at screening, enrolment, and follow-up. Recruitment was started in Djoliba followed by Siby. In these communities all available children in the target age group who were not selected for the baseline survey of drug resistance were screened and enrolled if they met the inclusion criteria. In the larger community of Ouelessebougou, children were screened for enrolment on a first-come first-served basis until the required sample size was met. Children were eligible to join the study if they were aged 3–59 mo at the time of enrolment and permanent residents of the study area with no intention of leaving during the study period. Exclusion criteria were the presence of a severe, chronic illness, such as severe malnutrition or AIDS, and a history of a significant adverse reaction to SP or AQ. Cases of an acute illness, such as malaria, were not excluded. Such cases were treated appropriately and the child randomised and retained in the trial. Ethics The study protocol was reviewed and approved by the Ethical Committee of the Faculty of Medicine, Pharmacy and Dentistry, University of Bamako, Mali and by the Ethics Committee of the London School of Hygiene and Tropical Medicine. Community consent was obtained at meetings with leaders, heads of families, and other community members of each locality prior to the start of the study. Individual, written, informed consent was obtained from a parent or guardian of each child prior to screening and enrolment. A Data and Safety Monitoring Board (DSMB) was established and monitored the trial with the support of a local medical safety monitor. Current good clinical practices (cGCP) monitoring of the trial was performed by PharmaClin (http://www.pharmaclin.com). Interventions Every child who was screened was provided with a LLIN (Permanet, Vestergaard Frandsen) that was marked with the child's identification number regardless of whether or not the child was enrolled. Instructions were given to the parent or guardian on how to use the net and the importance of using the net regularly was emphasized. Monitoring of utilisation of ITNs by study participants was made in 150 randomly selected children each week and in all study children during the cross-sectional survey conducted at the end of the malaria transmission season. Eligible children were treated with a course of SP+AQ or matching placebos on three occasions at monthly intervals during the malaria transmission season, starting in August 2008. SP and AQ were manufactured by Kinapharma Limited and quality control checks on the drugs for solubility and content were performed at the London School of Tropical Medicine and Hygiene, prior to their use in the trial. Tablets met internal standards for drug solubility and content. Doses of SP and AQ were based on weight with children stratified into one of the three weight categories (5–9 kg, 10–18 kg, and ≥19 kg). SP was given at a dose of 175/8.75 mg to children 5–9 kg, 350/17.5 mg to children 10–18 kg, and 550/26.25 mg to those who weighed ≥19 kg. The corresponding doses for AQ were 70 mg, 140 mg, and 220 mg, respectively. AQ was given over 3 d. Drugs were prepackaged to facilitate administration and put in envelopes with colour codes, one for each weight group. Within each weight stratum, children were individually randomised using a computer-generated random number sequence and blocks of varying length. Treatment allocations were provided within sealed, opaque envelopes. Drugs were given under direct observation at a research clinic by study staff. Children were observed for 30 min after drug administration. If vomiting occurred during this 30-min period, drugs were readministered. If vomiting occurred on a second occasion, this was noted but the drugs were not given again. Such children were not excluded from the trial and they were eligible to receive drugs on the subsequent 2 d and during subsequent monthly IPT rounds. If a child missed the day set for treatment, a home visit was made to enquire why the child had not been brought for treatment and the reason was recorded. If the family wished to continue with treatment but was unable to attend on the specified day, then treatment was reoffered within an interval of 7 d of the designated date. Children with an acute malaria episode were treated with artemether-lumefantrine (AL) and did not receive IPT with SP+AQ if the treatment for acute malaria was received within 7 d of the scheduled date of IPT. Such children were eligible for treatment in future treatment rounds Outcomes The primary endpoint of the study was the incidence of clinical malaria; this was defined as the presence of fever (axillary temperature ≥37.5°C) or a history of fever in the past 24 h and the presence of P. falciparum asexual parasitaemia at a density greater or equal to 5,000 parasites per microlitre. Secondary endpoints were: (i) the incidence of clinical malaria defined as the presence of fever or a history of fever in the past 24 h and the presence of P. falciparum asexual parasitaemia at any density; (ii) incidence of severe malaria defined according to the WHO criteria [12]; (iii) malaria infection defined as the presence of asexual parasitaemia; (iv) mild, moderate, or severe anaemia defined as an haemoglobin (Hb) concentration <11 g/dl, <8 g/dl, and <5 g/dl, respectively; (v) hospital admission defined as a stay of at least 24 h in hospital for treatment; (vi) anthropometric indicators including wasting, stunting, and being underweight as defined by WHO [13]; and (vii) safety and tolerability measured by the occurrence of nonserious and serious adverse events. Passive surveillance for clinical malaria started at the time of the administration of the first dose of IPTc in August 2008 and continued until the end of the malaria transmission season in November/December 2008, 6–7 wk after the last round of IPTc. Parents were encouraged to bring their child to a study health centre, where medical staff were available 24 h a day and 7 d a week, if the child became unwell. A finger prick blood sample was be obtained from all study children with fever (an axillary temperature of 37.5°C or higher) or a history of fever within the previous 24 h for preparation of a blood film, measurement of Hb concentration, and for a rapid diagnostic test (RDT) OPTIMAL_IT (Diamed AG) for malaria. Children who had a positive RDT for malaria were treated immediately with AL. Severe cases were admitted to the health centre or referred to the paediatric ward of the Gabriel Touré Hospital in Bamako. Causes of death were assessed within a month of death using a modified version of the INDEPTH post mortem questionnaire (http://www.indepth-network.org/index.php?option=com_content&task=view&id=95&Itemid=183). Use of a LLIN was assessed by asking if a child had slept under an LLIN the previous night and the presence of the net was checked by field staff. During these home visits, the axillary temperature of each child was taken and a blood film obtained regardless of whether or not the child had fever. A RDT was performed if a child had measured fever or a history of fever within the previous 24 h and if this was positive, treatment with AL was given according to national guidelines. At the end of the malaria transmission season, a cross-sectional survey was undertaken at which every child was examined, their height and weight recorded, and a finger prick blood sample obtained for determination of Hb concentration, preparation of blood films, and collection of a filter paper sample for subsequent molecular studies. Safety and tolerability of SP and AQ were monitored passively during the study period in all the children and actively in a subset at the time of the administration of IPT (days 0, 1, and 2) and 1 d after the last dose of treatment (day 3) at each round. Assessment of Molecular Markers of Drug Resistance Monitoring of the frequency of molecular markers of resistance to sulphadoxine, pyrimethamine, and AQ was performed in two cross-sectional surveys, the first at baseline in August 2008 and the second during the survey undertaken at the end of malaria transmission season. The baseline survey was conducted in 256 children randomly selected from the screening list. These children were not enrolled in the placebo control trial. Participants enrolled in the placebo control trial were surveyed about 6 wk after the third course of IPTc, at the end of malaria transmission season, to assess whether administration of IPT with SP+AQ had lead to an increase in molecular markers of resistance to these drugs. Thick and thin blood smears and blood blotted onto filter papers were collected during both surveys for molecular analysis as described below. Laboratory Methods Thick blood films were air dried, stained with Giemsa, and examined for malaria parasites by two well-trained technicians. 100 high power fields were counted before a film was declared negative. Parasite density was determined by counting the number of parasites present per white blood cell (WBC) on a thick smear and assuming a WBC count of 8,000 per µl. In the case of a discrepancy (positive/negative or a difference in parasite density greater than 30%), a third reading was done. The median parasite density of two or three readings was used. An external quality control of slide reading performed by the Malaria Diagnosis Centre of Excellence (MDCoE) of the Walter Reed/Kenya Medical Research Institute, in Kisumu, Kenya, showed an overall concordance of more than 90% on parasite detection and 100% on species identification (Text S4). Hb concentrations were measured using a haemoglobin analyzer (Hemocue HB 301) on blood obtained by finger prick. Filter paper samples from children with a mono-infection of P. falciparum on blood smears were analysed by nested PCR for mutations at codons 51, 59, and 108 of the dhfr gene, 437 and 540 of the dhps gene, 76 of mutations in the P. falciparum chloroquine transporter gene (pfcrt), and 86 of the P. falciparum multidrug resistance gene one (pfmdr1) according to published methods [14]–[16]. Cases of mixed infection (wild type and mutant) were categorized as mutant. Sample Size Calculation of sample size was based on the assumptions that the clinical attack rate measured by passive surveillance would be 1.0–2.0 attacks per child per year in unprotected children aged 3–59 mo living in the study areas and that sleeping under an LLIN would reduce this attack rate by half to 0.5 to 1.0 clinical episode per child per year. Assuming that children experienced an average of 0.5 clinical episodes per child per year of sufficient severity to present to a health facility, to detect a 20% reduction in this incidence (i.e., from 0.5 to 0.4 attacks per child per year) in children who receive IPTc, the smallest reduction that would be likely to make IPTc a worthwhile investment, and allowing for a 20% loss to follow-up, we estimated that approximately 2,000 children (1,000 in each arm) were required for a study with 90% power at the two-sided 5% level of significance [17]. After the site in Ghana was dropped, the sample size was increased to 1,500 participants per arm, after an amendment was made to the protocol (Text S5), which would have 80% power to detect a two-thirds reduction in the incidence of severe malaria, assuming an incidence of 2% in children in the control arm. The study was not powered to detect a smaller reduction in the incidence of severe malaria but the analysis plan included provision for combination of the results of this trial with those of a parallel study conducted in Burkina Faso to provide sufficient size to allow detection of a smaller impact of IPTc on this end point. Data Management and Analysis Data were collected on standardized forms, double-entered, and verified using MS Access and then exported to Stata (StataCorp) for additional cleaning and analysis. A data analysis plan was written and submitted to the DSMB prior to analysis. The final, cleaned database was locked and a copy sent to the DSMB. An intention-to-treat analysis was performed. Incidence rates of clinical malaria, severe malaria, and hospital admissions were calculated by dividing the number of episodes by the total child days at risk. Children were not considered at risk for 21 d after each type of a malaria episode and these days were not included in the calculation of the child days at risk. The incidence rates in the two treatment groups were compared using Cox regression to estimate the incidence rate ratio, with adjustment for age, gender, and locality, and using a robust standard error to allow for the lack of independence among repeated episodes in the same child. The protective effect (PE) of IPTc was computed as 1 minus the incidence rate ratio. Time to first episode of clinical malaria in the two arms was examined using Kaplan-Meier plots and compared using log rank test. Anthropometric data at enrollment and at the end of season cross-sectional survey were converted into weight-for-age, height-for-age, and weight-for-height z-scores using WHO's anthropometric software (www.who.int/childgrowth/software/en). Underweight, stunting, and wasting were defined as z-scores of <−2 for the relevant indicator [13]. Changes in weight and height between the two groups were compared using Student's t test. Frequencies of single mutations as well as the triple mutant (dhfr 51+59+108) and quadruple mutant (triple mutant + dhps 437) genotypes were determined and compared between treatment arms and between the beginning and end of the study. Proportions of children with binary outcomes were compared between the two groups using Pearson's Chi square test or generalized linear models adjusted for age, gender, and locality. Results Trial Profile and Baseline Data The trial profile is summarised in Figure 1. A total of 3,065 children were screened of whom 3,017 (1,509 in the IPTc arm and 1,508 in the placebo arm) (98%) were enrolled. Reasons for exclusion are shown in Figure 1. The proportion of children who completed the follow-up to day 42 after the last round of IPTc was similar in the control and in the intervention arms (98.5% and 98.1%, respectively). The reasons for withdrawal were withdrawal of consent (n = 29), migration to another location (n = 15), a history of allergy to study drugs (n = 4 with two cases confirmed), and death (n = 3). There were no significant differences between intervention and control groups with regard to their age and gender distribution, nor in the prevalence of fever, wasting, or stunting at the time of enrolment (Table 1). 10.1371/journal.pmed.1000407.g001 Figure 1 Trial profile. 10.1371/journal.pmed.1000407.t001 Table 1 Baseline characteristics of enrolled children at the time of administration of the first dose of IPTc. Characteristics IPTc Placebo Percent (n/N) Percent (n/N) Age (mo) 3–11 18.2 (274/1,509) 18.5 (278/1,508) 12–23 22.5 (339/1,509) 20.5 (309/1,508) 24–35 20.5 (310/1,509) 22.0 (332/1,508) 36–47 20.0 (302/1,509) 19.4 (293/1,508) 48–59 18.8 (284/1,509) 19.6 (296/1,508) Gender Male 47.7 (720/1,509) 50.1 (755/1,508) Female 52.3 (789/1,509) 49.9 (753/1,508) Weight (kg) 5–9 34.8 (525/1,509) 34.7 (523/1,508) 10–8 63.1 (952/1,509) 63.2 (953/1,508) ≥19 2.1 (32/1,509) 2.1 (32/1,508) Nutritional factors Underweight 16.1 (238/1,480) 15.1 (223/1,477) Wasting 11.0 (163/1,480) 12.5 (185/1,477) Stunting 22.7 (336/1,480) 23.8 (352/1,477) Fever 7.2 (105/1,460) 7.6 (111/1,464) LLIN Usage Usage of LLINs was assessed for 590 children in the control group and for 591 children in the intervention group during weekly home visits, undertaken without prior warning, during the course of the intervention period. Usage of an LLIN was high in each of the three study localities and similar between the two groups (99.7% in the control group versus 99.3% in the intervention arm; p = 0.45). The Impact of IPTc on Malaria Among children with fever or history of fever who had an RDT positive result, 8.8% (112/1,277) turned out to have negative parasitaemia after microscopical diagnosis of malaria. The impact of IPTc on episodes of malaria detected through passive surveillance is presented in Table 2. The incidence of episodes of uncomplicated malaria (fever or a history of fever in the last 24 h and asexual parasitaemia ≥5,000/µl) was much lower among children in the IPTc arm than among those in the control arm (0.34 episodes per child/year versus 1.9 episodes per child/year). The PE against malaria adjusted for age, gender, and location was 82% (95% confidence interval [CI] 78%–85%) (p<0.001). An analysis of time to the first episode of clinical malaria, defined as above, also indicated a strong protective effect of IPTc (p<0.001) (Figure 2). The incidence of malaria defined as fever or a history of fever in the last 24 h and positive asexual parasitaemia of any density was also much lower in children in the IPTc arm compared to those in the control arm (0.41 episodes per child/year versus 2.4 episodes per child/year), giving a protective efficacy of 83% (95% CI 80%–86%) (p<0.001). Only 17 cases of severe malaria occurred during the follow-up period, 15 in the control group, and two in the intervention group (Table 2), giving a protective efficacy of 87% (95% CI 42%–99%) (p = 0.001). The two cases of severe malaria in the intervention arm, one of whom died, occurred more than 3 wk after the third course of IPT. 10.1371/journal.pmed.1000407.g002 Figure 2 Time to first episode of clinical malaria defined as fever (temperature ≥37.5°C) or history of fever in the last 24 h and parasitaemia ≥5,000/µl in the intervention and control arms. Kaplan-Meier survival estimates with pointwise 95% confidence bands. 10.1371/journal.pmed.1000407.t002 Table 2 Impact of IPTc on episodes of clinical malaria in children in Mali. Outcomes IPTc Placebo Unadjusted IRRs (95% CI) p-Value Adjustedc IRRs (95% CI) PE (95% CI) p-Value n Episodes Years at Riska Incidence Rate (95% CI)b n Episodes Years at Risk Incidence Rate (95% CI)b Fever or history of fever and any asexual parasitaemia 149 362.15 0.41 (0.35–0.48) 832 345.64 2.40 (2.25–2.58) 0.17 (0.14–0.20) <0.001 0.17 (0.14–0.20) 83 (80–86) <0.001 Fever or history of fever and parasitaemia ≥5,000 126 369.41 0.34 (0.29–0.41) 672 354.14 1.90 (1.76–2.05) 0.18 (0.15–0.22) <0.001 0.18 (0.15–0.22) 82 (78–85) <0.001 Severe malaria 2 399.10 0.005 (0.0006–0.0181) 15 400.87 0.037 (0.0209–0.0617) 0.13 (0.01–0.58) 0.001 — 87 (42– 99) 0.001 a Children were not considered at risk for 21 d after each type of a malaria episode. b Incidence rate/child/year. Note the incidence relate refers to only the 3-mo surveillance period and is not an annual rate. c Adjusted for age, gender, and location. 95% CI constructed using a robust standard error. IRR, incidence rate ratio. Incidence rates and the PE of IPTc against clinical malaria by locality and age category are presented in Table 3. Although the incidence of clinical malaria varied substantially between the three study localities, the PE of IPTc was similar in all three areas regardless of the definition of clinical malaria used. PE was higher in the lower age groups (3–11 mo and 12–23 mo) compared to the older age groups (≥24 mo) when the definition of clinical malaria that incorporated the presence of parasitaemia ≥5,000/µl or any parasitaemia was used (test for effect modification p≤0.001 and p = 0.003, respectively). 10.1371/journal.pmed.1000407.t003 Table 3 Effect of area of residence and age on the protective efficacy of IPTc against clinical episodes of malaria. Outcomes According to Area of Residence and Age Category IPTc Placebo Unadjusted RR (95% CI) p-Value Adjusted RR (95% CI) PE (95% CI) p-Value Episodes (Years at Risk) Incidence Ratea Episodes (Years at Risk) Incidence Ratea Clinical malaria defined as fever or history of fever in the last 24 h and asexual parasitaemia ≥5,000/µl Locality Djoliba 11 (73.77) 0.15 (0.08–0.27) 74 (73.49) 1.00 (0.80–1.26) 0.13 (0.10–0.18) <0.001 0.15 (0.08–0.28) 85 (72–92) <0.001 Siby 70 (93.32) 0.75 (0.59–0.94) 308 (90.57) 3.40 (3.04–3.80) 0.13 (0.07–0.24) <0.001 0.22 (0.17–0.29) 78 (71–83) <0.001 Ouelessebougou 45 (202.55) 0.22 (0.17–0.30) 292 (190.20) 1.53 (1.37–1.72) 0.21 (0.16–0.26) <0.001 0.14 (0.10–0.20) 86 (80–90) <0.001 Age (mo) 3–11 6 (68.64) 0.09 (0.04–0.19) 52 (66.60) 0.78 (0.59–1.02) 0.11 (0.05–0.26) <0.001 0.13 (0.05–0.29) 87 (71–95) <0.001 12–23 12 (83.00) 0.14 (0.08–0.25) 134 (72.40) 1.85 (1.56–2.19) 0.08 (0.04–0.14) <0.001 0.07 (0.04–0.13) 93 (87–96) <0.001 24–35 38 (76.63) 0.50 (0.36–0.68) 173 (77.96) 2.22 (1.91–2.58) 0.22 (0.15–0.33) <0.001 0.23 (0.15–0.34) 77 (66–85) <0.001 36–47 36 (72.51) 0.50 (0.36–0.69) 153 (67.84) 2.26 (1.92–2.64) 0.22 (0.15–0.31) <0.001 0.21 (0.15–0.31) 79 (69–85) <0.001 48–59 34 (66.91) 0.51 (0.36–0.71) 156 (66.43) 2.34 (2.00–2.74) 0.21 (0.14–0.32) <0.001 0.22 (0.15–0.32) 78 (68–85) <0.001 Clinical malaria defined fever or history of fever in the last 24 h and asexual parasitaemia regardless of the density Locality Djoliba 12 (72.05) 0.17 (0.09–0.29) 90 (73.40) 1.22 (1.0–1.50) 0.13 (0.10–0.18) <0.001 0.14 (0.10–0.18) 86 (82 –90) <0.001 Siby 83 (90.86) 0.91 (0.74–1.13) 372 (86.41) 4.30 (3.88–4.76) 0.13 (0.07–0.24) <0.001 0.14 (0.07–0.26) 86 (74 –93) <0.001 Ouelessebougou 54 (199.25) 0.27 (0.21–0.35) 370 (185.82) 1.99 (1.80–2.20) 0.21 (0.16–0.26) <0.001 0.21 (0.16–0.26) 79 (74–84) <0.001 Age (mo) 3–11 10 (68.15) 0.15 (0.08–0.27) 72 (65.96) 1.09 (0.86–1.38) 0.13 (0.07–0.26) <0.001 0.14 (0.07–0.27) 86 (73–93) <0.001 12–23 15 (81.60) 0.18 (0.11–0.30) 153 (71.07) 2.15 (1.83–2.52) 0.08 (0.05–0.14) <0.001 0.08 (0.05–0.14) 92 (86–95) <0.001 24–35 47 (75.18) 0.62 (0.47–0.83) 206 (76.20) 2.70 (2.36–3.10) 0.23 (0.17–0.31) <0.001 0.23 (0.16–0.33) 77 (67–84) <0.001 36–47 39 (70.23) 0.55 (0.40–0.76) 200 (65.44) 3.06 (2.66–3.51) 0.18 (0.13–0.25) <0.001 0.18 (0.13–0.25) 82 (75–87) <0.001 48–59 38 (65.04) 0.58 (0.42–0.80) 194 (63.98) 3.03 (2.63–3.49) 0.19 (0.13–0.27) <0.001 0.19 (0.13–0.28) 81 (72–87) <0.001 a Incidence rate expressed as number of episodes/child/year. Note that this is based on the 3-mo surveillance period and does not correspond to an annual rate. The percentage of children with malaria infection detected at weekly active surveillance visits was 13.2% (74/563) in the control group compared to 1.9% (11/575) in the intervention group, giving a protective efficacy of 85%, (95% CI 73%–92%) (p<0.001). At the end of the transmission season, 13.2% (188/1,423) of children in the control group were parasitaemic compared to 7.2% (101/1,405) in the intervention group, giving a protective efficacy of 46% (95% CI 31%–68%) (p<0.001). The Impact of IPTc on Anaemia At the end of the malaria transmission season, the proportion of the children with anaemia (Hb <11 g/dl), was significantly higher in the control group compared to the intervention group (61.1% [875/1,433] versus 53.9% [766/1,422]) (PE = 12%; 95% CI 3%–20%) (p<0.001). The relative difference was larger for moderate anaemia (Hb <8 g/dl) with a prevalence of 3.5% (50/1,433) versus 1.9% (27/1,422) in the control and intervention groups, respectively (PE = 47%; 95% CI 15%–67%) (p = 0.007). No cases of severe anaemia (Hb <5 g/dl) were observed in either treatment group at the time of the postintervention survey. However, during the follow-up period, a total of eight cases of severe anaemia occurred, two in the intervention arm and six in the control arm. The two participants in the intervention group who developed severe anaemia had not received a complete course of IPT at the time that they developed their severe anaemia. The Impact of IPTc on Nutritional Indicators The impact of IPTc on nutritional indicators is presented in Table 4. The proportions of children with wasting, stunting, and being underweight at the end of the malaria transmission season were similar between the control and intervention arms However, weight gain during the intervention period was 97 g (95% CI 37 g–157 g) more among children in the intervention arm compared to that recorded among children in the control arm. Changes in height were similar between the two arms with an increase of 2.3 cm (95% CI 2.2 cm–2.5 cm) in children in the intervention arm compared to an increase of 2.4 cm (95% CI 2.2 cm–2.5 cm) in children in the control arm. 10.1371/journal.pmed.1000407.t004 Table 4 Effect of IPTc on nutritional indicators in children at the end of the malaria transmission season. Nutritional Indicators Placebo IPTc Adjusted Analysis Percent n Percent n OR (95% CI)a p-Value Wasting 5.6 1,364 4.3 1,360 0.75 (0.53–1.07) 0.12 Stunting 25.2 1,365 24.6 1,361 0.96 (0.81–1.15) 0.69 Underweight 12.8 1,365 10.9 1,361 0.84 (0.66–1.06) 0.15 a Adjusted for age, sex, and locality. The Impact of IPTc on Molecular Markers of Antimalarial Drug Resistance The frequencies of molecular markers associated with resistance to SP and AQ in the two groups at baseline and postintervention are presented in Table 5. The frequencies of individual and multiple dhfr and dhps mutations in the placebo group were similar in pre- and postintervention periods. The frequencies of all individual dhfr and dhps and of the triple dhfr (51, 59, 108) and quadruple dhfr (51, 59, 108) + dhps 437 mutations were higher in the intervention than in the control group at the end of the surveillance period and, for the dhfr 59, dhps 437, triple and quadruple mutations, differences between groups were statistically significant. Frequencies of the pfcrt 76 and pfmdr1 86 did not change significantly over time and were similar postintervention in the intervention and control groups. 10.1371/journal.pmed.1000407.t005 Table 5 Frequencies of molecular markers of resistance to SP and AQ at baseline and at the end of the intervention period in intervention and control arms. Molecular Markers Baseline Postintervention Baseline Versus Overall Postintervention p-Value IPTc Placebo n Percent Mutant n Percent Mutant n Percent Mutant p-Value DHFR 51 48 62.5 78 75.6 148 66.2 0.144 0.35 DHFR 59 48 60.4 78 76.9 148 59.5 0.009 0.50 DHFR 108 41 78.0 76 78.9 139 71.2 0.217 0.58 DHPS 437 47 38.3 83 67.5 165 43.6 <0.001 0.09 DHPS 540 45 0 82 7.3 165 3.6 0.205 0.82 Triple DHFR mutations 41 58.5 76 69.7 139 54.0 0.024 0.90 Quadruple mutants (triple DHFR + DHPS 437) 41 22.0 75 53.3 139 28.1 < 0.001 0.07 Pfcrt-76 46 80.4 79 84.8 156 75.0 0.085 0.25 Pfmdr1-86 46 45.6 76 36.8 156 34.6 0.739. 0.19 n = number of participants with parasitaemia at blood smear tested. The Impact of IPTc on Hospital Admissions and Death Hospital admissions and deaths that occurred during the study period are listed in Table 6. 19 hospital admissions of at least 24 h were recorded; nine of these were recorded in children in the control arm and ten in children in the intervention arm. The incidence rates of hospital admissions per child/year were 0.0225 episodes in the control group versus 0.0251 in the intervention arm (p = 0.81). There were five deaths, two in the control arm and three in the intervention arm. Two of the five deaths were due to malaria (one in each group). Both occurred during hospitalisation while the remaining three deaths occurred at home. On the basis of the results of a verbal autopsy, these deaths were thought to be due to poisoning by traditional medicines, meningitis and anaemia, and secondary bleeding following a circumcision, respectively. 10.1371/journal.pmed.1000407.t006 Table 6 Hospital admissions and deaths by treatment arms. Numbering Treatment Arm Date Cause Outcome Hospital admission 1 Placebo 11/8/2008 Severe malaria Recovered 2 Placebo 10/25/2008 Severe anaemia Recovered 3 Placebo 9/27/2008 Severe malaria Recovered 4 Placebo 11/9/2008 Severe malaria Recovered 5 Placebo 12/7/2008 Severe malaria Recovered 6 Placebo 9/18/2008 Severe malaria Recovered 7 Placebo 9/16/2008 Severe malaria Death 8 Placebo 9/18/2008 Severe malaria Recovered 9 Placebo 11/16/2008 Severe malaria Recovered 10 IPTc 11/23/2008 Gastro-enteritis Recovered 11 IPTc 11/5/2008 Severe malaria Death 12 IPTc 12/2/2008 Respiratory infection Recovered 13 IPTc 10/11/2008 Gastro-enteritis Recovered 14 IPTc 8/13/2008 Severe anaemia Recovered 15 IPTc 9/21/2008 Asthma Recovered 16 IPTc 12/3/2008 Severe malaria Recovered 17 IPTc 11/11/2008 Respiratory infection Recovered 18 IPTc 11/4/2008 Febrile convulsions Recovered 19 IPTc 9/19/2008 Respiratory infection Recovered Deaths out of hospital a 1 Placebo 11/08/08 Intoxication to traditional medicines — 2 IPTc 09/11/08 Meningitis — 3 IPTc 09/17/08 Anaemia secondary to circumcision — a Does not include death occurred following hospital admissions listed above. Safety and Tolerability There was no serious adverse event related to the study drugs. The frequencies of adverse events following the administration of IPTc with SP+AQ or placebo, using active surveillance are summarized in Table 7. The frequencies of adverse events were similar between the control and intervention arms. However, there was a tendency toward a higher frequency of vomiting and of loss of appetite in the intervention arm compared to the control arm (4.0% versus 1.9%, p = 0.06 for vomiting and 1.9% versus 0.8%, p = 0.08 for loss of appetite). Proportions of children with skin rash and itching on at least at one occasion were similar between the two arms. Four participants in the intervention arm were withdrawn from the study because of reactions to study drug versus none in the control arm. Two of these children had a documented skin rash at physical examination (one after the first dose of IPT and the other after the second dose of IPT) and these were assessed as being related to study drugs. Both were moderate in intensity, did not involve bullous eruptions, and resolved within 2 d. The parent of the third participant reported itching. Physical examination was normal but the child was withdrawn from the study on precautionary grounds. The fourth participant had an acute respiratory infection at the time of administration of the first dose of IPT. No adverse event was recorded at the time of routine surveillance but the parents requested withdrawal of their child from the study at the time of the second round of IPTc. 10.1371/journal.pmed.1000407.t007 Table 7 Proportions of children with adverse events on at least one occasion during three rounds of IPTc treatment using the active surveillance. Adverse Events IPTc Placebo ORs (95% CI) p-Value Percent (n/N) Percent (n/N) Fever 10.1 (69/686) 9.9 (66/669) 1.02 (0.72–1.46) 0.91 Vomiting 4.0 (19/475) 1.9 (9/473) 2.1 (0.96–4.80) 0.06 Drowsiness 0.1 (1/686) 0 (0/669) — — Itching 1.0 (7/686) 0.6 (4/667) 1.7 (0.50–5.86) 0.39 Diarrhoea 6.7 (46/686) 4.6 (31/669) 1.48 (0.92–2.36) 0.10 Skin rash 0.3 (2/686) 0.8 (5/668) 0.39 (0.7–2.0) 0.26 Coughing 8.2 (56/686) 6.0 (40/631) 1.40 (0.92–2.13) 0.12 Loss of appetite 1.9 (13/686) 0.8 (5/668) 2.56 (0.90–7.22) 0.08 Jaundice 0 (0/686) 0.1 (1/667) — — Discussion This study has shown that three doses of IPTc with SP+Q given at monthly intervals during the peak transmission season reduced the incidence of uncomplicated and severe malaria by 80% in children 3–59 mo of age who slept under an ITN in three localities in Mali despite the difference in ITN use at baseline. This level of protective efficacy is similar to that reported in a previous trial conducted in an area of Senegal with a coverage of ITNs of less than 1% [7], suggesting that the relative efficacy of IPTc is not reduced by the use of an ITN at the time of the intervention. Two studies have shown that in pregnant women, IPT adds little benefit to the protection afforded by an ITN, at least in multigravidae [18],[19]. This finding is not the case for IPTc in children, as the strategy remained highly efficacious even when deployed in a community with a high usage of ITNs. Despite the large difference in background incidence of malaria in the three sites, suggesting high variability in transmission intensity, the protective efficacy of IPTc against clinical malaria was high and similar between the three sites. This suggests that similar efficacies of IPTc against clinical malaria can be expected in areas with different transmission intensities and baseline ITN coverage. Surprisingly, Siby and Ouelessebougou, which had a low EIR (less than ten infective bites per person/season), had a higher malaria attack rate than Djoliba, which had a higher EIR (37 infective bites per person/season). High malaria infection and attack rates have been reported previously in the context of a low EIR (3.5 infective bites per person/season) in Mali [20], and similar malaria incidence rates were found in children aged 0–5 y in two areas despite a more than 10-fold difference in EIR [21]. However, these apparently anomalous results could have also been due to imprecision in the determination of the EIR, which can vary markedly with time and space or to a difference in the efficiency of transmission. Early detection and treatment of malaria cases is known to reduce hospital admission and deaths due to malaria [22],[23]. Early detection and prompt treatment was available in our carefully controlled study and the protective effect of IPTc on severe malaria or death might be more marked than we observed if IPTc was deployed in a community that did not have such ready access to health care. Parasite prevalence, as assessed by weekly surveys during the intervention period was reduced by 85% in children who received IPTc, but this difference dropped to 46% at the end of the intervention period suggesting that the prophylactic effect of the last dose of SP+AQ had begun to decline 6 wk after administration, as has been found in studies of IPTi [24]. We observed a 47% reduction in the proportion of children with moderately severe anaemia (Hb <8 g/dl) as a result of administration of IPTc. This impact on anaemia is consistent with the reduction of 45% in incidence of anaemia observed when AS+AQ was given at monthly intervals over 6 mo in Ghana, although in the Ghanaian study there was no difference in the proportion of children with anaemia at the end of the 6-mo intervention [9]. We did not detect any difference between the intervention and control arms in wasting, stunting, or under weight. This finding is consistent with a previous study in Senegal [25], which did not find evidence of an impact of IPTc on wasting, stunting, or being under weight at the end of the transmission season but only on triceps and subscapular skinfold, indicators that were not assessed in our study. However, in line with the Senegalese study, we found an increase in weight gain in the IPTc arm compared to the control arm during the course of the intervention period. More marked effects on nutritional measurements were found during a parallel study conducted in Burkina Faso [26], perhaps because the force of infection was higher in the Burkina Faso than in the Mali study areas and malaria, thus, a more important contributor to impairment of weight gain in the Burkina Faso than in the Mali study areas. SP+AQ was chosen as the drug combination for use in the trial on the basis of the results of previous studies that had shown this to be an effective combination for IPTc. This drug combination was generally well tolerated and no serious adverse event attributable to the study drugs was reported. The proportions of children with mild-to-moderate adverse events using active surveillance were not significantly different between the two arms, although there was a trend towards a higher frequency of vomiting and loss of appetite in the intervention group. In the parallel study in Burkina using the same drugs, a higher frequency of vomiting was found in the intervention arm [26]. However, even in the placebo group the frequency of vomiting was higher than in this study, suggesting a difference in the way in which minor side effects were solicited in the two study areas. Cisse et al. [7] reported a modest increase in vomiting in children who took SP+AS compared to those who took placebo in Senegal, while Kweku et al. [9] found no difference in incidence of these adverse events between IPTc intervention and control arms when using SP or AQ. Four withdrawals in the intervention arm were reported to be due to reactions to study drugs. In two cases, the presence of a skin rash was confirmed, another child had itching, and the final withdrawal followed the occurrence of an acute respiratory tract infection at the time of administration of the first round of IPTc. It is possible that this event was considered by the parents as a reaction to the study drugs. The safety of SP and AQ has been a concern in relation to their use for IPTc [27]–[30]. However, there is a growing body of evidence from studies in the last few years [4],[6],[7],[9],[26],[30] that these drugs are safe when used for IPT in pregnant women, infants, or children, and no safety concerns have arisen following the use of SP+AQ for IPTc on a large scale in Senegal. The efficacy of IPTc against clinical malaria has now been demonstrated in a number of studies, including the current trial and a parallel one conducted in Burkina Faso [26]. Is the evidence now strong enough to support the introduction of IPTc into countries with seasonal malaria transmission? Evidence from studies of IPT in infants [31],[32] suggests that prophylaxis is the key protective mechanism of IPT and that long-acting drugs are needed for effective IPTc. Currently, the SP+AQ combination meets this requirement in West Africa where both of these drugs are still reasonably effective as has been shown to be the case in the study area (Text S6). Studies conducted in Senegal and in Ghana [8],[30] have compared different drug combination and regimens and shown that currently SP+AQ at monthly intervals is the best combination. However, the continuing efficacy of SP cannot be guaranteed and alternative regimens for IPTc will be required in the future, which might include the long-acting drug piperaquine. Unlike the case of IPT in pregnant women and infants, IPT in children has no established delivery system, raising concerns as to whether it could be implemented as a control measure. However, studies conducted in Ghana and The Gambia have shown that high coverage with IPTc can be obtained using community health workers [30],[33], and this appears the most promising way of delivering this intervention. Another concern over the widespread deployment of IPTc is that this will enhance the spread of drug resistance. Therefore, we studied the presence of molecular markers associated with resistance before and after the intervention in children in the intervention or control group. The dhfr 59 and dhps 437 mutations associated with pyrimethamine and sulphadoxine resistance, respectively, were found significantly more frequently at the end of the malaria transmission season in parasites obtained from children in the intervention group than in those obtained from children in the control group, and this led to higher frequencies of the triple dhfr mutants and the quadruple mutant (triple dhfr + dhps 437) associated with significant resistance to SP in children who had received IPTc. This increase in the frequency of these mutations is consistent with a previous report in Senegal [7]. As in Senegal, the number of children in the intervention group carrying a resistant parasite was less than in children in the control group because of the substantial reduction in the overall prevalence of parasitaemia. Although IPTc may have contributed to the increase in frequency of some of resistant markers in this and other studies, the true impact on the resistance of SP and AQ remains to be established. Despite a prevalence of quadruple mutants of about 37%, the SP+AQ combination was highly effective in clearing parasitaemia from children resident in the study area with asymptomatic parasitaemia (Text S6). As is the case with any successful malaria intervention, administration of IPTc to children during several, successive malaria transmission seasons could interfere with the development of naturally acquired immunity, raising concerns that there would be an increased period of risk (rebound malaria) during the period immediately after the intervention was stopped if exposure levels remained high. The risk of malaria for children in this trial in the year after the intervention was stopped has been studied and the results are currently being analysed. However, several years of administration would be needed to define the degree to which acquisition of natural immunity would be impaired. It is very unlikely that this would outbalance the substantial gains made during the period when the drug was given. Our study has several strengths. First, the double-blind, randomised controlled design prevented a number of biases in the selection assignment of the participants to the two arms as well as in assessing the outcomes. A second strength is that this is the largest IPTc efficacy trial done so far, providing a more precise estimation of the outcomes measured. Third, the trial was conducted in three localities with different malaria incidence rates, allowing the efficacy of this strategy under different levels of malaria transmission to be assessed. The design would have been stronger if a factorial design had been used to assess the individual and combined impact of IPTc and ITN, but such a trial would be unethical as the efficacy of ITN is already established [3] and use of ITNs is policy in Mali. Other potential limitations of the study include the duration of evaluation, which focused only on about 15 wk of follow-up during the malaria transmission season. However, it is well established that the in the Sahel region of Mali, 85%–90% of clinical malaria cases occur during the period of August to November, and efficacy of this strategy remained high in a previous, smaller study when efficacy was computed over 12 mo period [6],[34]. In summary, IPTc given during the malaria transmission season, provided substantial additional protection against clinical malaria, infection with malaria, and anaemia to that provided by ITNs. IPTc with SP+AQ was safe and well tolerated. As the international community moves towards the target of malaria elimination, new malaria control tools will be needed [11]. IPT in children targeting the transmission season appears to be one of the strongest available tools to achieve this goal. Our findings support the need for an early review of whether IPTc can now be recommended as a component of malaria control in areas with seasonal malaria transmission. Supporting Information Text S1 Study protocol: A trial of the combined impact of IPT and ITNs on morbidity from malaria in African children. (0.19 MB PDF) Click here for additional data file. Text S2 CONSORT checklist. (0.22 MB DOC) Click here for additional data file. Text S3 Entomological investigations. (0.45 MB PDF) Click here for additional data file. Text S4 External quality assurance of malaria microscopic diagnosis. (0.10 MB PDF) Click here for additional data file. Text S5 Protocol amendment. (0.11 MB PDF) Click here for additional data file. Text S6 In vivo efficacy of the SP+AQ combination used for IPTc in the study area. (0.51 MB PDF) Click here for additional data file.

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Author and article information

Contributors

Julie Gutman: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 29 November 2016

Publication date Collection: 2016

Volume: 11

Issue: 11

Electronic Location Identifier: e0166951

Affiliations

[1 ]School of Public Health, Kwame Nkrumah University of Science and Technology, KNUST, Kumasi, Ghana

[2 ]Nuffield Centre for International Health and Development, Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom

[3 ]Centre for Global Health Research, KNUST, Kumasi, Ghana

[4 ]Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom

Centers for Disease Control and Prevention, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceptualization: GDA HT RK MC.
Data curation: GDA.
Formal analysis: LB GDA RK.
Funding acquisition: JN HT MC.
Investigation: GDA PM.
Methodology: GDA HT RK MC JN.
Project administration: GDA HT RK.
Resources: GDA HT RK.
Supervision: RK MC JN.
Validation: GDA.
Visualization: LB.
Writing – original draft: LB GDA.
Writing – review & editing: LB GDA HT PM RK MC JN.

‡ These authors are joint first authors on this work.

* E-mail: L.A.Bates@ 123456leeds.ac.uk

Author information

Laura A. Bates http://orcid.org/0000-0001-6172-9071

Article

Publisher ID: PONE-D-16-14983

DOI: 10.1371/journal.pone.0166951

PMC ID: 5127521

PubMed ID: 27898699

SO-VID: 3d806be3-c067-4f7c-8d63-3f19926d5575

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 13 April 2016

Date accepted : 7 November 2016

Page count

Figures: 0, Tables: 3, Pages: 18

Funding

Funded by: DFID

Award ID: 5245

Th grant number with Department for International Development is 5245 – ‘Delivering effective health services’. Their websites can be found here: www.dfid.gov.uk http://r4d.dfid.gov.uk/. COMDIS-HSD received the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability Requests for full written transcripts of interviews could be available to readers, subject to the study team seeking additional consent from the participants. The ethical approvals granted by the University of Leeds, London School of Hygiene and Tropical Medicine, and the Komfo Anokye Teaching Hospital School / Medical Sciences for the study did not include permission to share transcripts in full but instead to share extracts within the manuscript. Requests for transcripts in full should be directed to the corresponding author (Laura A. Bates).