SEARCH

SEARCH BY CITATION

Keywords:

  • IPTi;
  • public health impact;
  • malaria;
  • anaemia;
  • review
  • TPI;
  • nourrissons;
  • impact sur la santé publique;
  • malaria;
  • anémie;
  • examen
  • IPTi;
  • impacto en salud pública;
  • malaria;
  • anemia;
  • revisión

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

We discuss the potential public health impact of IPTi by estimating the cases of malaria, anaemia and hospital admissions likely to be averted in different transmission settings; and we review the mechanism of action, choice of drugs regimens, and the effect on immunity of IPTi. IPTi using an efficacious drug is likely to substantially reduce cases of clinical malaria in moderate to high transmission settings. However, geographical heterogeneity in malaria transmission could hamper rolling out IPTi as a national policy.

Nous discutons de l’impact potentiel pour la santé publique du TPI chez les nourrissons, en estimant les cas de malaria, d’anémie et d’admissions à l’hôpital, susceptibles d’être évités dans différentes zones de transmission et nous passons en revue le mécanisme d’action, le choix des régimes de médicaments et l’effet du TPI sur l’immunité. Le TPI basé sur l’utilisation d’un médicament efficace est susceptible de réduire sensiblement les cas de malaria clinique dans les zones de transmission modérée àélevée. Cependant, l’hétérogénéité géographique dans la transmission de la malaria risque d’entraver le déploiement du TPI en tant que politique nationale.

Discutimos el impacto potencial, a nivel de salud pública, del TPI en lactantes (TPIl), estimando los casos de malaria, anemia y admisiones hospitalarias que podrían evitarse en lugares con diferente transmisión; y hemos revisado el mecanismo de acción, escogencia de regimenes de medicamentos, y efecto del TPIl en la inmunidad. El TPIl, utilizando un medicamento eficaz, podría en principio reducir sustancialmente los casos de malaria clínica en lugares con una transmisión moderada a alta. Sin embargo la heterogeneidad geográfica en la transmisión de malaria podría dificultar la puesta en marcha de la TPIl como política nacional.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

Intermittent Preventive Treatment of malaria (IPT) is a form of chemoprevention achieved by giving therapeutic does of antimalarials at pre-defined time points (Greenwood 2007). IPT during pregnancy (IPTp) is now widely adopted in Africa to reduce low birth weight and maternal anaemia, the main consequences of malaria in pregnancy. Randomised placebo controlled trials of IPT in infants (IPTi) (Schellenberg et al. 2001; Massaga et al. 2003; Chandramohan et al. 2005; Macete et al. 2006; Grobusch et al. 2007; Kobbe et al. 2007; Mockenhaupt et al. 2007), in <5-year-old children (IPTc) (Cisse et al. 2006; Dicko et al. 2008; Sokhna et al. 2008) and in primary school children (ITPsc) (Clarke et al. 2008) have shown that IPT can reduce the incidence of malaria among these target groups. Both pregnant women and older children are mostly semi-immune and when infected are more likely to develop asymptomatic parasitaemia than to develop acute clinical malaria in moderate and high transmission areas. In these groups, where asymptomatic parasitaemia is common, clearing existing parasitaemia and preventing new infections would be important. By contrast, the prevalence of asymptomatic parasitaemia in infants is very low in areas of low and moderate transmission (Gosling et al. 2009) and varies remarkably between dry and rainy seasons in areas of highly seasonal transmission (Chandramohan et al. 2007). Thus the effects of IPTi will depend on the endemicity of malaria. We review the evidence of the mechanism of action of IPTi, and its efficacy and potential public health impact.

The mechanism of IPTi

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

An effective antimalarial given to an asymptomatic child will clear existing parasites (treatment effect) and prevent new blood stage infections (prophylactic effect) (White 2005). Two separate mathematical models based on this simple mechanism of action of IPTi were able to predict protective efficacies against malaria within the 95% confidence intervals in published IPTi trials in all but one study (Gosling et al. 2008b; Ross et al. 2008). Secondary analyses of three IPTi trials showed that the length of protection against malaria provided by IPTi is approximately equal to the likely period of prophylaxis given by the drugs used (Cairns et al. 2008; May et al. 2008). In a recent study, comparing long-acting and short-acting drugs for IPTi (Gosling et al. 2009) the long-acting drug, mefloquine was efficacious in preventing clinical episodes of malaria up to 12 months of age (PE 38%; 95% CI 12%, 57%) whereas the short-acting drug combination, chlorproguanil-dapsone was not (PE 11%, 95% CI −25%, 36%).

The first published IPTi trial (Schellenberg et al. 2001) showed a high protective efficacy of IPTi against malaria (62%; 95% CI 44%, 75%) and prolonged protection into the second year of life (Schellenberg et al. 2005). Some investigators hypothesise that the extended period of protection was a ‘vaccination effect’ caused by persistence of low levels of parasitaemia, providing prolonged stimulation of the immune system (Sutherland et al. 2007). Others argue that this high estimate of protective efficacy was a function of the fast decline in malaria incidence during the study period, and would not be seen in areas of stable or slowly declining incidence (Gosling et al. 2008b) as found in two separate modelling exercises (Gosling et al. 2008b; Ross et al. 2008). This argument is supported by evidence of a decline in the incidence of malaria in the study area during the time of the study (Schellenberg et al. 2004) and by a reduction in malaria incidence in the placebo group from a peak of 0.92 cases per year at the age of 9 months (Institute of Medicine 2008) to a mean of 0.41 cases per year between 10 and 24 months of age (Schellenberg et al. 2005), which is unlikely to be explained by the age-distribution of malaria cases alone.

The efficacy of IPTi

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

Results from eight IPTi trials have been published – seven trials tested the protective efficacy of sulphadoxine–pyrimethamine (SP-IPTi) (Chandramohan et al. 2005; Schellenberg et al. 2001; Macete et al. 2006; Kobbe et al. 2007; Grobusch et al. 2007; Mockenhaupt et al. 2007; Gosling et al. 2009). The protective efficacies of chlorproguanil–dapsone (CD-IPTi) and mefloquine (MQ-IPTi) were compared with SP in one study (Gosling et al. 2009) and amodiaquine was tested (AQ-IPTi) (Massaga et al. 2003) in another. We excluded the trial of AQ-IPTi from this analysis as: (i) it was carried out during the 6-month high transmission season only with a 2-month follow-up after the last IPTi dose, (ii) the doses of IPTi were given only 2 months apart and (iii) the doses were not given at times of immunisation. This is akin to seasonal administration of IPTi with short intervals effectively providing chemoprophylaxis and a short follow-up time, and this would lead to a higher estimate of the protective effect of AQ-IPTi in comparison to the protective effect of IPTi administered along with EPI vaccination as was estimated over an 11-month period for the other trials.

The protective efficacies against clinical malaria, moderate anaemia and all cause hospital admissions observed in the trials included in this review are shown in Table 1. SP-IPTi had a protective efficacy against malaria ranging from 14% to 62% (95% CI 1.6%, 74.6%) in five sites where day 28 parasitological failure of SP ranged from 14% to 40%. In an area with high SP resistance [day 28 failure rates >80% (Gesase et al. 2009)], SP-IPTi had no effect on malaria but MQ-IPTi had a high protective efficacy (38%; 95% CI 12%, 57%) (Gosling et al. 2009).

Table 1.   Summary of published IPTi trials
Years of studySite & CountryrefDrug testedAge at dosing (months)Resistance levels to study drug at day 28Incidence in placebo group (PYAR)Protective efficacy (PE) % (95% Confidence intervals)Protective efficacy measured from first dose to age
Clinical malaria (fever or history of fever plus parasites)Moderate anaemiaAll cause hospital admissions
  1. SP, Sulphadoxine–Pyrimethamine, MQ, Mefloquine, *Resistance at Day 14 post treatment (no data available for day 28), Anaemia measured as aPCV <25%, bPCV <24%, cHb <7 g/dl, dHb <7.5 g/dl, eHb <9 g/dl and fHb <8 g/dl. gParasite density >500 per microlitre.

1999–2001Ifakara, Tanzania (Schellenberg et al. 2001)SP2, 3 & 940%0.4362.3 (44.2, 74.6)50.3 (7.6, 73.2)a30.0 (8.1, 46.6)12 months
2000–2004Navrongo, Ghana (Chandramohan et al. 2005)SP3, 4, 9 & 1222%*124.9 (14.5, 34.1)35.5 (11.2, 53.1)b12.7 (- 4.8, 27.3)15 months
2002–2005Mahnica, Mozambique (Macete et al. 2006)SP3, 4 & 921%*0.5522.6 (1.6, 39.2)12.7 (−17.3, 35.1) a19.0 (4.0, 31.0)12 months
2003–2004Tamale, Ghana (Mockenhaupt et al. 2007)SP3, 9 &1514%*1.1622.5 (11.8, 31.9)31.3 (2.9, 51.4)c23.6 (4.1, 39.1)18 months
2003–2005Ashanti, Ghana (Kobbe et al. 2007)SP3, 9 &15NA1.220.3 (10.6, 28.9)g7.2 (−7.7 20.1)d8.7 (−23.4, 32.4)18 months
2004–2006Lambarene, Gabon (Grobusch et al. 2007)SP3, 9 &1531%0.1617 (−24,44)22 (−1, 40)eNA18 months
2004–2008Korogwe, Tanzania (Gosling et al. 2009)SP2, 3 & 980%0.31−6.7 (−45.9, 22.0)−15.9 (−56.9, 14.3)f−14.7 (−51.7, 13.2)12 months
2004–2008Korogwe, Tanzania (Gosling et al. 2009)MQ2, 3 & 9NA0.3138.1 (11.8, 56.5)−6.0 (−44.0, 22.0) f2.3 (−30.6, 26.9)12 months
2004–2008Same, Tanzania (Gosling et al. 2009)SP2, 3 & 980%0.018−77.2 (−505.4, 48.1)20.7 (−26.7, 50.4) f13.8 (−15.1, 35.5)12 months
2004–2008Same, Tanzania (Gosling et al. 2009)MQ2, 3 & 9NA0.01850.2 (−171.9, 90.9)24.7 (−20.9, 53.1) f−9.2 (−43.3, 16.7)12 months

The effect of IPTi on anaemia varied substantially between studies. The first IPTi trial in Ifakara showed a 50% protective efficacy and two subsequent studies in northern Ghana showed protective efficacies of 35% and 31% respectively. However, none of the other studies, including the MQ-IPTi trial, showed a significant effect on anaemia. Similarly the Ifakara trial showed a protective efficacy of 30% against all cause hospital admissions supported by two further studies in Ghana that showed protective efficacies of 24% and 19% against this end-point. However, none of four other studies including MQ-IPTi showed a protective effect against all cause admissions.

An analysis of pooled data of the first six of the SP-IPTi trials (Schellenberg et al. 2001; Chandramohan et al. 2005; Macete et al. 2006; Grobusch et al. 2007; Kobbe et al. 2007; Mockenhaupt et al. 2007) showed a combined protective efficacy of 30% (95% CI 20%, 39%) against clinical malaria, 15% (95% CI 6%, 23%) against anaemia (Hb <8 g/dl) and 23% (95% CI 10%, 34%) against hospital admissions (Institute of Medicine 2008).

No study showed an effect on mortality but none had adequate power to detect this outcome. Furthermore, in trial settings early diagnosis and prompt treatment of most malaria cases could have prevented the development of severe disease and death. A large study on effectiveness of IPTi conducted in southern Tanzania (clinicaltrial.gov NCT00152204) that was completed recently would provide evidence on the effect of IPTi on mortality.

Cases averted using IPTi in different transmission settings

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

For any intervention to be acceptable for implementation the benefits must outweigh the risks and costs of the program. Cases of malaria, anaemia and all cause admissions averted per 1000 infants given IPTi estimated from the published studies are shown in Figures 1, 2 and 3 respectively. Cases averted were calculated by multiplying the incidence of malaria, anaemia and all cause hospital admissions in the placebo group by the protective efficacy of IPTi against each of these outcomes reported by the trials. A robust modelling of cases averted in non-trial settings has been undertaken previously (Ross et al. 2008), and here we present a more intuitive interpretation of the actual data available from the trial sites.

image

Figure 1.  Cases of clinical malaria averted per 1000 children receiving IPTi from seven trials by incidence rate of clinical malaria in the placebo group, Cases averted were calculated by multiplying the incidence of clinical malaria in the placebo group by the protective efficacy of IPTi against this outcome reported by the trials. Lines show fixed PE s of 15%, 25% and 40% by incidence of clinical malaria per year at risk.

Download figure to PowerPoint

image

Figure 2.  Cases of moderate anaemia per 1000 children receiving IPTi from seven trials by incidence rate of clinical malaria in the placebo group, Cases averted were calculated by multiplying the incidence of moderate anaemia in the placebo group by the protective efficacy of IPTi against this outcome reported by the trials.

Download figure to PowerPoint

image

Figure 3.  Cases of all cause hospital admission averted per 1000 children receiving IPTi from seven trials by incidence rate of clinical malaria in the placebo group, Cases averted were calculated by multiplying the incidence of all cause hospital admissions in the placebo group by the protective efficacy of IPTi against this outcome reported by the trials.

Download figure to PowerPoint

The relationship between the cases of malaria, anaemia and hospital admissions averted and the endemicity of malaria was explored by plotting these outcomes against the incidence of malaria in the placebo group in each trial as a proxy for transmission intensity. In addition, the expected number of cases averted based on fixed protective efficacies against clinical malaria are shown to indicate the range of potential benefits of IPTi and how this varies with transmission intensity.

As expected, the number of malaria cases averted by IPTi increased as the incidence of malaria increased, ranging from 125 to 275 per 1000 infants in moderate to high transmission settings with an average IPTi protective efficacy of 25%. Neither numbers of cases of moderate anaemia nor all cause hospital admissions averted seem to be related to malaria incidence. Most studies showed small numbers of cases of anaemia and hospital admissions averted and the majority are not statistically significant.

Choice of drug regimen

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

Factors that might influence the choice of drug for IPTi include its length of action, efficaciousness and safety. Drugs that have been used in trials and seem to have a suitable half life are SP, MQ and AQ. SP appears to have a good safety record. Only two serious adverse events (Steven-Johnsons syndrome) possibly linked to SP (Kobbe et al. 2007) (dose given at 15 months of age) were reported from approximately 4500 children involved in the seven trials. However, the declining efficacy of this drug means that it may not be useful in some regions. In the trial using MQ, the formulation used caused vomiting and irritability in 8% of children (Gosling et al. 2009). A bimonthly regimen of AQ-IPTi had a high protective efficacy against malaria in Tanzania (65%, CI 42%, 77%) (Massaga et al. 2003) and a monthly regimen of SP+AQ had higher protective efficacy than monthly SP+ single dose of artesunate in a seasonal IPTc study in Senegal (Sokhna et al. 2008). However, AQ has to be given over 3 days and the adherence to a 3 day IPTi regimen may not be optimal.

Another drug under consideration for IPTi is piperiquine, which is long-acting and could be given as a single dose. The combination of SP plus piperaquine had a better protective efficacy against malaria than SP plus AQ in an IPTc trial in Senegal (Sokhna et al. 2008). However, the combination of SP plus piperaquine has not yet gone through the rigorous clinical development process required for registration. Furthermore dihydroartemisisin plus piperaquine is currently undergoing clinical development and this ACT is considered to be the next generation first line treatment for non-severe malaria. It is probably better to use a different drug combination for first line treatment of non-severe malaria and for IPT in order to minimise the risk of over dosing and to prolong the usefulness of the drugs reserved for treatment purposes. Thus dihydroarteminsisin plus piperaquine may not be appropriate for IPT programs.

Frequency of doses and age at administration

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

The number of doses in an IPTi programme and the optimum ages at which to administer them are debatable. So far, IPTi doses have been given in varying combinations at 2, 3, 9, 12 and 15 months of age. The time and frequency of IPTi will depend on the age-specific incidence of malaria which varies between settings and the age-specific protective efficacy of IPTi. In the published trials, the protective efficacies during the 35-day post IPTi period after each dose differ considerably. The protective efficacies generally decrease as age increases. This may be explained by a suboptimal dose regimen given by age instead of by weight and by the fact that the children in the placebo group gain immunity and become less susceptible compared with the IPTi groups. Predicted effects of single doses of IPTi at different ages have been modelled (Ross et al. 2008) and show greatest benefits between 5 and 10 months of age in high transmission settings.

Timing of IPTi

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

As the number of cases averted is linked to incidence, IPTi should be administered at times when incidence is high. This is affected by the age of children, as discussed above, but also by seasonality (Chandramohan et al. 2007). Duration and seasonal pattern of transmission varies greatly over the African continent. Administration of IPTi at times of high malaria transmission would maximise the number of cases averted but it requires a delivery system other than the EPI programme as the doses of IPTi need to be linked to a calendar date and not to the EPI vaccination schedule. How this would affect effectiveness of IPTi is unknown. However, seasonal IPTc delivered by community-based volunteers in controlled study settings showed promising results (Cisse et al. 2006; Sokhna et al. 2008).

Effects on immunity

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

There are few studies of the effects of IPTi on immunity. Quelhas et al. (2008) showed that there is no difference in IgG and IgM against erythrocyte antigens (MSP-119, AMA-1 and EBA-175) between children who received SP-IPTi or placebo and that in some children IgG levels were increased in the SP-IPTi group. By contrast, Schreiber et al. (2007) showed a decrease of antibodies to Plasmodium falciparum lysate after a single dose of SP in one of the IPTi studies. The first study was designed to look at correlates of immunity during an IPTi study with follow up to 24 months of age, whereas the second was designed to detect exposure to blood stage infection following a single dose of SP. In addition the first study took place in Mozambique (Mayor et al. 2008) where the frequency of resistant alleles to SP was higher than in the second study in Ghana (Marks et al. 2004).

It is assumed that children will be exposed to malaria in between doses of IPTi when the drug concentration falls below the required levels for effective prophylaxis and will thus develop immunity. This appears to be true as there has not been a significant increase in the overall number of cases of clinical malaria in any of the trials during the period after IPTi administration. However, in one trial, there was an increased incidence of high parasitaemia malaria (Chandramohan et al. 2005) and in another an increased risk of severe anaemia cases in the second year of life (Mockenhaupt et al. 2007).

There are methodological issues in measuring immunity or lack of it in these studies due to the focal nature of malaria (Mwangi et al. 2008). Control groups have to be carefully selected to represent children at similar risk of malaria. In one IPTi study (Gosling et al. 2009) more than 60% of participants never reported a case of malaria up to 24 months of age and in another only 17% had a recorded episode of clinical malaria (Schwarz et al. 2008). Thus, using the whole cohort to explore immunity could result in a dilution of true differences to an undetectable level. One might expect that the effect of IPTi on immunity would be less pronounced in areas of high transmission because children are exposed to malaria outside the protected time and develop immunity. Equally, at low levels of transmission the chance of exposure to malaria during the period protected by IPTi will be low and thus IPTi may have no effect on the development of immunity. Moderate transmission settings probably offer the best opportunity to detect an impact of IPTi on the development of immunity to malaria. Stratifying for risk of malaria infection by using entomological data and other risk factors such as house type, ITN use, maternal education, distance to health facility and more may allow for improved assessment of differences in immunity comparing children with similar exposure.

Role of IPTi for control of malaria

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

To understand the role of IPTi for malaria control, it is important to recognise that risk of malaria is heterogeneous (Mwangi et al. 2008) and in some parts of sub-Saharan Africa malaria transmission has fallen substantially (Gosling et al. 2008a). This means that many parts of sub-Saharan Africa that were previously recognised as having moderate or high transmission may now have low transmission or contain pockets of low transmission (Guerra et al. 2008). For instance, endemicity of malaria in Tanzania is considered to be high (WHO 2008, MARA 2004). However, 40% of the population live in areas with a malaria parasite prevalence <10% in <5-year-old children (Table 2) (Tanzania Commission For Aids & Zanzibar Aids Commission, National Bureau Of Statistics & Measures 2008) Although the parasite prevalences are estimated from a small but representative sample in each region, the variation in transmission is remarkable and about one quarter of the population has a very low risk of malaria.

Table 2.   Proportions of Tanzanian population living in regions with different levels of prevalence of malaria parasite
 parasite prevalence in <5-year-old children
<2%2–9%10–19%20–30%>30%
  1. Parasite prevalence figures are from the Tanzanian National HIV and Malaria Indicator Survey Preliminary Report 2007–2008.

  2. Population proportions calculated from the 2002 census http://www.tanzania.go.tz/census/tables.htm.

Number of regions64535
% of population of Tanzania23.918.822.213.523.0

There is strong evidence that IPTi using an efficacious drug has a substantial impact on clinical cases of malaria and, in some settings, also has an effect on all cause hospital admissions. The public health impact i.e. cases of malaria averted, is proportional to the endemicity of malaria and thus IPTi will be most useful in highly endemic areas (Institute of Medicine 2008). IPTi using a drug with 25% protective efficacy would be expected to prevent approximately 100 cases of malaria per 1000 children receiving IPTi when the incidence of clinical malaria is 0.4 episodes per infant year of observation (Figure 1). What proportion of these 100 cases of clinical malaria prevented would have gone on to require hospital admission or have died is unknown. Assuming that 1% of these clinical cases die (Greenwood et al. 1991), 1000 children must be treated with three doses of IPTi to prevent one death. Clearly this calculation is crude, however the result is in agreement with a robust modelling exercise which suggests between 1 and 4 deaths averted per 1000 children treated, depending on the transmission setting (Ross et al. 2008) .. This compares to approximately five deaths prevented for 1000 children vaccinated with the nine valent pneumococcal vaccine (Cutts et al. 2005) and 5.5 deaths per 1000 among those using insecticide treated bed-nets (Lengeler 2004). These estimates of deaths prevented by pneumococcal vaccination and ITNs are in children <5 years of age and thus are not directly comparable to the expected number of infant deaths prevented by IPTi. However these estimates are helpful to understand the relative role of IPTi in reducing child mortality in malaria endemic areas.

No malaria control strategy works in isolation and interventions should be tested in real life situations where a combination of strategies is in place. Strategies that are likely to interact are ITN distribution and Insecticide Residual Spraying (IRS) as they may reduce transmission and improving access to effective case management particularly through home management of malaria. The IPTi effectiveness trials in Southern Tanzania and UNICEF pilot implementation projects in Benin, Ghana, Mali, Senegal, Madagascar and Malawi (http://www.ipti-malaria.org/) will go some way in exploring how some of these strategies interact. However, unlike mass distribution of ITNs and improved access to treatment, IPTi is unlikely to affect transmission of malaria as only a small proportion of those at risk will be treated and given prophylaxis (Ghani et al. 2009).

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References

IPTi with an efficacious drug is likely to reduce cases of clinical malaria substantially in areas of moderate to high transmission. Although theoretically this should lead to a reduction in severe hospitalised cases and maybe deaths, there is inadequate evidence to support this. This may be due to the close follow up achieved in clinical trials. In addition, the impact of IPTi will probably be lower than expected due to decreasing malaria incidence in some parts of Africa. Thus, IPTi will be of benefit to malaria control primarily when it is applied to areas with moderate to high transmission with good EPI uptake.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. The mechanism of IPTi
  5. The efficacy of IPTi
  6. Cases averted using IPTi in different transmission settings
  7. Choice of drug regimen
  8. Frequency of doses and age at administration
  9. Timing of IPTi
  10. Effects on immunity
  11. Role of IPTi for control of malaria
  12. Conclusion
  13. References
  • Cairns M, Carneiro I, Milligan P et al. (2008) Duration of protection against malaria and anaemia provided by intermittent preventive treatment in infants in Navrongo, Ghana. PLoS ONE 3, e2227.
  • Chandramohan D, Owusu-Agyei S, Carneiro I et al. (2005) Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ 331, 727733.
  • Chandramohan D, Webster J, Smith L et al. (2007) Is the Expanded Programme on Immunisation the most appropriate delivery system for intermittent preventive treatment of malaria in West Africa? Tropical Medicine and International Health 12, 743750.
  • Cisse B, Sokhna C, Boulanger D et al. (2006) Seasonal intermittent preventive treatment with artesunate and sulfadoxine–pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet 367, 659667.
  • Clarke SE, Jukes MC, Njagi JK et al. (2008) Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet 372, 127138.
  • Cutts FT, Zaman SM, Enwere G et al. (2005) Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 365, 11391146.
  • Dicko A, Sagara I, Sissoko MS et al. (2008) Impact of intermittent preventive treatment with sulphadoxine–pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Malaria Journal 7, 123.
  • Gesase S, Gosling RD, Hashim R et al. (2009) High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581. PLoS ONE 4, e4569.
  • Ghani AC, Sutherland CJ, Riley EM et al. (2009) Loss of population levels of immunity to malaria as a result of exposure-reducing interventions: consequences for interpretation of disease trends. PLoS ONE 4, e4383.
  • Gosling RD, Drakeley CJ, Mwita A & Chandramohan D (2008a) Presumptive treatment of fever cases as malaria: help or hindrance for malaria control? Malaria Journal 7, 132.
  • Gosling RD, Ghani AC, Deen JL et al. (2008b) Can changes in malaria transmission intensity explain prolonged protection and contribute to high protective efficacy of intermittent preventive treatment for malaria in infants? Malaria Journal 7, 54.
  • Gosling RD, Gesase S, Mosha JF et al. (2009) Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, placebo-controlled trial. Lancet in press.
  • Greenwood B (2007) Intermittent preventive antimalarial treatment in infants. Clinical Infectious Diseases, 45, 2628.
  • Greenwood B, Marsh K & Snow R (1991) Why do some African children develop severe malaria? Parasitol Today 7, 277281.
  • Grobusch MP, Lell B & Schwarz NG (2007) Intermittent preventive treatment against malaria in infants in Gabon – a randomized, double-blind, placebo-controlled trial. Journal of Infectious Diseases 196, 15951602.
  • Guerra CA, Gikandi PW, Tatem AJ et al. (2008) The limits and intensity of Plasmodium falciparum transmission: implications for malaria control and elimination worldwide. PLoS Medicine 5, e38.
  • Institute of Medicine (2008) Assessment of the Role of Intermittent Preventive Treatment for Malaria in Infants. The National Academic Press, Washington, DC.
  • Kobbe R, Kreuzberg C, Adjei S et al. (2007) A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. Clinical Infectious Diseases 45, 1625.
  • Lengeler C (2004) Insecticide-treated bed nets and curtains for preventing malaria. Cochrane Database Systemic Review, 2, CD000363.
  • Macete E, Aide P, Aponte JJ et al. (2006) Intermittent preventive treatment for malaria control administered at the time of routine vaccinations in Mozambican infants: a randomized, placebo-controlled trial. Journal of Infectious Diseases 194, 276285.
  • MARA (2004) Mapping malaria risk in Africa: Malaria Distribution Model, MARA. http://www.mara.org.za/mapsinfo.htm (accessed on 11 June 2009).
  • Marks F, Meyer CG, Sievertsen J et al. (2004) Genotyping of Plasmodium falciparum pyrimethamine resistance by matrix-assisted laser desorption–ionization time-of-flight mass spectrometry. Antimicrobial Agents and Chemotherapy 48, 466472.
  • Massaga JJ, Kitua AY, Lemnge MM et al. (2003) Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet, 361, 18531860.
  • May J, Adjei S, Busch W et al. (2008) Therapeutic and prophylactic effect of intermittent preventive anti-malarial treatment in infants (IPTi) from Ghana and Gabon. Malar J 7, 198.
  • Mayor A, Serra-Casas E, Sanz S et al. (2008) Molecular markers of resistance to sulfadoxine–pyrimethamine during intermittent preventive treatment for malaria in Mozambican infants. Journal of Infectious Diseases 197, 17371742.
  • Mockenhaupt FP, Reither K, Zanger P et al. (2007) Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrobial Agents and Chemotherapy 51, 32733281.
  • Mwangi TW, Fegan G, Williams TN, Kinyanjui SM, Snow RW & Marsh K (2008) Evidence for over-dispersion in the distribution of clinical malaria episodes in children. PLoS ONE 3, e2196.
  • Quelhas D, Puyol L, Quinto L et al. (2008) Impact of intermittent preventive treatment with sulfadoxine–pyrimethamine on antibody responses to erythrocytic-stage Plasmodium falciparum antigens in infants in Mozambique. Clinical Vaccine Immunology 15, 12821291.
  • Ross A, Penny M, Maire N et al. (2008) Modelling the epidemiological impact of intermittent preventive treatment against malaria in infants. PLoS ONE 3, e2661.
  • Schellenberg D, Menendez C, Kahigwa E et al. (2001) Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet, 357, 14711477.
  • Schellenberg D, Menendez C, Aponte J et al. (2004) The changing epidemiology of malaria in Ifakara Town, southern Tanzania. Tropical Medicine and International Health 9, 6876.
  • Schellenberg D, Menendez C, Aponte JJ et al. (2005) Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial. Lancet, 365, 14811483.
  • Schreiber N, Kobbe R, Adjei S et al. (2007) Immune responses after single-dose sulphadoxine–pyrimethamine indicate underestimation of protective efficacy of intermittent preventive treatment in infants. Tropical Medicine and International Health 12, 11571163.
  • Schwarz NG, Adegnika AA, Breitling LP et al. (2008) Placental malaria increases malaria risk in the first 30 months of life. Clinical Infectious Diseases 47, 10171025.
  • Sokhna C, Cisse B, Ba EL H et al. (2008) A trial of the efficacy, safety and impact on drug resistance of four drug regimens for seasonal intermittent preventive treatment for malaria in Senegalese children. PLoS ONE 3, e1471.
  • Sutherland CJ, Drakeley CJ & Schellenberg D (2007) How is childhood development of immunity to Plasmodium falciparum enhanced by certain antimalarial interventions? Malaria Journal 6, 161.
  • Tanzania Commission For Aids & Zanzibar Aids Commission, National Bureau Of Statistics & Measures (2008) Tanzania HIV/AIDS and Malaria Indicator Survey 2007–8: Preliminary Report. Ministry of Health, Dar Es Salaam.
  • White NJ (2005) Intermittent presumptive treatment for malaria. PLoS Medicine 2, e3.
  • WHO (2008) World Malaria Report: Tanzania Country profile. WHO, Geneva.