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Keywords:

  • malaria;
  • prevention;
  • children;
  • intermittent preventive treatment
  • malaria;
  • prévention;
  • enfants;
  • traitement préventif intermittent
  • malaria;
  • prevención;
  • niños;
  • tratamiento preventivo intermitente

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

Intermittent preventive treatment, the administration of a full course of an anti-malarial treatment to a population at risk at specified time points regardless of whether or not they are known to be infected, is now a recommended approach to the prevention of malaria in pregnancy and is being explored as a potential way of preventing malaria in infants. However, in many malaria endemic areas, the main burden of malaria is in older children and increasing use of insecticide treated bednets is likely to increase further the proportion of episodes of malaria that occur in older children. Recently, it has been shown in Senegal and in Mali that intermittent preventive treatment given to older children during the malaria transmission season can be remarkably effective in preventing malaria. This approach to malaria control is likely to be most effective in areas with a high level of malaria transmission concentrated in a short period of the year. However, several issues need to be addressed before intermittent preventive treatment in children can be advocated for use in malaria control programmes. These include: (1) determination of whether intermittent preventive treatment adds to the protection afforded by other control measures such as insecticide-treated bednets; (2) whether an effective and sustainable delivery system can be found; (3) choice of drug to be used; (4) optimum timing of drug administration; (5) the requisite interval between treatments. The potential benefits of intermittent preventive treatment in children are substantial; more research is needed to determine if this is a practical approach to malaria control.

Le traitement préventif intermittent i.e. l'administration du schéma complet de traitement antimalarique à une population à risque à des périodes définis quelque soit la présence ou non d'infection, est maintenant une approche recommandée pour la prévention de la malaria dans la grossesse. Il est sous investigation comme moyen potentiel de prévention de la malaria chez les enfants. Toutefois, dans les régions endémiques pour la malaria, la plupart des cas de malaria surviennent chez les enfants plus âgés et l'utilisation de moustiquaires imprégnées d'insecticide est susceptible d'accroître la proportion des épisodes de malaria survenant chez les enfants plus âgés. Récemment, il a été démontré au Sénégal et au Mali que le traitement préventif intermittent administré aux enfants plus âgés durant la saison de transmission de la maladie, pouvait être remarquablement efficace dans les régions avec une transmission élevée de malaria, concentrée sur une courte période de l'année. Cependant, plusieurs problèmes devraient être résolus avant que l'administration de traitement préventif intermittent ne puisse être évoquée pour son utilisation dans les programmes de contrôle de la malaria. Ceux-ci impliquent de déterminer 1) si le traitement préventif intermittent apporte un bénéfice supplémentaire sur la protection conférée par d'autres mesures de contrôle telles que les moustiquaires imprégnées d'insecticide, 2) si un système de délivrance effective et durable peut être trouvée, 3) le choix des médicaments à utiliser, 4) la période optimum pour l'administration des médicaments et 5) l'intervalle requis entre les traitements. Le bénéfice potentiel du traitement préventif intermittent de la malaria chez les enfants est substantiel. Des recherches supplémentaires sont nécessaires pour déterminer si c'est une approche pratique dans le contrôle de la malaria.

El tratamiento preventivo intermitente, es decir la administración de un tratamiento completo para la malaria a una población a riesgo en momentos puntuales determinados, independientemente del hecho de que estén o no infectados, se recomienda ahora como una nueva alternativa para la prevención de la malaria durante el embarazo y se está explorando como un camino potencial para prevenir la malaria en niños. Sin embargo, en muchas áreas endémicas para malaria, la principal carga de enfermedad es en niños mayores y el aumento en el uso de mosquiteras impregnadas probablemente aumente aún más la proporción de episodios de malaria que ocurren en niños mayores. Recientemente se ha demostrado en Senegal y en Mali, que el tratamiento preventivo intermitente suministrado a niños mayores durante la época de transmisión de malaria puede ser extraordinariamente efectivo para prevenirla. Este camino hacia el control de la malaria podría ser más efectivo en áreas con un alto nivel de transmisión concentradas durante un período corto de tiempo durante el año. Sin embargo, hay varias cuestiones que deben ser resueltas antes de que el tratamiento preventivo intermitente en niños pueda ser recomendado para su uso en programas de control de malaria. Estas cuestiones incluyen: (1) el determinar si el tratamiento preventivo intermitente añade a la protección ofrecida por otras medidas de control, como es el caso de las mosquiteras impregnadas; (2) si se encuentra un sistema efectivo y sostenible para su administración; (3) el tipo de medicamento a usar; (4) el mejor momento para administrar el medicamento; (5) el intervalo requerido entre los tratamientos. Los beneficios potenciales del tratamiento preventivo intermitente en niños son considerables. Son necesarias más investigaciones para determinar si se trata de un enfoque práctico para el control de la malaria.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

The use of drugs to prevent malaria in children resident on a long-term basis in a malaria endemic area is controversial but the concept is attracting renewed interest (Greenwood 2004). Much of this has focused on the prevention of malaria in infants (children less than 1 year old) by intermittent preventive treatment (IPTi). However, it has been reported recently that IPT can also be effective in older children who live in areas where malaria transmission is seasonal (Dicko et al. 2004; Cisse et al. 2006) and this is the topic of this review.

Definitions

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

Chemoprophylaxis describes the administration of a drug in such a way that its blood concentration is maintained above the level that inhibits parasite growth, at the pre-erythrocytic or erythrocytic stage of the parasite's life-cycle, for the duration of the period at risk. Therapeutic or sub-therapeutic doses may be used depending upon the kinetics of the drug prescribed. Mass drug administration (MDA) describes the administration of a full therapeutic course of an anti-malarial drug to a whole population at risk, whether or not they are known to be infected, usually with the aim of interrupting transmission. Intermittent preventive treatment, sometimes called intermittent presumptive treatment (IPT), involves administration of a full therapeutic course of an anti-malarial drug to the whole of a population at risk, whether or not they are known to be infected, at specified times with the aim of preventing mortality or morbidity. In contrast to chemoprophylaxis, drug concentrations fall below inhibitory levels between treatments. There are, however, considerable overlaps between these different forms of chemoprevention (Figure 1). If compliance with chemoprophylaxis is inconsistent, an inhibitory blood concentration will be achieved only intermittently, as in the case for IPT. Conversely, when a long-acting drug such as sulfadoxine/pyrimethamine (SP) is used for IPT, a protective blood concentration may be sustained for several weeks thus providing a period of chemoprophylaxis. There is also overlap between MDA and IPT. While the term MDA is usually associated with campaigns in which an anti-malarial drug is given only once, several of the most frequently cited MDA trials, such as the one undertaken at Garki, northern Nigeria in the 1970s (Molineaux & Grammiccia 1980), which involved 10–20 rounds of drug administration with a long acting drug given over a two year period, could be considered to be early examples of IPT or even chemoprophylaxis. Use of a more generic term such as chemoprevention to describe these different forms of prophylactic drug administration might be helpful.

image

Figure 1.  Overlap between the different forms of malaria chemoprevention. (MDA = mass drug administration; IPT = intermittent preventive treatment).

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Malaria chemoprophylaxis in children

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

The benefits of chemoprophylaxis for children resident in malaria endemic areas have been demonstrated clearly. These include a marked reduction in overall child mortality, a reduction in the incidence of clinical attacks of malaria and anaemia, improved nutrition and, in older children, a decrease in absenteeism from school (Geerligs et al. 2003; Greenwood 2004). However, this approach to malaria control has never been adopted widely or recommended by WHO because of concerns that widespread deployment of chemoprophylaxis would encourage the spread of drug-resistant parasites and/or inhibit the development of naturally acquired immunity to malaria. There have been few studies to investigate either of these hypotheses but these are valid concerns. Intermittent preventive treatment is less likely to select for drug resistance than chemoprophylaxis, because exposure of parasites to sub-therapeutic drug concentrations is less, and it is also less likely to impair the development of immunity because exposure to infection will be greater. Thus, IPT may be able to provide many of the benefits of chemoprophylaxis with fewer drawbacks.

Intermittent preventive treatment in infants

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

Intermittent preventive treatment with SP delivered through antenatal clinics is now a recommended strategy for the prevention of malaria in pregnancy, reducing the incidence of maternal anaemia and low birth weight. In 2001, it was reported that IPT could also be used successfully to prevent malaria in infants using the EPI programme as the delivery system (Schellenberg et al. 2001). Three doses of SP given to Tanzanian infants living in an area of perennial transmission at the time of vaccination with DPT2, DPT3 and measles vaccines reduced the incidence of clinical attacks of malaria and anaemia during the first year of life by 59% and 50% respectively. Furthermore, protection persisted into the second year of life (Schellenberg et al. 2005). A second Tanzanian study, which used amodiaquine given at three-monthly intervals during the first year of life, gave similar results (Massaga et al. 2003). However, IPTi may be less effective in areas where malaria is more seasonal. Thus, in northern Ghana, where malaria transmission is intense and highly seasonal, IPTi with SP gave only 25% protection against clinical attacks of malaria and 35% protection against hospital admissions with anaemia during the first year of life and no protection during the second (Chandramohan et al. 2005). A similar level of protection against clinical attacks of malaria during the first year of life was seen in Mozambique but no protection against anaemia was detected in this study (Macete et al. 2005). Further trials of IPTi with SP have been completed or are underway in areas with differing epidemiological patterns of malaria in Ghana, Kenya and Gabon. Additional studies on alternative drugs to SP for use in IPTi, the effect of IPTi on the immune response, the acceptability of IPTi, its cost effectiveness and the way in which it could be implemented on a large scale are under way under the auspices of the IPTi consortium (IPTi Consortium, 2005).

Intermittent preventive treatment in older children

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

Introduction

A critical outcome of on-going trials of IPTi will be determination of whether protection extends into the second year of life, as seen in Tanzania (Schellenberg et al. 2005), or if it is restricted to the period during which drugs are given, as was the case in Ghana (Chandramohan et al. 2005). If the latter is the more usual outcome, IPTi will have its largest impact on the overall burden of malaria in children in communities where a high proportion of cases of malaria occur during the first year of life. The proportion of malaria endemic areas that meets this criterion is uncertain for there is surprisingly little information on the exact age distribution of malaria deaths, episodes of severe malaria or uncomplicated malaria in children. In many reports, incidence rates are presented only in the categories of <1 year and 1–4 years. A review of the information available on the exact age distribution of malaria during the first few years of life in different ecological situations is now being undertaken under the auspices of the IPTi Consortium and a parallel study is being done by staff of the Welcome Trust Laboratories in Kenya. The results of these studies will help to identify the geographical situations in which IPTi is likely to be most effective.

Information on the age distribution of nearly 20 000 cases of severe malaria admitted to a representative group of hospitals in Gabon, Ghana, The Gambia, Kenya or Malawi has been collected by members of the Severe Malaria in African Children Consortium (SMAC) (T. Taylor, personal communication). Preliminary analysis indicates that the mean age of cases is around 36 months, with little variation between sites, and that only 25% of cases occurred in children under the age of 18 months. In such situations, an IPTi programme that provided 50% protection against severe disease during the first 18 months of life would prevent only 12.5% of cases of severe malaria overall.

In countries of the Sahel and sub-Sahel (population 200–250 million – about one-third of the total population of sub-Saharan Africa) most deaths from malaria occur after the first year of life. In Niakhar, Senegal, mortality from malaria peaks in the age group 2–3 years (Etard et al. 2004) and in The Gambia malaria deaths peak at around 30 months of age (Jaffar et al. 1997).

Increasing coverage with ITNs is likely to have a major impact on the age distribution of cases of malaria. This is illustrated by experience in Kisumu, Kenya. In this area near to Lake Victoria, which had one of the highest levels of malaria transmission in the world, widespread deployment of ITNs has resulted in a shift in the mean age of a first malaria infection from 3.3 to 10.5 months (ter Kuile et al. 2003). Thus, an increasing proportion of cases of malaria is likely to occur in older children as coverage with ITNs improves. If chemoprevention is to make a major contribution to malaria control overall, it is therefore essential to find ways in which it could be used to protect older children as well as infants.

Experience with intermittent preventive treatment in children

Only a few studies have investigated the impact of IPT in children. Initial studies assessed whether IPT with SP might be useful in the management of children with anaemia. A trial conducted in the Eastern province of Kenya, where malaria transmission is seasonal, studied the impact of oral iron and IPT with SP in the management of children with anaemia (Hb 60 – 110 g/l) using a two by two factorial design (Verhoef et al. 2002). SP was given in a therapeutic dose every 4 weeks for 12 weeks, a regimen that is likely to have given protective blood concentrations for most of the surveillance period, so this could be considered to be a study of chemoprophylaxis rather than IPT. Children who received iron alone or iron and SP had a significantly higher mean Hb concentration at week 12 than did children who received placebo. SP and SP plus iron reduced the number of attacks of clinical malaria (hazards ratios 0.59 and 0.76, respectively) but the number of episodes of malaria was small and these reductions were not statistically significant. A second study with a similar design was undertaken in an area of western Kenya with intense, perennial malaria transmission and high coverage with ITNs (Desai et al. 2003). Results were similar to those obtained in the previous trial – iron and iron plus SP increased mean Hb concentrations significantly but SP alone did not. Clinical attacks of malaria were reduced by about a half in children who received SP but the difference from the placebo group was only of border-line statistical significance ( P = 0.07). In Tanzania, Schellenberg et al. (2004) compared the outcome in anaemic children (PCV < 25%) of administration of oral iron and IPT with SP given three times over a period of three months with a conventional two-week course of treatment. A modest reduction in the prevalence of anaemia was seen after 6 months of follow up in children who were compliant with the extended period of treatment.

More recent studies of IPT in children have focused on its impact on malaria. In Mali, two treatments with SP reduced the annual incidence of clinical attacks of malaria in children aged 6 months to 10 years by 40% (Dicko et al. 2004). An even more impressive level of protection was seen at Niakhar, Senegal (Cisse et al. 2006). In this part of Senegal, malaria transmission occurs during only a few months of the year but malaria is the most important cause of death in children; very few children sleep under an ITN. Children, aged 3–59 months, enrolled in this study received either a single dose of SP and artesunate (4 mg/kg) or placebo given on three occasions at monthly intervals during the peak malaria transmission season. Iron was not given routinely but anaemic children were identified at the commencement of the study and treated with iron. Drugs were given under observation at a health centre. The incidence of clinical attacks of malaria was reduced by 87% in children who received IPT. No significant impact on haemoglobin concentration was observed, perhaps due to prior treatment of anaemic children and because children who developed malaria during the course of the study were detected promptly and treated.

The efficacy of IPTc in the same study area was confirmed during a second trial undertaken in 2004 in which four drug combinations were tried (SP + 1 dose of artesunate, SP + 3 doses of artesunate, SP + amodiaquine given for 3 days and amodiaquine + artesunate given for 3 days). Although there was no placebo group in this study, comparison with results obtained in 2002 suggested efficacies against clinical attacks of malaria of around 90% in all groups with the SP + amodiaquine group being the most effective (C. Sokhna et al. in preparation).

A further study of seasonal IPT is underway in children aged 3–59 months in Volta River division of Ghana in which three different drug regimens are being compared (SP or amodiaquine + artesunate given monthly or every 2 months). Preliminary analysis suggests efficacies intermediate between those of Senegal and Mali (M. Kweku et al. personal communication).

Challenges and research priorities for intermittent preventive treatment in children

IPT has promise as a method of malaria control in older children living in an area with a short transmission season but a number of important issues need to be resolved before this approach could be implemented on a large scale. Many of these issues are similar to those faced previously by chemoprophylaxis programmes and experience gained during these studies is taken into account in the following discussion. Issues that need to be addressed, and the ways in which these might be tackled through further research (Table 1) are considered in the following paragraphs.

Table 1.   A possible research strategy for the evaluation of intermittent preventive treatment in children
ObjectiveStudies neededNumbersEnd-points
Study of the interaction of IPT with other control measures such as ITNsA multi-centre trial in sites with different levels of transmission1000 per siteclinical malaria
Devising a delivery system3 or 4 studies in sites with different health systems1000s per siteeffectiveness coverage cost effectiveness acceptability
Determining the optimum drug, number of doses and timing between doses3 or 4 studies in sites with different patterns of resistance100s per siteefficacy safety acceptability drug resistance
Impact on immunity2 studies in areas with different epidemiology1000 per siterebound malaria
Investigation of the role of IPT in groups at special risk eg. sickle cell patients and those with HIV or anaemiaSingle efficacy trials100s per trialclinical malaria

Interaction with other malaria control measures

Seasonal IPT in children is unlikely to be implemented as a single malaria control measure. Thus, it is essential to establish whether it adds to the protection provided by ITNs, indoor residual spraying (IRS) or, in due course, vaccination. Because ITNs have been adopted as the primary form of malaria prevention in most parts of Africa it will be particularly important to establish the impact of seasonal IPT in ITN users; ITN coverage was low in the populations studied in Mali and in Senegal. The results of previous studies of chemoprophylaxis given in conjunction with ITNs suggest that an additive effect will be seen. Thus, in The Gambia, children who slept under ITNs had about 50% less clinical attacks of malaria than control children whilst protection among children who received chemoprophylaxis with pyrimethamine/dapsone in addition was 97% (Alonso et al. 1993). Similar, although slightly less impressive, results were obtained in Sierra Leone (Marbiah et al. 1998).

Further studies, preferably at several sites with different levels of exposure, are needed to determine whether seasonal IPT provides substantial added benefit to that provided by ITNs in order to justify the work that will be needed to establish effective and sustainable delivery systems.

Delivery and sustainability

IPTi has a major advantage over seasonal IPT in that an effective delivery system already exists – the EPI programme. Finding a way to deliver IPT to children outside the age range of the administration of EPI vaccines is a major challenge that was also faced by chemoprophylaxis programmes. Most of these employed volunteers, either village health workers (VHWs) or ‘community mothers’ to deliver anti-malarial drugs. High initial levels of coverage were achieved in many programmes but few investigated sustainability. An exception was a study undertaken in The Gambia, which specifically addressed this issue. On completion of a large controlled trial of chemoprophylaxis (Menon et al. 1990), high levels of coverage were maintained for a further 5 years in about one-third of the villages that had participated and a respectable level of coverage was seen in another third (Allen et al. 1990). Subsequent experience with onchocerciasis, filariasis, schistosomiasis and trachoma control programmes has shown that high levels of coverage with community-based treatment programmes can be achieved, provided that the community is fully involved.

Supervising a national or regional programme for seasonal IPT in children would be challenging. It would be necessary to ensure that appropriate supplies of drugs reached each community at the correct time each year, that community volunteers fulfilled their responsibilities and that drugs intended for IPT were not used for other purposes. Establishing an independent system to do this would probably not be cost effective but it might be possible to integrate drug delivery into an established programme. For example, EPI outreach clinics might be used to deliver drugs to the community and to provide some supervision of community volunteers. Experience gained during mass treatment programmes for the control of onchocerciasis, filariasis, schistosomiasis, intestinal worms and trachoma, which are now delivering drugs to many millions of people each year through community-based programmes, could be valuable in suggesting ways in which this might be done. It is possible that, in some areas, anti-malarial drug delivery could be linked to one of these existing programmes.

Research is needed on how seasonal IPT could be implemented in an effective and sustainable way. Although local solutions to local situations may be needed, a small number of studies conducted in carefully selected sites could provide results, which have general applicability. In 2006, studies will be undertaken in The Gambia and in Ghana which will compare delivery through EPI clinics with that provided by community volunteers. However, other possible methods of drug delivery need to be explored.

Choice of drug, frequency of administration and drug resistance

It seems likely that a long acting drug is needed for effective IPT in both infants and in older children and SP is, therefore, a good choice for IPT programmes. However, SP resistance is increasing in many parts of Africa and an alternative is needed. Mefloquine is a possible choice but the safety of this drug when used for IPT has not been established. Piperaquine is eliminated slowly and is another possible alternative. If the IPT approach becomes widely adopted in infants and/or older children, it may be necessary to develop new drugs with a long half-life specifically for this purpose; the ideal for areas where seasonal IPT might be introduced would be a drug which, in a single treatment, gave 12 weeks of protection. Single dose treatment is highly desirable for IPT programmes so that administration can be given under supervision, thus reducing the risk that subsequent doses will not be taken and/or used by others in the community.

A drug used for IPT in infants or children must be very safe as it will be given to large numbers of non-infected subjects. It must have few minor side effects as these will influence compliance and the acceptability of the intervention, and any other interventions given at the same time. Determination of acceptability should be an important feature of future studies.

The frequency of administration and the time interval between treatments are likely to be critical in determining the efficacy and effectiveness of IPT (White 2005). This is illustrated by the fact that a single dose of SP and artesunate given at the beginning of the malaria transmission season in The Gambia had no impact on the overall incidence of clinical attacks of malaria during the malaria transmission season (von Seidlein et al. 2003) whilst in neighbouring Senegal three doses of the same drug combination gave almost 90% protection (Cisse et al. 2006). Further research will be needed to define optimum treatment regimens in different epidemiological situations.

A major concern over the widespread use of IPT in infants and children is that this will encourage the spread of drug resistant parasites. Four recent studies have investigated the impact of IPT on drug resistance, two in infants and two in older children. In Ghana, parasites carrying molecular markers of resistance to pyrimethamine and sulphadoxine were found more frequently during a six-month follow-up period in infants who had received a single dose of SP than in control infants but the number of infants in this study was only small (Marks et al. 2005). Preliminary analysis of the outcome of a trial of IPTi with SP in Mozambique indicates no increase in the prevalence of resistant parasites (Mayor et al. 2005). In Senegal, parasites obtained at the end of the malaria transmission season from children who had received seasonal IPT with SP and artesunate carried molecular markers of resistance to pyrimethamine or sulphonamides significantly more frequently that did parasites obtained from control children (Cisse et al. 2006). However, because many fewer children who had received IPT were parasitaemic, the number of children who carried resistant parasites was less in children who had received IPT than in control children. Furthermore, fewer children who had received IPT were gametocytaemic and likely to transmit their infection. In the second study undertaken in Niakhar, in which four treatment groups were compared there were no major differences between groups in the prevalence of molecular markers of resistance (C. Sokhna et al. in preparation). Thus, findings on the impact of IPT on the selection of drug resistant parasites are somewhat contradictory and more studies addressing this issue specifically are needed.

It is possible that the risk of selection of drug resistant parasites by seasonal IPT could be reduced by the use of a drug combination, although a single dose of artesunate administered with SP did not prevent the selection of parasites resistant to SP in Niakhar. Combination therapy would, however, increase cost and perhaps decrease compliance if several doses of an artemisinin were needed. Artemisinin combinations, although highly effective in the treatment of acute cases of malaria because of their rapid action, may not be the best option for IPT for which a combination of two long-acting drugs might be preferable.

Widespread implementation of IPT will increase drug pressure and favour drug-resistant parasites. How marked this effect will be in any specific community will be influenced by many variables including the background pattern of resistance, the drug or drug combination chosen and the overall pattern of anti-malarial usage, especially for treatment, in that community. Thus, monitoring the effect of IPT on the prevalence of parasites resistant to the drug(s) being used should be an essential part of any implementation study. Cluster randomized designs will be needed to allow the possible spread of resistant parasites from those receiving IPT into the community to be determined.

Impairment of immunity

A further major concern over the use of any form of chemoprevention in children resident in an endemic area is that this will impair their acquisition of naturally acquired immunity to malaria. In The Gambia and in Tanzania, an increase in clinical attacks of malaria was observed in children who had previously received chemoprophylaxis during the year after chemoprophylaxis was stopped (Greenwood et al. 1995; Menendez et al. 1997). Reduction of the level of exposure to malaria below a critical point by any means will impair the development of naturally acquired immunity to the infection but it is not known what the critical level is. It is possible that modest exposure may more effective at inducing immunity than massive exposure. Thus, in The Gambia, children who received chemoprophylaxis had greater cellular immune responses to malaria antigens than control children, although they had lower antibody concentrations (Otoo et al. 1989). The sustained protection against malaria seen in children who had received IPTi in Tanzania is in keeping with this concept (Schellenberg et al. 2005).

No significant increase in the incidence of malaria was seen in Senegalese children who had received seasonal IPT for one year during the following transmission season, although there was a trend in this direction in older but not in younger children (Cisse et al. 2006). However, to be maximally effective, seasonal IPT will need to be given to children each year until they reach the age of 3 or 5 years old. Whether this will impair the development of natural immunity to malaria is not known and needs to be investigated. This will require a study of up to 6 years duration but useful information will be obtained at intermediary time points. The results of the trials in Senegal and Mali may make an individually randomized, placebo controlled trial ethically unacceptable and more complex study designs may be needed to address this issue.

Cost

Seasonal IPT is likely to be cost effective if it produces results similar to those seen in Mali and Senegal. The direct costs of giving a drug such as SP three times a year are less than US$1 but drug costs will be higher if an artemisinin combination therapy (ACT) is used. Delivery costs at national and community level may double this sum. Nevertheless, seasonal IPT is likely to be well within the range of other cost-effective anti-malarial interventions (Goodman et al. 1999; Morel et al. 2005). Evaluation of cost should be an important component of further studies that explore different delivery systems.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References

This review has focussed on the potential of IPT to protect children from malaria in areas with seasonal transmission. However, there may be other groups of children who are at particular risk from malaria who could benefit from this approach. These include children with sickle cell disease or HIV and those who have recently been treated for severe anaemia. Studies to investigate the latter are in progress in Kenya and The Gambia. In older children, seasonal IPT might improve school attendance and performance and this is being investigated in Kenya.

Seasonal IPT was as effective in preventing clinical attacks of malaria in Senegalese children under the age of five years old as seasonal chemoprophylaxis had been in a neighbouring area of The Gambia. The latter led to a 40% reduction in overall child mortality. It is, therefore, a reasonable assumption that an effective seasonal IPT programme would have a substantial impact on mortality in areas where the epidemiology of malaria is similar to that of The Gambia and Senegal. At least 50 million children under the age of five years live in such areas, about 300 000 of whom die each year from malaria. Devising an effective delivery system for IPT will not be easy but IPT, employed as part of an integrated malaria control programme, has the potential to make an immediate impact on the many preventable deaths from malaria that occur in areas where the transmission of malaria is seasonal.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Definitions
  5. Malaria chemoprophylaxis in children
  6. Intermittent preventive treatment in infants
  7. Intermittent preventive treatment in older children
  8. Conclusion
  9. Acknowledgments
  10. References
  • Allen SJ, Snow RW, Menon A & Greenwood BM (1990) Compliance with malaria chemoprophylaxis over a five year period among children in a rural area of The Gambia. Journal of Tropical Medicine and Hygiene 93, 313322.
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