Determinants of the cost-effectiveness of intermittent preventive treatment for malaria in infants and children

Background

Trials of intermittent preventive treatment in infants (IPTi) and children (IPTc) have shown promising results in reducing malaria episodes but with varying efficacy and cost-effectiveness. The effects of different intervention and setting characteristics are not well known. We simulate the effects of the different target age groups and delivery channels, seasonal or year-round delivery, transmission intensity, seasonality, proportions of malaria fevers treated and drug characteristics.

Methods

We use a dynamic, individual-based simulation model of Plasmodium falciparum malaria epidemiology, antimalarial drug action and case management to simulate DALYs averted and the cost per DALY averted by IPTi and IPTc. IPT cost components were estimated from economic studies alongside trials.

Results

IPTi and IPTc were predicted to be cost-effective in most of the scenarios modelled. The cost-effectiveness is driven by the impact on DALYs, particularly for IPTc, and the low costs, particularly for IPTi which uses the existing delivery strategy, EPI. Cost-effectiveness was predicted to decrease with low transmission, badly timed seasonal delivery in a seasonal setting, short-acting and more expensive drugs, high frequencies of drug resistance and high levels of treatment of malaria fevers. Seasonal delivery was more cost-effective in seasonal settings, and year-round in constant transmission settings. The difference was more pronounced for IPTc than IPTi due to the different proportions of fixed costs and also different assumed drug spacing during the transmission season. The number of DALYs averted was predicted to decrease as a target five-year age-band for IPTc was shifted from children under 5 years into older ages, except at low transmission intensities.

Conclusions

Modelling can extend the information available by predicting impact and cost-effectiveness for scenarios, for outcomes and for multiple strategies where, for practical reasons, trials cannot be carried out. Both IPTi and IPTc are generally cost-effective but could be rendered cost-ineffective by characteristics of the setting, drug or implementation.     

The Cost-Effectiveness of Intermittent Preventive Treatment for Malaria in Infants in Sub-Saharan Africa

Background

Intermittent preventive treatment in infants (IPTi) has been shown to decrease clinical malaria by approximately 30% in the first year of life and is a promising malaria control strategy for Sub-Saharan Africa which can be delivered alongside the Expanded Programme on Immunisation (EPI). To date, there have been limited data on the cost-effectiveness of this strategy using sulfadoxine pyrimethamine (SP) and no published data on cost-effectiveness using other antimalarials.

Methods

We analysed data from 5 countries in sub-Saharan Africa using a total of 5 different IPTi drug regimens; SP, mefloquine (MQ), 3 days of chlorproguanil-dapsone (CD), SP plus 3 days of artesunate (SP-AS3) and 3 days of amodiaquine-artesunate (AQ3-AS3).The cost per malaria episode averted and cost per Disability-Adjusted Life-Year (DALY) averted were modeled using both trial specific protective efficacy (PE) for all IPTi drugs and a pooled PE for IPTi with SP, malaria incidence, an estimated malaria case fatality rate of 1.57%, IPTi delivery costs and country specific provider and household malaria treatment costs.

Findings

In sites where IPTi had a significant effect on reducing malaria, the cost per episode averted for IPTi-SP was very low, USD 1.36–4.03 based on trial specific data and USD 0.68–2.27 based on the pooled analysis. For IPTi using alternative antimalarials, the lowest cost per case averted was for AQ3-AS3 in western Kenya (USD 4.62) and the highest was for MQ in Korowge, Tanzania (USD 18.56). Where efficacious, based only on intervention costs, IPTi was shown to be cost effective in all the sites and highly cost-effective in all but one of the sites, ranging from USD 2.90 (Ifakara, Tanzania with SP) to USD 39.63 (Korogwe, Tanzania with MQ) per DALY averted. In addition, IPTi reduced health system costs and showed significant savings to households from malaria cases averted. A threshold analysis showed that there is room for the IPTi-efficacy to fall and still remain highly cost effective in all sites where IPTi had a statistically significant effect on clinical malaria.

Conclusions

IPTi delivered alongside the EPI is a highly cost effective intervention against clinical malaria with a range of drugs in a range of malaria transmission settings. Where IPTi did not have a statistically significant impact on malaria, generally in low transmission sites, it was not cost effective.     

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 {"type":"clinical-trial","attrs":{"text":"NCT00158574","term_id":"NCT00158574"}}NCT00158574     

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.     

The Impact of IPTi and IPTc Interventions on Malaria Clinical Burden – In Silico Perspectives

Background

Clinical management of malaria is a major health issue in sub-Saharan Africa. New strategies based on intermittent preventive treatment (IPT) can tackle disease burden by simultaneously reducing frequency of infections and life-threatening illness in infants (IPTi) and children (IPTc), while allowing for immunity to build up. However, concerns as to whether immunity develops efficiently in treated individuals, and whether there is a rebound effect after treatment is halted, have made it imperative to define the effects that IPTi and IPTc exert on the clinical malaria scenario.

Methods and Findings

Here, we simulate several schemes of intervention under different transmission settings, while varying immunity build up assumptions. Our model predicts that infection risk and effectiveness of acquisition of clinical immunity under prophylactic effect are associated to intervention impact during treatment and follow-up periods. These effects vary across regions of different endemicity and are highly correlated with the interplay between the timing of interventions in age and the age dependent risk of acquiring an infection. However, even when significant rebound effects are predicted to occur, the overall intervention impact is positive.

Conclusions

IPTi is predicted to have minimal impact on the acquisition of clinical immunity, since it does not interfere with the occurrence of mild infections, thus failing to reduce the underlying force of infection. On the contrary, IPTc has a significant potential to reduce transmission, specifically in areas where it is already low to moderate.     

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.     

Defining Disease Heterogeneity to Guide the Empirical Treatment of Febrile Illness in Resource Poor Settings

Background

Malaria incidence is in decline in many parts of SE Asia leading to a decreasing proportion of febrile illness that is attributable to malaria. However in the absence of rapid, affordable and accurate diagnostic tests, the non-malaria causes of these illnesses cannot be reliably identified. Studies on the aetiology of febrile illness have indicated that the causes are likely to vary by geographical location within countries (i.e. be spatially heterogeneous) and that national empirical treatment policies based on the aetiology measured in a single location could lead to inappropriate treatment.

Methods

Using data from Vientiane as a reference for the incidence of major febrile illnesses in the Lao People''s Democratic Republic (Laos) and estimated incidences, plausible incidence in other Lao provinces were generated using a mathematical model for a range of national and local scale variations. For a range of treatment protocols, the mean number of appropriate treatments was predicted and the potential impact of a spatially explicit national empirical treatment protocol assessed.

Findings

The model predicted a negative correlation between number of appropriate treatments and the level of spatial heterogeneity. A spatially explicit national treatment protocol was predicted to increase the number of appropriate treatments by 50% for intermediate levels of spatial heterogeneity.

Conclusions

The results suggest that given even only moderate spatial variation, a spatially explicit treatment algorithm will result in a significant improvement in the outcome of undifferentiated fevers in Laos and other similar resource poor settings.     

Rural-urban differences in maternal responses to childhood fever in South East Nigeria

Background

Childhood fevers due to malaria remain a major cause of morbidity and mortality among under-five children in Nigeria. The degree of vulnerability perceived by mothers will affect their perception of the severity and threat of their child''s fever and the patterns of health care use. This study was undertaken to compare maternal responses to childhood fever in urban and rural areas of Enugu, south east Nigeria.

Methodology/Principal Findings

Data was collected with pre-tested interviewer-administered questionnaires from 276 and 124 urban and rural households respectively. In each household, only one woman aged 15–49 years who had lived in each of the urban and rural communities for at least one year and had at least one child less than 5 years old was interviewed. Malaria was mentioned as the commonest cause of childhood fevers. Rural mothers were more likely to recognize danger signs and symptoms than urban mothers. Rural mothers use more of informal than formal health services, and there is more home management of the fever with urban than rural mothers. Chloroquine, ACT, SP and Paracetamol are the main drugs given at home for childhood fevers, but the rural mothers were more likely to use leftover drugs from previous treatment to treat the fevers than urban mothers. The urban respondents were also more likely to use a preventive measure. Urban mothers sought actions faster than rural mothers and the total cost of treatment was also higher in urban areas.

Conclusions/Significance

Both urban and rural mothers are aware that malaria is the major cause of childhood fevers. Although rural mothers recognize childhood fever and danger signs better than urban mothers, the urban mothers'' responses to fever seem to be better than that for rural mothers. These responses and differences may be important for geographical targeting by policy makers for malaria interventions.     

Prevention of the Recurrence of Anaemia in Gambian Children Following Discharge from Hospital

Background

In malaria endemic countries, children who have experienced an episode of severe anaemia are at increased risk of a recurrence of anaemia. There is a need to find ways of protecting these at risk children from malaria and chemoprevention offers a potential way of achieving this objective.

Methods

During the 2003 and 2004 malaria transmission seasons, 1200 Gambian children with moderate or severe anaemia (Hb concentration <7 g/dL) were randomised to receive either monthly sulfadoxine-pyrimethamine (SP) or placebo until the end of the malaria transmission season in which they were enrolled, in a double-blind trial. All study subjects were treated with oral iron for 28 days and morbidity was monitored through surveillance at health centres. The primary endpoint was the proportion of children with moderate or severe anaemia at the end of the transmission season. Secondary endpoints included the incidence of clinical episodes of malaria during the surveillance period, outpatient attendances, the prevalence of parasitaemia and splenomegaly, nutritional status at the end of the malaria transmission season and compliance with the treatment regimen.

Results

The proportions of children with a Hb concentration of <7 g/dL at the end of the malaria transmission season were similar in the two study groups, 14/464 (3.0%) in children who received at least one dose of SP and 16/471 (3.4%) in those who received placebo, prevalence ratio 0.89 (0.44,1.8) P = 0.742. The protective efficacy of SP against episodes of clinical malaria was 53% (95% CI 37%, 65%). Treatment with SP was safe and well tolerated; no serious adverse events related to SP administration were observed. Mortality following discharge from hospital was low among children who received SP or placebo (6 in the SP group and 9 in the placebo group respectively).

Conclusions

Intermittent treatment with SP did not reduce the proportion of previously anaemic children with moderate or severe anaemia at the end of the malaria season, although it prevented malaria. The combination of appropriate antimalarial treatment plus one month of iron supplementation and good access to healthcare during follow-up proved effective in restoring haemoglobin to an acceptable level in the Gambian setting.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00131716","term_id":"NCT00131716"}}NCT00131716     

The effect of monthly sulfadoxine-pyrimethamine, alone or with azithromycin, on PCR-diagnosed malaria at delivery: a randomized controlled trial

Background

New regimens for intermittent preventive treatment in pregnancy (IPTp) against malaria are needed as the effectiveness of the standard two-dose sulfadoxine-pyrimethamine (SP) regimen is under threat. Previous trials have shown that IPTp with monthly SP benefits HIV-positive primi- and secundigravidae, but there is no conclusive evidence of the possible benefits of this regimen to HIV-negative women, or to a population comprising of both HIV-positive and –negative women of different gravidities.

Methods

This study analyzed 484 samples collected at delivery as part of a randomized, partially placebo controlled clinical trial, conducted in rural Malawi between 2003 and 2007. The study included pregnant women regardless of their gravidity or HIV-infection status. The participants received SP twice (controls), monthly SP, or monthly SP and two doses of azithromycin (AZI-SP). The main outcome was the prevalence of peripheral Plasmodium falciparum malaria at delivery diagnosed with a real-time polymerase chain reaction (PCR) assay.

Findings

Overall prevalence of PCR-diagnosed peripheral P. falciparum malaria at delivery was 10.5%. Compared with the controls, participants in the monthly SP group had a risk ratio (95% CI) of 0.33 (0.17 to 0.64, P<0.001) and those in the AZI-SP group 0.23 (0.11 to 0.48, P<0.001) for malaria at delivery. When only HIV-negative participants were analyzed, the corresponding figures were 0.26 (0.12 to 0.57, P<0.001) for women in the monthly SP group, and 0.24 (0.11 to 0.53, P<0.001) for those in the AZI-SP group.

Conclusions

Our results suggest that increasing the frequency of SP administration during pregnancy improves the efficacy against malaria at delivery among HIV-negative women, as well as a population consisting of both HIV-positive and –negative pregnant women of all gravidities, in a setting of relatively low but holoendemic malaria transmission, frequent use of bed nets and high SP resistance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00131235","term_id":"NCT00131235"}}NCT00131235     

Incidence of Malaria and Efficacy of Combination Antimalarial Therapies over 4 Years in an Urban Cohort of Ugandan Children

Background

Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda.

Methodology/Principal Findings

Children aged 1–10 years were enrolled from randomly selected households in 2004–05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen.

Conclusions/Significance

With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time.

Trial Registration

isrctn.org ISRCTN37517549     

Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial

Background

Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).

Methods and Findings

In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10–43, p≤0.001) in children receiving SP-AQ and 12% (95% CI, −11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9–54, p = 0.012) and Pv incidence was 23% (95% CI, 0–41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4–51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, −24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p>0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%–2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.

Conclusions

IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00285662","term_id":"NCT00285662"}}NCT00285662 Please see later in the article for the Editors'' Summary     

Effect of Bednets and Indoor Residual Spraying on Spatio-Temporal Clustering of Malaria in a Village in South Ethiopia: A Longitudinal Study

Background

Understanding the spatio-temporal pattern of malaria transmission where prevention and control measures are in place will help to fine-tune strategies. The objective of this study was to assess the effect of mass distribution of bednets and indoor residual spraying (IRS) with insecticides on the spatio-temporal clustering of malaria in one malaria endemic village in south Ethiopia.

Methods

A longitudinal study was conducted from April 2009 to April 2011. The average population was 6631 in 1346 locations. We used active and passive searches for malaria cases for 101 weeks. SatScan v9.1.1 was used to identify statistically significant retrospective space–time clusters. A discrete Poisson based model was applied with the aim of identifying areas with high rates. PASW Statistics 18 was used to build generalized Poisson loglinear model.

Results

The total number of both types of malaria episodes was 622, giving 45.1 episodes per 1000 persons per year; among these, episodes of Plasmodium falciparum and vivax infection numbered 316 (22.9 per 1000 per year) and 306 (22.2 per 1000 per year), respectively. IRS with Dichlorodiphenyltrichloroethane (DDT) and later with Deltamethrin and free mass distribution of insecticide-treated nets (ITNs) were carried out during the study period. There was space–time clustering of malaria episodes at a household level. The spatio-temporal clustering of malaria was not influenced by free mass distribution of ITNs; however, the time-span of the spatio-temporal clustering of malaria cases ended after IRS with Deltamethrin. The presence of clusters on the south-east edge of the village was consistent with the finding of an increasing risk of acquiring malaria infection for individuals who lived closer to the identified vector breeding site.

Conclusion

The risk of getting malaria infection varied significantly within one village. Free mass distribution of ITNs did not influence the spatio-temporal clustering of malaria, but IRS might have eliminated malaria clustering.     

Diagnostic Testing of Pediatric Fevers: Meta-Analysis of 13 National Surveys Assessing Influences of Malaria Endemicity and Source of Care on Test Uptake for Febrile Children under Five Years

Background

In 2010, the World Health Organization revised guidelines to recommend diagnosis of all suspected malaria cases prior to treatment. There has been no systematic assessment of malaria test uptake for pediatric fevers at the population level as countries start implementing guidelines. We examined test use for pediatric fevers in relation to malaria endemicity and treatment-seeking behavior in multiple sub-Saharan African countries in initial years of implementation.

Methods and Findings

We compiled data from national population-based surveys reporting fever prevalence, care-seeking and diagnostic use for children under five years in 13 sub-Saharan African countries in 2009–2011/12 (n = 105,791). Mixed-effects logistic regression models quantified the influence of source of care and malaria endemicity on test use after adjusting for socioeconomic covariates. Results were stratified by malaria endemicity categories: low (PfPR_2–10<5%), moderate (PfPR_2–10 5–40%), high (PfPR_2–10>40%). Among febrile under-fives surveyed, 16.9% (95% CI: 11.8%–21.9%) were tested. Compared to hospitals, febrile children attending non-hospital sources (OR: 0.62, 95% CI: 0.56–0.69) and community health workers (OR: 0.31, 95% CI: 0.23–0.43) were less often tested. Febrile children in high-risk areas had reduced odds of testing compared to low-risk settings (OR: 0.51, 95% CI: 0.42–0.62). Febrile children in least poor households were more often tested than in poorest (OR: 1.63, 95% CI: 1.39–1.91), as were children with better-educated mothers compared to least educated (OR: 1.33, 95% CI: 1.16–1.54).

Conclusions

Diagnostic testing of pediatric fevers was low and inequitable at the outset of new guidelines. Greater testing is needed at lower or less formal sources where pediatric fevers are commonly managed, particularly to reach the poorest. Lower test uptake in high-risk settings merits further investigation given potential implications for diagnostic scale-up in these areas. Findings could inform continued implementation of new guidelines to improve access to and equity in point-of-care diagnostics use for pediatric fevers.     

Estimating the Number of Paediatric Fevers Associated with Malaria Infection Presenting to Africa's Public Health Sector in 2007

Background

As international efforts to increase the coverage of artemisinin-based combination therapy in public health sectors gather pace, concerns have been raised regarding their continued indiscriminate presumptive use for treating all childhood fevers. The availability of rapid-diagnostic tests to support practical and reliable parasitological diagnosis provides an opportunity to improve the rational treatment of febrile children across Africa. However, the cost effectiveness of diagnosis-based treatment polices will depend on the presumed numbers of fevers harbouring infection. Here we compute the number of fevers likely to present to public health facilities in Africa and the estimated number of these fevers likely to be infected with Plasmodium falciparum malaria parasites.

Methods and Findings

We assembled first administrative-unit level data on paediatric fever prevalence, treatment-seeking rates, and child populations. These data were combined in a geographical information system model that also incorporated an adjustment procedure for urban versus rural areas to produce spatially distributed estimates of fever burden amongst African children and the subset likely to present to public sector clinics. A second data assembly was used to estimate plausible ranges for the proportion of paediatric fevers seen at clinics positive for P. falciparum in different endemicity settings. We estimated that, of the 656 million fevers in African 0–4 y olds in 2007, 182 million (28%) were likely to have sought treatment in a public sector clinic of which 78 million (43%) were likely to have been infected with P. falciparum (range 60–103 million).

Conclusions

Spatial estimates of childhood fevers and care-seeking rates can be combined with a relational risk model of infection prevalence in the community to estimate the degree of parasitemia in those fevers reaching public health facilities. This quantification provides an important baseline comparison of malarial and nonmalarial fevers in different endemicity settings that can contribute to ongoing scientific and policy debates about optimum clinical and financial strategies for the introduction of new diagnostics. These models are made publicly available with the publication of this paper. Please see later in the article for the Editors'' Summary     

Malaria morbidity in children in the year after they had received intermittent preventive treatment of malaria in Mali: a randomized control trial

Background

Intermittent preventive treatment of malaria in children (IPTc) is a promising strategy for malaria control. A study conducted in Mali in 2008 showed that administration of three courses of IPTc with sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) at monthly intervals reduced clinical malaria, severe malaria and malaria infection by >80% in children under 5 years of age. Here we report the results of a follow-on study undertaken to establish whether children who had received IPTc would be at increased risk of malaria during the subsequent malaria transmission season.

Methods

Morbidity from malaria and the prevalence of malaria parasitaemia and anaemia were measured in children who had previously received IPTc with SP and AQ using similar surveillance methods to those employed during the previous intervention period.

Results

1396 of 1508 children (93%) who had previously received IPTc and 1406 of 1508 children (93%) who had previously received placebos were followed up during the high malaria transmission season of the year following the intervention. Incidence rates of clinical malaria during the post-intervention transmission season (July –November 2009) were 1.87 (95% CI 1.76 –1.99) and 1.73 (95% CI; 1.62–1.85) episodes per child year in the previous intervention and placebo groups respectively; incidence rate ratio (IRR) 1.09 (95% CI 0.99 –1.21) (P = 0.08). The prevalence of malaria infection was similar in the two groups, 7.4% versus 7.5%, prevalence ratio (PR) of 0.99 (95% CI 0.73–1.33) (P = 0.95). At the end of post-intervention malaria transmission season, the prevalence of anaemia, defined as a haemoglobin concentration<11g/dL, was similar in the two groups (56.2% versus 55.6%; PR = 1.01 [95% CI 0.91 – 1.12]) (P = 0.84).

Conclusion

IPTc with SP+AQ was not associated with an increase in incidence of malaria episodes, prevalence of malaria infection or anaemia in the subsequent malaria transmission season.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00738946","term_id":"NCT00738946"}}NCT00738946     

Recognising and Treatment Seeking for Acute Bacterial Meningitis in Adults and Children in Resource-Poor Settings: A Qualitative Study

Objective

High mortality burden from Acute Bacterial Meningitis (ABM) in resource-poor settings has been frequently blamed on delays in treatment seeking. We explored treatment-seeking pathways from household to primary health care and referral for ABM in Malawi.

Design

A cross-sectional qualitative study using narrative in-depth interviews, semi-structured interviews and focus group discussions.

Participants

Adults and children with proven and probable acute bacterial meningitis and/or their carers; adults from urban and peri-urban communities; and primary health care workers (HCW).

Setting

Queen Elizabeth Central Hospital (QECH), urban and peri-urban private and government primary health centres and communities in Blantyre District, Malawi.

Results

Whilst communities associated meningitis with a stiff neck, in practice responses focused on ability to recognise severe illness. Misdiagnosis of meningitis as malaria was common. Subsequent action by families depended on the extent to which normal social life was disrupted by the illness and depended on the age and social position of the sufferer. Seizures and convulsions were considered severe symptoms but were often thought to be malaria. Presumptive malaria treatment at home often delayed formal treatment seeking. Further delays in treatment seeking were caused by economic barriers and perceptions of inefficient or inadequate primary health services.

Conclusions

Given the difficulties in diagnosis of meningitis where malaria is common, any intervention for ABM at primary level must focus on recognising severe illness, and encouraging action at the household, community and primary health levels. Overcoming barriers to recognition and social constraints at community level require broad community-based strategies and may provide a route to addressing poor clinical outcomes.     

High Resistance of Plasmodium falciparum to Sulphadoxine/Pyrimethamine in Northern Tanzania and the Emergence of dhps Resistance Mutation at Codon 581

Background

Sulphadoxine-pyrimethamine (SP) a widely used treatment for uncomplicated malaria and recommended for intermittent preventive treatment of malaria in pregnancy, is being investigated for intermittent preventive treatment of malaria in infants (IPTi). High levels of drug resistance to SP have been reported from north-eastern Tanzania associated with mutations in parasite genes. This study compared the in vivo efficacy of SP in symptomatic 6–59 month children with uncomplicated malaria and in asymptomatic 2–10 month old infants.

Methodology and Principal Findings

An open label single arm (SP) standard 28 day in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old symptomatic children and a modified protocol used in 2 to 10 months old asymptomatic infants. Enrolment was stopped early (87 in the symptomatic and 25 in the asymptomatic studies) due to the high failure rate. Molecular markers were examined for recrudescence, re-infection and markers of drug resistance and a review of literature of studies looking for the 581G dhps mutation was carried out. In symptomatic children PCR-corrected early treatment failure was 38.8% (95% CI 26.8–50.8) and total failures by day 28 were 82.2% (95% CI 72.5–92.0). There was no significant difference in treatment failures between asymptomatic and symptomatic children. 96% of samples carried parasites with mutations at codons 51, 59 and 108 in the dhfr gene and 63% carried a double mutation at codons 437 and 540. 55% carried a third mutation with the addition of a mutation at codon 581 in the dhps gene. This triple: triple haplotype maybe associated with earlier treatment failure.

Conclusion

In northern Tanzania SP is a failed drug for treatment and its utility for prophylaxis is doubtful. The study found a new combination of parasite mutations that maybe associated with increased and earlier failure.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00361114","term_id":"NCT00361114"}}NCT00361114     

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.