Risks of Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficient Infants Exposed to Chlorproguanil-Dapsone, Mefloquine and Sulfadoxine-Pyrimethamine as Part of Intermittent Presumptive Treatment of Malaria in Infants.

BACKGROUND: Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi) antimalarial regimens. We sought to examine the joint effects of G6PD status and IPTi antimalarial treatment on incidence of hemolysis in asymptomatic children treated with CD, sulfadoxine-pyrimethamine (SP), and mefloquine (MQ). METHODS: A secondary analysis of data from a double-blind, placebo-controlled trial of IPTi was conducted. Hemoglobin (Hb) measurements were made at IPTi doses, regular follow-up and emergency visits. G6PD genotype was determined at 9 months looking for SNPs for the A- genotype at coding position 202. Multivariable linear and logistic regression models were used to examine hemolysis among children with valid G6PD genotyping results. Hemolysis was defined as the absolute change in Hb or as any post-dose Hb <8 g/dL. These outcomes were assessed using either a single follow-up Hb on day 7 after an IPTi dose or Hb obtained 1 to 14 or 28 days after each IPTi dose. FINDINGS: Relative to placebo, CD reduced Hb by approximately 0.5 g/dL at day 7 and within 14 days of an IPTi dose, and by 0.2 g/dL within 28 days. Adjusted declines in the CD group were larger than in the MQ and SP groups. At day 7, homo-/hemizygous genotype was associated with higher odds of Hb <8 g/dL (adjusted odds ratio = 6.7, 95% CI 1.7 to 27.0) and greater absolute reductions in Hb (-0.6 g/dL, 95% CI -1.1 to 0.003). There was no evidence to suggest increased reductions in Hb among homo-/hemizygous children treated with CD compared to placebo, SP or MQ. CONCLUSIONS: While treatment with CD demonstrated greater reductions in Hb at 7 and 14 days after an IPTi dose compared to both SP and MQ, there was no evidence that G6PD deficiency exacerbated the adverse effects of CD, despite evidence for higher hemolysis risk among G6PDd infants.

A household randomized, controlled trial of the efficacy of 0.03% transfluthrin coils alone and in combination with long-lasting insecticidal nets on the incidence of Plasmodium falciparum and Plasmodium vivax malaria in Western Yunnan Province, China.

BACKGROUND: Mosquito coils are the most commonly used household insecticidal product in the world with sales exceeding 50 billion coils, used by two billion people worldwide annually. Despite strong evidence that coils prevent mosquito bites a systematic review concluded that there is no evidence that burning mosquito coils prevents malaria acquisition. Therefore, the current trial was designed to measure and compare prevention of malaria infection by mosquito coils or long-lasting insecticidal net (LLIN) or a combination of the two in Yunnan, China in the Greater Mekong sub-region. METHODS: A four-arm single blind household-randomized design was chosen as coils emanate insecticide throughout the household. Households enrolled at baseline were randomly allocated by the lottery method to one of the four intervention arms: (i) nothing, (ii) 0.03% transfluthrin coils alone, (iii) deltamethrin long-lasting insecticide treated nets, (LLINs) alone or (iv) a combination of transfluthrin coils and deltamethrin LLINs. All household members were recruited to the study, with only those households excluded with pregnant or breastfeeding mothers, members with chest complaints or allergies or members that regularly slept away from home. The main outcome of interest was Plasmodium falciparum malaria prevalence detected by rapid diagnostic tests (RDTs) during six repeated monthly cross-sectional surveys. The secondary outcome of interest was the effect on Plasmodium vivax prevalence detected in the same way. RESULTS: A total of 2,052 households were recruited into the study, comprising 7,341 individuals The odds ratios of testing positive by RDT with P. falciparum or P. vivax were >75% lower for all intervention arms compared with the control arm. Coils alone provided 77% protection (95% CI: 50%-89%), LLINs provided 91% protection (95% CI: 72%-97%) and the combination of coils and LLINs provided 94% protection (95% CI: 77%-99%) against P. falciparum compared with the control arm. There was no statistically significant difference between the protective efficacies of the different interventions. CONCLUSIONS: This is the first robust clinical evaluation of transfluthrin mosquito coils as a means to reduce malaria and the high degree of infection prevented would indicate they represent a potentially highly effective tool, which could be integrated into larger vector control programmes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00442442, March 2007.

Can topical insect repellents reduce malaria? A cluster-randomised controlled trial of the insect repellent N,N-diethyl-m-toluamide (DEET) in Lao PDR.

BACKGROUND: Mosquito vectors of malaria in Southeast Asia readily feed outdoors making malaria control through indoor insecticides such as long-lasting insecticidal nets (LLINs) and indoor residual spraying more difficult. Topical insect repellents may be able to protect users from outdoor biting, thereby providing additional protection above the current best practice of LLINs. METHODS AND FINDINGS: A double blind, household randomised, placebo-controlled trial of insect repellent to reduce malaria was carried out in southern Lao PDR to determine whether the use of repellent and long-lasting insecticidal nets (LLINs) could reduce malaria more than LLINs alone. A total of 1,597 households, including 7,979 participants, were recruited in June 2009 and April 2010. Equal group allocation, stratified by village, was used to randomise 795 households to a 15% DEET lotion and the remainder were given a placebo lotion. Participants, field staff and data analysts were blinded to the group assignment until data analysis had been completed. All households received new LLINs. Participants were asked to apply their lotion to exposed skin every evening and sleep under the LLINs each night. Plasmodium falciparum and P. vivax cases were actively identified by monthly rapid diagnostic tests. Intention to treat analysis found no effect from the use of repellent on malaria incidence (hazard ratio: 1.00, 95% CI: 0.99-1.01, p = 0.868). A higher socio-economic score was found to significantly decrease malaria risk (hazard ratio: 0.72, 95% CI: 0.58-0.90, p = 0.004). Women were also found to have a reduced risk of infection (hazard ratio: 0.59, 95% CI: 0.37-0.92, p = 0.020). According to protocol analysis which excluded participants using the lotions less than 90% of the time found similar results with no effect from the use of repellent. CONCLUSIONS: This randomised controlled trial suggests that topical repellents are not a suitable intervention in addition to LLINs against malaria amongst agricultural populations in southern Lao PDR. These results are also likely to be applicable to much of the Greater Mekong Sub-region. TRIAL REGISTRATION: This trial is registered with number NCT00938379.

Insecticide-treated plastic sheeting for emergency malaria prevention and shelter among displaced populations: an observational cohort study in a refugee setting in Sierra Leone.

A double-blind phase III malaria prevention trial was conducted in two refugee camps using pre-manufactured insecticide-treated plastic sheeting (ITPS) or untreated polyethylene sheeting (UPS) randomly deployed to defined sectors of each camp. In Largo camp the ITPS or UPS was attached to inner walls and ceilings of shelters, whereas in Tobanda the ITPS or UPS was used to line only the ceiling and roof. In Largo the Plasmodium falciparum incidence rate in children up to 3 years of age who were cleared of parasites and monitored for 8 months was 163/100 person-years under UPS and 63 under ITPS (adjusted odds ratio [AOR] = 0.40, 95% confidence interval [CI] = 0.33-0.47). In Tobanda incidence was 157/100 person-years under UPS and 134 under ITPS (AOR = 0.85, 95% CI = 0.75-0.95). Protective efficacy was 61% under fully lined ITPS and 15% under roof lined ITPS. Anemia rates improved under ITPS in both camps. This novel tool proved to be a convenient, safe, and long-lasting method of malaria control when used as a full shelter lining in an emergency setting.

IgG responses to Anopheles gambiae salivary antigen gSG6 detect variation in exposure to malaria vectors and disease risk.

Assessment of exposure to malaria vectors is important to our understanding of spatial and temporal variations in disease transmission and facilitates the targeting and evaluation of control efforts. Recently, an immunogenic Anopheles gambiae salivary protein (gSG6) was identified and proposed as the basis of an immuno-assay determining exposure to Afrotropical malaria vectors. In the present study, IgG responses to gSG6 and 6 malaria antigens (CSP, AMA-1, MSP-1, MSP-3, GLURP R1, and GLURP R2) were compared to Anopheles exposure and malaria incidence in a cohort of children from Korogwe district, Tanzania, an area of moderate and heterogeneous malaria transmission. Anti-gSG6 responses above the threshold for seropositivity were detected in 15% (96/636) of the children, and were positively associated with geographical variations in Anopheles exposure (OR 1.25, CI 1.01-1.54, p = 0.04). Additionally, IgG responses to gSG6 in individual children showed a strong positive association with household level mosquito exposure. IgG levels for all antigens except AMA-1 were associated with the frequency of malaria episodes following sampling. gSG6 seropositivity was strongly positively associated with subsequent malaria incidence (test for trend p = 0.004), comparable to malaria antigens MSP-1 and GLURP R2. Our results show that the gSG6 assay is sensitive to micro-epidemiological variations in exposure to Anopheles mosquitoes, and provides a correlate of malaria risk that is unrelated to immune protection. While the technique requires further evaluation in a range of malaria endemic settings, our findings suggest that the gSG6 assay may have a role in the evaluation and planning of targeted and preventative anti-malaria interventions.

Modelling the protective efficacy of alternative delivery schedules for intermittent preventive treatment of malaria in infants and children.

BACKGROUND: Intermittent preventive treatment in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is recommended by WHO where malaria incidence in infancy is high and SP resistance is low. The current delivery strategy is via routine Expanded Program on Immunisation contacts during infancy (EPI-IPTi). However, improvements to this approach may be possible where malaria transmission is seasonal, or where the malaria burden lies mainly outside infancy. METHODS AND FINDINGS: A mathematical model was developed to estimate the protective efficacy (PE) of IPT against clinical malaria in children aged 2-24 months, using entomological and epidemiological data from an EPI-IPTi trial in Navrongo, Ghana to parameterise the model. The protection achieved by seasonally-targeted IPT in infants (sIPTi), seasonal IPT in children (sIPTc), and by case-management with long-acting artemisinin combination therapies (LA-ACTs) was predicted for Navrongo and for sites with different transmission intensity and seasonality. In Navrongo, the predicted PE of sIPTi was 26% by 24 months of age, compared to 16% with EPI-IPTi. sIPTc given to all children under 2 years would provide PE of 52% by 24 months of age. Seasonally-targeted IPT retained its advantages in a range of transmission patterns. Under certain circumstances, LA-ACTs for case-management may provide similar protection to EPI-IPTi. However, EPI-IPTi or sIPT combined with LA-ACTs would be substantially more protective than either strategy used alone. CONCLUSION: Delivery of IPT to infants via the EPI is sub-optimal because individuals are not protected by IPT at the time of highest malaria risk, and because older children are not protected. Alternative delivery strategies to the EPI are needed where transmission varies seasonally or the malaria burden extends beyond infancy. Long-acting ACTs may also make important reductions in malaria incidence. However, delivery systems must be developed to ensure that both forms of chemoprevention reach the individuals who are most exposed to malaria.

Intermittent preventive treatment for malaria in infants: a decision-support tool for sub-Saharan Africa.

OBJECTIVE: To develop a decision-support tool to help policy-makers in sub-Saharan Africa assess whether intermittent preventive treatment in infants (IPTi) would be effective for local malaria control. METHODS: An algorithm for predicting the effect of IPTi was developed using two approaches. First, study data on the age patterns of clinical cases of Plasmodium falciparum malaria, hospital admissions for infection with malaria parasites and malaria-associated death for different levels of malaria transmission intensity and seasonality were used to estimate the percentage of cases of these outcomes that would occur in children aged <10 years targeted by IPTi. Second, a previously developed stochastic mathematical model of IPTi was used to predict the number of cases likely to be averted by implementing IPTi under different epidemiological conditions. The decision-support tool uses the data from these two approaches that are most relevant to the context specified by the user. FINDINGS: Findings from the two approaches indicated that the percentage of cases targeted by IPTi increases with the severity of the malaria outcome and with transmission intensity. The decision-support tool, available on the Internet, provides estimates of the percentage of malaria-associated deaths, hospitalizations and clinical cases that will be targeted by IPTi in a specified context and of the number of these outcomes that could be averted. CONCLUSION: The effectiveness of IPTi varies with malaria transmission intensity and seasonality. Deciding where to implement IPTi must take into account the local epidemiology of malaria. The Internet-based decision-support tool described here predicts the likely effectiveness of IPTi under a wide range of epidemiological conditions.

The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings.

BACKGROUND: A greater understanding of the relationship between transmission intensity, seasonality and the age-pattern of malaria is needed to guide appropriate targeting of malaria interventions in different epidemiological settings. METHODS: A systematic literature review identified studies which reported the age of paediatric hospital admissions with cerebral malaria (CM), severe malarial anaemia (SMA), or respiratory distress (RD). Study sites were categorized into a 3 × 2 matrix of Plasmodium falciparum transmission intensity and seasonality. Probability distributions were fitted by maximum likelihood methods, and best fitting models were used to estimate median ages and to represent graphically the age-pattern of each outcome for each transmission category in the matrix. RESULTS: A shift in the burden of CM towards younger age groups was seen with increasing intensity of transmission, but this was not the case for SMA or RD. Sites with 'no marked seasonality' showed more evidence of skewed age-patterns compared to areas of 'marked seasonality' for all three severe malaria syndromes. CONCLUSIONS: Although the peak age of CM will increase as transmission intensity decreases in Africa, more than 75% of all paediatric hospital admissions of severe malaria are likely to remain in under five year olds in most epidemiological settings.

Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi) using sulfadoxine-pyrimethamine and parasite resistance.

BACKGROUND: Intermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi) is recommended by WHO for implementation in settings where resistance to SP is not high. Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance. METHODS AND RESULTS: We analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50 km of the trial sites. We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi. This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times. However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively. CONCLUSIONS: A significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose. An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias. It was not possible to define a more definite relationship based on the data available from these trials.

Identification of hot spots of malaria transmission for targeted malaria control.

BACKGROUND: Variation in the risk of malaria within populations is a frequently described but poorly understood phenomenon. This heterogeneity creates opportunities for targeted interventions but only if hot spots of malaria transmission can be easily identified. METHODS: We determined spatial patterns in malaria transmission in a district in northeastern Tanzania, using malaria incidence data from a cohort study involving infants and household-level mosquito sampling data. The parasite prevalence rates and age-specific seroconversion rates (SCRs) of antibodies against Plasmodium falciparum antigens were determined in samples obtained from people attending health care facilities. RESULTS: Five clusters of higher malaria incidence were detected and interpreted as hot spots of transmission. These hot spots partially overlapped with clusters of higher mosquito exposure but could not be satisfactorily predicted by a probability model based on environmental factors. Small-scale local variation in malaria exposure was detected by parasite prevalence rates and SCR estimates for samples of health care facility attendees. SCR estimates were strongly associated with local malaria incidence rates and predicted hot spots of malaria transmission with 95% sensitivity and 85% specificity. CONCLUSIONS: Serological markers were able to detect spatial variation in malaria transmission at the microepidemiological level, and they have the potential to form an effective method for spatial targeting of malaria control efforts.

Duration of protection against clinical malaria provided by three regimens of intermittent preventive treatment in Tanzanian infants.

BACKGROUND: Intermittent preventive treatment in infants (IPTi) is a new malaria control tool. However, it is uncertain whether IPTi works mainly through chemoprophylaxis or treatment of existing infections. Understanding the mechanism is essential for development of replacements for sulfadoxine-pyrimethamine (SP) where it is no longer effective. This study investigated how protection against malaria given by SP, chlorproguanil-dapsone (CD) and mefloquine (MQ), varied with time since administration of IPTi. METHODS AND FINDINGS: A secondary analysis of data from a randomised, placebo-controlled trial in an area of high antifolate resistance in Tanzania was conducted. IPTi using SP, CD, MQ or placebo was given to 1280 infants at 2, 3 and 9 months of age. Poisson regression with random effects to adjust for potential clustering of malaria episodes within children was used to calculate incidence rate ratios for clinical malaria in defined time strata following IPTi. The short-acting antimalarial CD gave no protection against clinical malaria, whereas long-acting MQ gave two months of substantial protection (protective efficacy (PE) 73.1% (95% CI: 23.9, 90.5) and 73.3% (95% CI: 0, 92.9) in the first and second month respectively). SP gave some protection in the first month after treatment (PE 64.5% (95% CI: 10.6, 85.9)) although it did not reduce the incidence of malaria up to 12 months of age. There was no evidence of either long-term protection or increased risk of malaria for any of the regimens. CONCLUSION: Post-treatment chemoprophylaxis appears to be the main mechanism by which IPTi protects children against malaria. Long-acting antimalarials are therefore likely to be the most effective drugs for IPTi, but as monotherapies could be vulnerable to development of drug resistance. Due to concerns about tolerability, the mefloquine formulation used in this study is not suitable for IPTi. Further investigation of combinations of long-acting antimalarials for IPTi is needed. TRIAL REGISTRATION: Clinicaltrials.gov NCT00158574.

Age-patterns of malaria vary with severity, transmission intensity and seasonality in sub-Saharan Africa: a systematic review and pooled analysis.

BACKGROUND: There is evidence that the age-pattern of Plasmodium falciparum malaria varies with transmission intensity. A better understanding of how this varies with the severity of outcome and across a range of transmission settings could enable locally appropriate targeting of interventions to those most at risk. We have, therefore, undertaken a pooled analysis of existing data from multiple sites to enable a comprehensive overview of the age-patterns of malaria outcomes under different epidemiological conditions in sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review using PubMed and CAB Abstracts (1980-2005), contacts with experts and searching bibliographies identified epidemiological studies with data on the age distribution of children with P. falciparum clinical malaria, hospital admissions with malaria and malaria-diagnosed mortality. Studies were allocated to a 3x2 matrix of intensity and seasonality of malaria transmission. Maximum likelihood methods were used to fit five continuous probability distributions to the percentage of each outcome by age for each of the six transmission scenarios. The best-fitting distributions are presented graphically, together with the estimated median age for each outcome. Clinical malaria incidence was relatively evenly distributed across the first 10 years of life for all transmission scenarios. Hospital admissions with malaria were more concentrated in younger children, with this effect being even more pronounced for malaria-diagnosed deaths. For all outcomes, the burden of malaria shifted towards younger ages with increasing transmission intensity, although marked seasonality moderated this effect. CONCLUSIONS: The most severe consequences of P. falciparum malaria were concentrated in the youngest age groups across all settings. Despite recently observed declines in malaria transmission in several countries, which will shift the burden of malaria cases towards older children, it is still appropriate to target strategies for preventing malaria mortality and severe morbidity at very young children who will continue to bear the brunt of malaria deaths in sub-Saharan Africa.

A simple method for defining malaria seasonality.

BACKGROUND: There is currently no standard way of defining malaria seasonality, resulting in a wide range of definitions reported in the literature. Malaria cases show seasonal peaks in most endemic settings, and the choice and timing for optimal malaria control may vary by seasonality. A simple approach is presented to describe the seasonality of malaria, to aid localized policymaking and targeting of interventions. METHODS: A series of systematic literature reviews were undertaken to identify studies reporting on monthly data for full calendar years on clinical malaria, hospital admission with malaria and entomological inoculation rates (EIR). Sites were defined as having 'marked seasonality' if 75% or more of all episodes occurred in six or less months of the year. A 'concentrated period of malaria' was defined as the six consecutive months with the highest cumulative proportion of cases. A sensitivity analysis was performed based on a variety of cut-offs. RESULTS: Monthly data for full calendar years on clinical malaria, all hospital admissions with malaria, and entomological inoculation rates were available for 13, 18, and 11 sites respectively. Most sites showed year-round transmission with seasonal peaks for both clinical malaria and hospital admissions with malaria, with a few sites fitting the definition of 'marked seasonality'. For these sites, consistent results were observed when more than one outcome or more than one calendar year was available from the same site. The use of monthly EIR data was found to be of limited value when looking at seasonal variations of malaria transmission, particularly at low and medium intensity levels. CONCLUSION: The proposed definition discriminated well between studies with 'marked seasonality' and those with less seasonality. However, a poor fit was observed in sites with two seasonal peaks. Further work is needed to explore the applicability of this definition on a wide-scale, using routine health information system data where possible, to aid appropriate targeting of interventions.

Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Administration of sulfadoxine-pyrimethamine at times of vaccination-intermittent preventive treatment in infants (IPTi)-is a promising strategy to prevent malaria. However, rising resistance to this combination is a concern. We investigated a shortacting and longacting antimalarial drug as alternative regimens for IPTi. METHODS: We undertook a double-blind, placebo-controlled trial of IPTi in an area of high resistance to sulfadoxine-pyrimethamine at sites of moderate (n=1280 infants enrolled) and low (n=1139) intensity of malaria transmission in Tanzania. Infants aged 8-16 weeks were randomly assigned in blocks of 16 to sulfadoxine (250 mg) plus pyrimethamine (12.5 mg; n=319 in moderate-transmission and 283 in low-transmission sites), chlorproguanil (15 mg) plus dapsone (18.75 mg; n=317 and 285), mefloquine (125 mg; n=320 and 284), or placebo (n=320 and 284), given at the second and third immunisations for diphtheria, pertussis, and tetanus, and for measles. Research team and child were masked to treatment. Recruitment was stopped early at the low-transmission site because of low malaria incidence. The primary endpoint was protective efficacy against all episodes of clinical malaria at 2-11 months of age. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00158574. FINDINGS: All randomly assigned infants were analysed. At the moderate-transmission site, mefloquine had a protective efficacy of 38.1% (95% CI 11.8-56.5, p=0.008) against clinical malaria in infants aged 2-11 months, but neither sulfadoxine-pyrimethamine (-6.7%, -45.9 to 22.0) nor chlorproguanil-dapsone (10.8%, -24.6 to 36.1) had a protective effect. No regimen had any protective efficacy against anaemia or hospital admission. Mefloquine caused vomiting in 141 of 1731 (8%) doses given on day 1 (odds ratio vs placebo 5.50, 95% CI 3.56-8.46). More infants died in the chlorproguanil-dapsone and mefloquine groups (18 and 15, respectively) than in the sulfadoxine-pyrimethamine or placebo groups (eight deaths per group; p=0.05 for difference between chlorproguanil-dapsone and placebo). INTERPRETATION: IPTi with a longacting, efficacious drug such as mefloquine can reduce episodes of malaria in infants in a moderate-transmission setting. IPTi with sulfadoxine-pyrimethamine has no benefit in areas of very high resistance to this combination. The appropriateness of IPTi should be measured by the expected incidence of malaria and the efficacy, tolerability, and safety of the drug. FUNDING: IPTi Consortium and the Gates Malaria Partnership.

Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials.

BACKGROUND: Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS: We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHO's Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS: The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION: IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING: Bill & Melinda Gates Foundation.

Setting priorities in global child health research investments: guidelines for implementation of CHNRI method.

This article provides detailed guidelines for the implementation of systematic method for setting priorities in health research investments that was recently developed by Child Health and Nutrition Research Initiative (CHNRI). The target audience for the proposed method are international agencies, large research funding donors, and national governments and policy-makers. The process has the following steps: (i) selecting the managers of the process; (ii) specifying the context and risk management preferences; (iii) discussing criteria for setting health research priorities; (iv) choosing a limited set of the most useful and important criteria; (v) developing means to assess the likelihood that proposed health research options will satisfy the selected criteria; (vi) systematic listing of a large number of proposed health research options; (vii) pre-scoring check of all competing health research options; (viii) scoring of health research options using the chosen set of criteria; (ix) calculating intermediate scores for each health research option; (x) obtaining further input from the stakeholders; (xi) adjusting intermediate scores taking into account the values of stakeholders; (xii) calculating overall priority scores and assigning ranks; (xiii) performing an analysis of agreement between the scorers; (xiv) linking computed research priority scores with investment decisions; (xv) feedback and revision. The CHNRI method is a flexible process that enables prioritizing health research investments at any level: institutional, regional, national, international, or global.

Modelling the epidemiological impact of intermittent preventive treatment against malaria in infants.

BACKGROUND: Trials of intermittent preventive treatment against malaria in infants (IPTi) using sulphadoxine-pyrimethamine (SP) have shown a positive, albeit variable, protective efficacy against clinical malaria episodes. The impact of IPTi in different epidemiological settings and over time is unknown and predictions are hampered by the lack of knowledge about how IPTi works. We investigated mechanisms proposed for the action of IPTi and made predictions of the likely impact on morbidity and mortality. METHODS/PRINCIPAL FINDINGS: We used a comprehensive, individual-based, stochastic model of malaria epidemiology to simulate recently published trials of IPTi using SP with site-specific characteristics as inputs. This baseline model was then modified to represent hypotheses concerning the duration of action of SP, the temporal pattern of fevers caused by individual infections, potential benefits of avoiding fevers on immunity and the effect of sub-therapeutic levels of SP on parasite dynamics. The baseline model reproduced the pattern of results reasonably well. None of the models based on alternative hypotheses improved the fit between the model predictions and observed data. Predictions suggest that IPTi would have a beneficial effect across a range of transmission intensities. IPTi was predicted to avert a greater number of episodes where IPTi coverage was higher, the health system treatment coverage lower, and for drugs which were more efficacious and had longer prophylactic periods. The predicted cumulative benefits were proportionately slightly greater for severe malaria episodes and malaria-attributable mortality than for acute episodes in the settings modelled. Modest increased susceptibility was predicted between doses and following the last dose, but these were outweighed by the cumulative benefits. The impact on transmission intensity was negligible. CONCLUSIONS: The pattern of trial results can be accounted for by differences between the trial sites together with known features of malaria epidemiology and the action of SP. Predictions suggest that IPTi would have a beneficial impact across a variety of epidemiological settings.

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

BACKGROUND: Intermittent preventive treatment for malaria in Infants (IPTi) has been shown to give effective and safe protection against malaria. It has been suggested that IPTi might have long-lasting beneficial effects but, in most settings, the protection provided by IPTi appears to be short-lived. Knowledge of the duration of protection given by IPTi would help interpret the results of existing trials and suggest optimal delivery schedules for IPTi. This study investigated how the protective efficacy of IPTi against malaria and anaemia changes over time. METHODS AND FINDINGS: A secondary analysis of data from a cluster-randomised, placebo-controlled trial of IPTi using sulfadoxine-pyrimethamine (SP) in Ghana was conducted. In this trial IPTi was given to 2485 infants at 3, 4, 9 and 12 months of age; children remained in follow-up until two years of age. Poisson regression with a random effect to adjust for the cluster-randomised design was used to determine protective efficacy of IPTi against clinical malaria and anaemia in defined time strata following administration of IPTi. Analysis of first-or-only clinical malaria episode following the individual IPTi doses showed that some protection against malaria lasted between 4 to 6 weeks. A similar pattern was seen when the incidence of all malaria episodes up to 2 years of age was analysed in relation to the most recent IPT, by pooling the incidence of malaria after the individual IPTi doses. Protective efficacy within four weeks of IPTi was 75.2% (95% CI: 66-82) against malaria, 78.9% (95% CI: 69-86) against high parasite density malaria, and 93.8% (95% CI: 73-99) against anaemia. Protection against these outcomes was short-lived, with evidence of any effect lasting for only 6, 6 and 4 weeks respectively. Protection in children who were parasitaemic when receiving IPTi appeared to be of shorter duration than in uninfected children. There was no evidence of any benefit of IPTi after the immediate period following the IPTi doses. CONCLUSIONS: Intermittent preventive treatment provides considerable protection against malaria and anaemia for short periods, even in an area of intense seasonal transmission. Due to the relatively short duration of protection provided by each dose of IPTi, this treatment will be of most benefit when delivered at the time of peak malaria incidence.