The projects and results

Overview of the Consortium projects

The Consortium conducted randomized, double-blinded, placebo-controlled efficacy trials of IPTi-SP in Mozambique and Gabon, and with alternative medicines and combinations in Kenya, Tanzania and Papua New Guinea (PNG) using artesunate plus SP and artesunate plus amodiaquine and chloproguanil-dapsone [lapdap] in Kenya, mefloquine and chloproguanil-dapsone [lapdap] in Tanzania, and artesunate plus SP and amodiaquine plus SP in PNG.

Through two sets of implementation studies of IPTi with SP, conducted in parallel to the efficacy trials, the Consortium generated information on operational issues, acceptability, and the costs of implementation in a variety of countries and different health systems. One study was a community-level effectiveness study in southern Tanzania where IPTi-SP was delivered by health clinic staff along with EPI vaccines to approximately 12,000 infants per year. The other implementation study was undertaken by UNICEF in six African countries (Benin, Mali, Senegal, Ghana, Malawi, Madagascar) involving over 250,000 infants per year.

The Projects

Pooled analysis of the efficacy of IPTi with SP
Pooled analysis of the safety of IPTi with SP
Effect of IPTi-SP on immune responses to EPI vaccines
Effect of IPTi-SP on the development of naturally-acquired immunity to malaria
Effect of SP drug resistance on efficacy of IPTi-SP
Alternative drugs and combinations for IPTi
Effectiveness of IPTi delivered through the existing health system
UNICEF pilot implementation of IPTi in six African countries
Cost effectiveness of IPTi
Acceptability of IPTi
The age pattern of malaria and the applicability of IPTi & Web-based decision-support tool of where to implement IPTi
Modelling the impact of IPTi

Pooled analysis of the efficacy of IPTi with SP

Six safety and efficacy trials were conducted on IPTi with SP (one each in Tanzania, Mozambique and Gabon, and three in Ghana) (Schellenberg et al Lancet 2001, Chandramohan et al BMJ 2005, Macete et al JID 2006, Kobbe et al Clin Infect Dis 2007, Mockenhaupt et al Antimicrobial Agents & Chemotherapy 2007, Grobusch et al JID 2007). The trials started before the formation of the Consortium and so did not have a standardized dose regime (including timing of doses, number of doses, and the drug dose), and had different follow up periods for efficacy and potential rebound, making a meaningful comparison between the published results from the individual trials difficult. However, all the trials gave at least two doses of IPTi in the first year of life and therefore it was possible to reanalyze the trial data using standardized outcome definitions, time periods and statistical methodology to generate a meaningful pooled analysis of IPTi given at the time of EPI vaccines in the first year of life. A Statistical Working Group (SWG) made, made up of the statistician from each trial, was convened to conduct pooled on the information from 7,930 infants (3,958 IPTi and 3,972 placebo) from the six studies.

During the first year of life the protective efficacy of IPTi-SP against clinical malaria ranged from 21% to 59% in the six trials, and was statistically significant in five of the six trials, with a combined pooled estimate of 30% protective efficacy. There was significant heterogeneity between trials due to the higher protective efficacy in the Ifakara trial (59%). However this was a relatively small trial (700 participants) which had little weight on the pooled analysis and removal of this trial reduced heterogeneity to non-significant levels and the combined efficacy estimate to 26%. The effect of IPTi on the relative risk of anaemia ranged from 5% to 50% in the six trials, and was statistically significant in three of the six trials. The results had moderate hetereogeneity and gave a combined pooled estimate of 21% protective efficacy. The combined pooled estimate of protective efficacy against all-cause hospital admissions was 23% and for hospital admissions with malaria parasites it was 38%. There was moderate heterogeneity for these two outcomes but removing one trial at a time in the sensitivity analysis made little difference to the estimates.

There was no significant rebound in episodes of clinical malaria, anaemia or hospital admissions in the pooled analysis of the 5 month period after the IPTi schedule was finished. However, in three studies in Ghana, there was an increase in high parasitemia density clinical malaria (Navrongo), in anaemia (Kumasi) and in severe malaria and severe anaemia (Tamale). In the initial trial in Ifakara there was sustained protection against clinical malaria into the second year of life with infants receiving IPTi-SP having 36% less malaria in the second year of life.

For the full details of results of the pooled efficacy analysis see the SWG report and the paper published in the Lancet in 2009 (Aponte et al Lancet 2009).

A trial of IPTi, which included testing IPTi with SP, was conducted in an area of known high parasite resistance to SP to investigate alternative anti-malaria drugs that could be used for IPTi (Gosling et al Lancet 2009). IPTi with SP was not protective in this area of very high resistance to SP. The pooled analysis of the efficacy of IPTi-SP will be updated with these results.

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Pooled analysis of the safety of IPTi with SP

Six trials on IPTi with SP were included in the safety analysis which was supervised by a Consortium Safety Panel (CSP) (Schellenberg et al Lancet 2001, Chandramohan et al BMJ 2005, Macete et al JID 2006, Kobbe et al Clin Infect Dis 2007, Mockenhaupt et al Antimicrobial Agents & Chemotherapy 2007, Grobusch et al JID 2007). The information gathered was classified as the number of deaths, serious adverse events (as defined by the WHO) non-fatal hospitalisations, and dermatological serious adverse events, in the SP and placebo treated groups. Passive clinical surveillance was used to assess safety in all trials, and in addition active detection of safety was undertaken in three centres either 1 week (two centres) or within four weeks (one centre). Approximately 4,000 infants received 12,000 doses of IPTi-SP in the six trials.

Two sets of analysis were undertaken, the first up to 12 months of age, or 3 months after the last dose whichever was earlier, and the second up the three months after the actual dose was received. There was no statistically significant difference in the risk of death for infants compared to placebo in either analysis. One death was considered possibly related to SP treatment in an infant who was slide positive for malaria at the time of his second dose of IPTi at 9 months of age. Hospitalisations which could be attributed to IPTi occurred in three of the trials but as these occurred in both SP and placebo groups causality assignation was difficult.

The main adverse events of interest were dermatological, especially the possibility of Stevens Johnson Syndrome (SJS). Overall, there were fewer dermatological adverse events in SP recipients than placebo recipients. In one centre, three cases were diagnosed as SJS, two in the SP group and one in the placebo group. Both of the SP treated patients occurred after the third dose of SP at 15 months of age delivered outside the EPI delivery mechanism at 15 months of age, a dose that would not normally be given in IPTi which focuses on the first year of life. None of these cases was seriously ill and all recovered without treatment or hospitalisation. It is highly unlikely that non-hospitalised cases of SJS in Africa would self-solve, however intensive investigation of these cases was undertaken. A photograph of one child’s rash was shared with an expert in the condition who considered SJS an unlikely diagnosis. Blood samples were obtained from the three children and T cell proliferation assays to test for hypersensitivity to SP were carried out. The cells from one child were not considered viable, but the cells from the other two (one SP and one placebo) had negative results when challenged with SP. While such tests are not absolutely predictive, since sensitivity and specificity values could not be provided, the package of information as a whole suggested to CSP that SJS was an unlikely diagnosis.

For the full details of results of the pooled safety analysis see the CSP report and the paper published in the Lancet in 2009 (Aponte et al Lancet 2009).

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Effect of IPTi-SP on immune responses to EPI vaccines

As IPTi is given alongside EPI vaccines it was important that there is no detrimental affect on infants’ responsiveness to the EPI vaccinations. To oversee and guide this area of work, WHO established a 5-member, independent Ad Hoc Advisory Committee of experts. The Advisory Committee assisted with the design of the project, and reviewed the data. The Advisory Committee issued an Interim Report in July 2006 that IPTi with SP has no detrimental effects on responses to EPI vaccines.
To oversee and guide this area of work, WHO established a 5-member, independent Ad Hoc Advisory Committee of experts. The Advisory Committee assisted with the design of the project, and reviewed the data. The Advisory Committee issued an Interim Report in July 2006 that IPTi with SP has no detrimental effects on responses to EPI vaccines. A final report, which includes IPTi with alternative medicines and combinations, will be issued in October 2009.

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Effect of IPTi-SP on the development of naturally-acquired immunity to malaria

The Consortium has investigated the impact that IPTi with SP may have on the development of naturally-acquired immunity to malaria. Early studies of continuous malaria chemoprophylaxis raised concerns regarding the loss or delay in the acquisition of protective immunity to malaria (Geerligs et al Bull WHO 2003, Laing Bull WHO 1984, Menendez et al Lancet 1997). However, studies of IPTi in showed that intermittent prevention reduced the risk of malaria without being followed by a clinical rebound once the intervention was stopped.

In the IPTi-SP study conducted in Mozambique (Macete et al JID 2006), bllod samples were collected for the investigation of whether IPTi-SP administered alongside the EPI vaccines affected the qualitative and/or quantitative immune responses to malaria antigens. As surrogates of protective immunity, the type and quality of antibodies were measured to the blood stage antigens MSP-1, AMA-1, and EBA-175, considered as targets of immunity to malaria.

IPTi-SP did not modify the levels of antibodies to P. falciparum erythrocytic stage antigens in the first 2 years of life, indicating that this intervention did not negatively affect the development of naturally-acquired antibody responses to malaria (Quelhas et al Clin Vaccine Immunol 2008). These results contrasted with previous studies of continuous chemoprophylaxis which reported a significant reduction of antibody responses to P. falciparum (Otoo et al TRSTMH 1988, Hogh et al Acta Trop 1994) which in some cases was accompanied by a rebound in malaria. In addition, the Mozambican study showed some evidence that IPTi-SP might be associated with higher IgG responses to certain antigens at certain time points. It is hypothesised that a partially effective drug such as SP, with long serum half-life and activity against developing hepatic parasite stages, could result in the generation of low dose blood stage inocula and attenuated infections that may contribute to acquisition of protective immunity by the induction of higher IgG responses, particularly to highly immunogenic antigens. In light of this hypothesis, it remains to be established whether IPTi with more efficacious drug combinations tested in other trials would have a similar impact on the development of naturally-acquired immune responses.

For the full details of this study see Quelhas et al Clin Vaccine Immunol 2008.

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Effect of SP drug resistance on efficacy of IPTi-SP

The pooled efficacy analysis of the six trials of IPTi-SP demonstrate that during these trials, levels of resistance to SP up to 31% as measured by the standard (at the time) WHO day 14 in vivo clinical and parasitological resistance in 6 to 59 months old symptomatic children, did not preclude significant protective efficacy when used as IPTi. This level of resistance corresponds to intermediate levels of resistance. Interestingly, the site with the highest level of resistance to SP (31% in Ifakara) had the highest IPTi efficacy against the incidence of clinical malaria (59%), and in all trials apart from Lambaréné and the last dose of IPTi in Kumasi, there was significant protection in the month after an IPTi-SP dose (see the SWG report and Aponte et al Lancet 2009). These observations call into question the value of estimates of curative efficacy to inform the use of antimalarial drugs for prevention where infections may be low density and asymptomatic.

Parasite resistance to SP has spread across Africa, and in the latest trial of IPTi-SP in an area of very high SP resistance IPTi-SP was not protective (Gosling et al Lancet 2009). It is important to know at what level of SP resistance IPTi-SP no longer works. The Consortium developed a drug resistance working group (DRWG) to examine the relationship between the protective efficacy of IPTi-SP against episodes of clinical malaria and various markers of resistance including in vivo efficacy studies and molecular markers associated with SP resistance from studies carried out within two years and within 50km of the IPTi-SP studies. This was examined in the seven studies of IPTi-SP; six with day 14 and four with day 28 results of in vivo efficacy studies for uncomplicated malaria in children under the age of five years and for molecular markers for all seven studies. There was no relationship between all measures of resistance and protective efficacy, and at this moment we can only say that at high levels of in vivo resistance (day 28 Adequate Clinical and Parasitological Response (ACPR) of 20%) and with high frequencies of the quintuple molecular mutation (dhfr triple and dhps double of 90%) IPTi-SP is unlikely to be efficacious (Gosling et al Lancet 2009), but where day 14 ACPR is greater than 60% (Schellenberg et al Lancet 2001) and where the frequency of the quintuple mutation is less than 56%, IPTi-SP is likely to be efficacious (publication in preparation, Gosling et al).

The WHO will be further investigating at what level of drug resistance IPTi-SP is no longer efficacious. With the increasing use of artemisinin-based combination therapy for treatment of malaria, and therefore decrease use of SP, the spread of SP resistance might slow down and therefore prolong the duration for which SP could be useful for IPTi.

A corresponding concern is that IPTi-SP will facilitate the spread of SP resistance. Although changes in the prevalence of SP resistance markers have been reported after IPTi-SP doses in infants (Mayor et al JID 2008, Marks et al JID 2005), mathematical models suggest that the size of such effect in the global spread of resistance will be small (Alexander et al Malaria J 2007).

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Alternative drugs and combinations for IPTi

For areas where resistance to SP is high, alternative drugs or combinations of drugs would be required for IPTi. The Consortium conducted three randomized, double-blinded, placebo-controlled efficacy trials to investigate alternative drugs and combinations:

In the Tanzanian trial, mefloquine was efficacious against clinical malaria (39%), and in Kenya artesunate plus SP and artesunate plus amodiaquine were efficacious against clinical malaria (22% and 25% respectively). In both trials chloproguanil-dapsone was not efficacious. This demonstrates that long acting drugs are needed for IPTi (chloproguanil-dapsone is a short acting drug). To give a full treatment dose of artesunate and amodiaquine, they have to be given over three days which adds a complication to delivering IPTi for the second and third day. SP and mefloquine are single dose drugs and can be given under observation at the clinic.

There were no safety concerns for the use of mefloquine, artesunate plus SP, artesunate plus amodiaquine for IPTi, and there were no detrimental affect on the infants’ responsiveness to the EPI vaccinations. However, many infants vomited after the use of mefloquine so an infant formulation of mefloquine should be developed if used for IPTi.

For more details on the Tanzania study see Gosling et al Lancet 2009. The Kenya study is submitted for publication. The trial in PNG is still on-going; the results will be available in 2010.

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Effectiveness of IPTi delivered through the existing health system

A project in southern Tanzania developed a strategy for the routine deployment of IPTi with SP through existing health services and evaluated the operational feasibility of district-level implementation of IPTi (Mushi et al Malaria J 2008). In addition, the safety, effect on drug resistance, acceptability, financial costs and health benefits of IPTi-SP were evaluated. The project area comprised five districts, separated into 24 sub-district administrative divisions. Following a baseline household survey in 2004 (Armstrong Schellenberg et al BMC Public Health 2008), and thanks to the use of handheld digital technology (Shirima et al Emerging Themes in Epidemiology 2007), restricted randomisation was allocated to divisions to start IPTi implementation or to act as comparison areas from early 2005. Implementation was introduced and supervised as part of the routine health activities (Manzi et al TRSTMH 2008). IPTi-SP was safe, acceptable (Pool et al Malaria J 2008), implementable with existing health staff and relatively inexpensive (Manzi et al BMC Health Services Research 2008); the total cost of implementing the strategy across Tanzania would be about $1.5 million in the first year, with annual running costs in the order of $600,000 thereafter. After two years’ implementation of IPTi-SP there was a suggestion of an increase in one of the genes associated with drug resistance (DHFR) but not the other (DHPS). The investigators hypothesise that differential selection of genotypes may occur when SP is no longer used for first-line malaria treatment. This project also showed that, within a year of IPTi programme initiation, the prevalence of anaemia and malaria was reduced in the target age group in areas implementing IPTi compared to comparison areas. Further papers have been submitted for publication.

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UNICEF pilot implementation of IPTi in six African countries

UNICEF conducted a pilot implementation of IPTi with SP in 20 districts in six African countries (Benin, Ghana, Mali, Senegal, Madagascar and Malawi) covering a population of 5 million people and 270,000 infants, with half a million SP doses administered. Besides analysis of implementation bottlenecks and best practices, UNICEF evaluated the impact of IPTi on the EPI coverage and other malaria interventions, its cost, acceptability, drug resistance and pharmacovigilance safety profile. Full IPTi coverage i.e. all infants receiving EPI vaccines also receiving IPTi, was reached within the first two months of implementation, and the main bottleneck identified was the absence of a pediatric SP formulation for infants. It was also found that IPTi significantly boosted the EPI coverage. Delivery costs for three doses of IPTi-SP was 15.48 US cents per infant. IPTi was well accepted by health workers, mothers and communities, and did not increase the level of parasite molecular makers of resistance to SP after one year of implementation. No serious adverse events related to IPTi were reported, either by active follow up of a cohort of 24,000 infants in two countries, or reported spontaneously in the six countries.

Publications are in preparation.

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Cost effectiveness of IPTi

The Consortium formed a cost effectiveness working group (CEWG) to measure cost effectiveness in all the IPTi trials in a standarised way using the same methodology. Results showed that IPTi with SP when delivered alongside the EPI is a highly cost effective intervention; ranging from US$1.36 to US$4.03 per malaria episode averted, and from US$2.90 to US$8.63 per Disability-Adjusted Life-Year (DALY) averted.

IPTi also reduced health system costs and showed significant savings to households from malaria cases averted. Therefore IPTi delivered alongside the EPI is highly cost effective in a range of malaria transmission settings. The EPI, as an already successful delivery mechanism that reaches a high proportion of target IPTi recipients, helps make IPTi a very cost effective intervention. The biggest factor in the cost effectiveness of IPTi is the cost of the antimalarial drug used. As SP is cheap, using site specific sensitivity analysis, IPTi with SP would remain highly cost effective even if the cost of delivering a dose were to rise considerably. A substantial decline in the PE of IPTi-SP, or in the incidence of malaria, or in the case fatality rate (on which DALYs are calculated).

A study investigating the cost effectivenessof alternative anti-malarial drugs and combinations is submitted for publication. See the following publication for cost effectiveness analysis of IPTi-SP in two of the studies – Hutton et al Bull WHO 2009.

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Acceptability of IPTi

The Consortium formed an acceptability working group (AWG) to measure the acceptability of IPTi in a standarised way using the same methodology. Acceptability studies were carried out in seven sites in six countries in the context of randomised controlled trials and in pilot implementation studies. Mixed methods were used, including structured questionnaires (1296), semi-structured interviews (168), in-depth interviews (748) and focus group discussions (95) with mothers, fathers, health workers, community members, opinion leaders, and traditional healers. Participant observation was also carried out in clinics. IPTi was found to be widely acceptable across all study sites. The main reasons were that it resonated with existing traditional preventive practices and a general concern about infant health and good motherhood. It also fit relatively unobtrusively within already widely accepted routine vaccination (EPI). Acceptance and adherence were further facilitated by the hierarchical relationship between health staff and mothers (mothers tended to obey health workers). Clinic attendance was enhanced by the popularity of infant weighing and by the fact that clinic attendance had a social function for women: it was an excuse to get away from daily routine and socialise. Type of drug and regimen were important, with newer drugs being seen as more effective, but potentially also more dangerous. Single dose infant formulations delivered in the clinic were the most acceptable. There was little evidence that IPTi per se had a negative impact on attitudes to EPI or that it had any affect on EPI adherence. There was also little evidence of IPTi having a negative impact on health seeking for infants with febrile illness or existing preventive practices, for example because mothers mistakenly assumed that their infants were immunised against malaria and therefore no longer susceptible. In conclusion, IPTi was generally acceptable across a wide range of settings in Africa and involving different drugs and regimens, though there is a strong preference for a single dose infant formulation. IPTi does not appear to have any negative effect on attitudes to EPI, and it is not interpreted as immunisation against malaria.

For further information see Pool et al TMIH 2006 and Gysels et al Malaria Journal 2009.

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The age pattern of malaria and the applicability of IPTi

The age-pattern of malaria is known to vary with transmission intensity, and a better understanding of how this varies with severity of the outcome and across a range of epidemiological settings was needed to assess the local applicability of IPTi.

Systematic literature reviews identified studies with data on the age distribution of community-based non-severe malaria fever incidence, hospital admissions with malaria and malaria-diagnosed mortality from demographic surveillance systems across a range of epidemiological settings. Studies were allocated to a 3x2 matrix of transmission intensity (Entomological Inoculation Rate: < 10, 10-100 or >100 bites per person per year) and seasonality (≥75% cases concentrated in ≤6 months of the year considered to be markedly seasonal transmission). Maximum likelihood methods were used to fit five continuous probability distributions to the relative proportion of each outcome by age for each matrix cell.

The burden of non-severe malaria was relatively evenly distributed throughout childhood (0-10 years), whereas severe malaria hospital admissions were more focused in young children, and malaria-diagnosed deaths were even more skewed to the very young. All outcomes showed a shift towards younger age groups with increasing transmission intensity, and with increasing severity of the outcome, although this effect was dampened in areas with markedly seasonal transmission. The proportion of cases that would occur in infants aged 3-12 months (the age-group targeted by IPTi) was calculated for each outcome and epidemiological setting. Between 2-17% of non-severe malaria fevers, 9-29% of hospital admissions with malaria and 17-41% of malaria-diagnosed deaths would be targeted by three doses of IPTi administered between 3-10 months of age.

The study is submitted for publication.

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Web-based decision-support tool of where to implement IPTi

These results are incorporated into a web-based decision-support tool (www.iptiwebtool.org), together with the estimated number of cases averted from the stochastic model. The tool provides policy makers with information needed to assess the applicability of IPTi at a sub-national (first administrative) level. IPTi is likely to be a valuable addition to malaria control in areas of moderate to high malaria transmission, and the decision on where to implement should take into account the local epidemiology of malaria.

The study is submitted for publication.

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Modelling of the impact of IPTi

Modelling of the impact of IPTi was conducted to predict the impact for those severe outcomes for which trials provide only limited data, and to make predictions over longer time periods and in a greater variety of epidemiological settings. By allowing for potential dynamic effects on transmission and acquired immunity, modelling can indicate whether descriptions of age-distributions of disease will give reliable indications of the likely burden averted or whether shifts in these age distributions are likely.

A comprehensive, individual-based model of malaria epidemiology had previously been developed and fitted to both historical and recent data from multiple sites across sub-Saharan Africa (Smith et al AJTMH 2006, Smith et al Parasitology 2008). To this was added a component for pharmacodynamics and the model was validated by inputting the trial characteristics of the IPTi-SP trials and comparing the trial-specific estimates of protective efficacy for each age-group with the model predictions (Aponte et al Lancet 2009). Such comparisons also allow testing of hypotheses about trial characteristics and interactions with clinical immunity (Ross et al PLoS One 2008, Gosling et al Malaria J 2008). The best-fitting models used only trial characteristics and known features of malaria biology and relied on the action of SP.

The predictions were consistent with a short-term impact of IPTi on immunity. Modest short-term increased susceptibility was predicted between doses and following the last dose, but was outweighed by the cumulative benefits. The predicted cumulative benefits are proportionately greater for mortality and severe episodes than for acute episodes. The impact of an IPTi program on community incidence of illness is predicted to remain constant over many years, contrasting with interventions such as vaccines or vector control which have longer term dynamics.

These models suggest that IPTi would have a beneficial impact across a variety of settings, averting a greater number of episodes where EPI coverage was higher, the health system treatment coverage was lower, and with drugs that were more efficacious and had longer prophylactic periods. The impact on transmission intensity was negligible. A greater number of episodes will be averted in moderate or high transmission settings than in low transmission settings.

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