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Background: Intermittent preventive treatment of malaria in infants (IPTi) consists of the administration of a treatment dose of sulphadoxine-pyrimethamine (SP) at the time of routine vaccinations. The use of routine Health Management and Information Services (HMIS) data to investigate the effect of IPTi on malaria, anaemia, and all-cause attendance in children aged 2-11 months presenting to 11 health centres in southern Tanzania is described., Methods: Clinical diagnosis of malaria was confirmed with a positive blood slide reading from a quality assurance laboratory. Anaemia was defined using two thresholds (mild [Hb<11 g/dL], severe [Hb<8 g/dL]). Incidence rates between IPTi and non-implementing health centres were calculated using Poisson regression, and all statistical testing was based on the t test due to the clustered nature of the data., Results: Seventy two per cent of infants presenting in intervention areas received at least one dose of IPTi--22% received all three. During March 2006-April 2007, the incidence of all cause attendance was two attendances per person, per year (pppy), including 0.2 episodes pppy of malaria, 0.7 episodes of mild and 0.13 episodes of severe anaemia. Point estimates for the effect of IPTi on malaria varied between 18% and 52%, depending on the scope of the analysis, although adjustment for clustering rendered these not statistically significant., Conclusions: The point estimate of the effect of IPTi on malaria is consistent with that from a large pooled analysis of randomized control trials. As such, it is plausible that the difference seen in health centre data is due to IPTi, even thought the effect did not reach statistical significance. Findings draw attention to the challenges of robust inference of effects of interventions based on routine health centre data. Analysis of routine health information can reassure that interventions are being made available and having desired effects, but unanticipated effects should trigger data collection from representative samples of the target population.

In addition to parasite resistance, inadequate levels of exposure to antimalarial drugs may contribute to treatment failure. We developed population pharmacokinetic (PK) models to describe the distribution of sulfadoxine (SDX) and pyrimethamine (PYM) in children with uncomplicated malaria in Malawi. The concentration levels of antimalarial drugs in whole blood were determined using high-performance liquid chromatography. We found no evidence of underdosing in children as compared with adults; the children had drug exposure levels similar to those described in adults. Treatment failure was more likely in children with lower PYM concentrations on day 14 (P = 0.024), and there was a trend for lower SDX concentrations on day 14 (P = 0.061). SDX and PYM concentrations at levels predictive of treatment failure have been identified at day 14. Less than one-third of the children displayed drug concentration levels above these thresholds after receiving the recommended SDX-pyrimethamine (SP) dose. Our findings suggest that PK factors contributed to the observed high rate of treatment failure, and we therefore recommend a higher SP dose for children under the age of 5 years.

The efficiency of malaria prevention during pregnancy was compared between three studies in Benin for malaria infection of the placenta (MIP) and low birth weight (LBW). The first was carried out when chloroquine prophylaxis was still recommended, the second was an intermittent preventive treatment in pregnancy (IPTp) clinical trial comparing sulfadoxine pyrimetamine (SP) versus mefloquine, and the third was an observational study after SP-IPTp national implementation. We showed an association between the use of IPTp and the reduction of LBW (10% with national IPTp and 8.7% in IPTp trial versus 15.7% in pre-trial study). The effect on MIP was better in the trial (2.9% versus 11.2% and 16.7% for national IPTp and pre-trial studies, respectively). In spite of a good overall compliance with the national IPTp (with 84% of women taking at least one dose of SP), there are still failures in adherence to the directly observed therapy (DOT) scheme and needs for better training of health staff.

Background: Individual malaria interventions provide only partial protection in most epidemiological situations. Thus, there is a need to investigate whether combining interventions provides added benefit in reducing mortality and morbidity from malaria. The potential benefits of combining IPT in children (IPTc) with home management of malaria (HMM) was investigated., Methods: During the 2008 malaria transmission season, 1,277 children under five years of age resident in villages within the rural Farafenni demographic surveillance system (DSS) in North Bank Region, The Gambia were randomized to receive monthly IPTc with a single dose of sulphadoxine/pyrimethamine (SP) plus three doses of amodiaquine (AQ) or SP and AQ placebos given by village health workers (VHWs) on three occasions during the months of September, October and November, in a double-blind trial. Children in all study villages who developed an acute febrile illness suggestive of malaria were treated by VHWs who had been taught how to manage malaria with artemether-lumefantrine (Coartem™). The primary aims of the project were to determine whether IPTc added significant benefit to HMM and whether VHWs could effectively combine the delivery of both interventions., Results: The incidence of clinical attacks of malaria was very low in both study groups. The incidence rate of malaria in children who received IPTc was 0.44 clinical attacks per 1,000 child months at risk while that for control children was 1.32 per 1,000 child months at risk, a protective efficacy of 66% (95% CI -23% to 96%; p = 0.35). The mean (standard deviation) haemoglobin concentration at the end of the malaria transmission season was similar in the two treatment groups: 10.2 (1.6) g/dL in the IPTc group compared to 10.3 (1.5) g/dL in the placebo group. Coverage with IPTc was high, with 94% of children receiving all three treatments during the study period., Conclusion: Due to the very low incidence of malaria, no firm conclusion can be drawn on the added benefit of IPTc in preventing clinical episodes of malaria among children who had access to HMM in The Gambia. However, the study showed that VHWs can successfully combine provision of HMM with provision of IPTc.

Background: Factors involved in the development of resistance to sulphadoxine-pyrimethamine (SP) by Plasmodium falciparum, particularly in the context of intermittent preventive treatment during pregnancy (IPTp), are not well known. We aimed to determine the impact of IPTp and human immunodeficiency virus (HIV) infection on molecular markers of SP resistance and the clinical relevance of resistant infections., Methods: SP resistance alleles were determined in peripheral (n = 125) and placental (n = 145) P. falciparum isolates obtained from pregnant women enrolled in a randomized, placebo-controlled trial of IPTp in Manhiça, Mozambique., Results: Prevalence of quintuple mutant infections was 12% (23 of 185 isolates) in pregnant women who received placebo and 24% (20 of 85 isolates) in those who received SP (P = .031). When the last IPTp dose was administered at late pregnancy, mutant infections at delivery were more prevalent in placental samples (7 [23%] of 30, samples) than in peripheral blood samples (2 [7%] of 30 samples; P = .025), more prevalent in women who received IPTp-SP than in those who received placebo (odds ratio [OR], 8.13; 95% confidence interval [CI], 1.69-39.08), and more prevalent in HIV-positive women than in HIV-negative women (OR, 5.17; 95% CI, 1.23-21.66). No association was found between mutant infections and increased parasite density or malaria-related morbidity in mothers and children., Conclusions: IPTp with SP increases the prevalence of resistance markers in the placenta and in HIV-infected women at delivery, which suggests that host immunity is key for the clearance of drug-resistant infections. However, this effect of IPTp is limited to the period when blood levels of SP are likely to be significant and does not translate into more-severe infections or adverse clinical outcomes.

Objective: To assess the effect of intermittent preventive treatment with sulfadoxine and pyrimethamine (IPT-SP) on placental parasitemia and maternal and perinatal outcome., Methods: We compared placental malaria parasitemia during pregnancy and pregnancy outcome in 2 groups of women receiving antenatal care at University of Benin Teaching Hospital. One group was prophylactically treated with IPT-SP and the other was not treated., Results: The parasitemia rates for peripheral, placental, and cord blood were 11.9%, 11.4%, and 2.7% in the IPT-SP group (n=370) and 19.1%, 22.6%, and 6.2% in the control group (n=371) (P=0.006, P=0.002, and P=0.02, respectively). The treatment reduced the odds of placental parasitemia by 37% (OR 0.63; 95% CI, 0.48-0.81). Peripheral (P=0.002) and placental (P=0.001) parasitemia were significantly reduced in the subgroup of women who took 2 or 3 doses of SP. Fewer women (16.2%) in the IPT-SP group than the control group (23.7%) had symptomatic malaria. Anemia at delivery was significantly lower in the IPT-SP group (10.8 vs 1.6%). The risks of abortion, preterm delivery, and low birth weight were also significantly lower in the IPT-SP group., Conclusion: IPT-SP is effective in preventing placental parasitemia, and reduces rates of malaria, maternal anemia, abortion, preterm delivery and low birth weight among pregnant women., (Copyright © 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Pregnant women are susceptible to Plasmodium falciparum parasites that sequester in the placenta. The massive accumulation of infected erythrocytes in the placenta has been suggested to trigger the deleterious effects of malaria in pregnant women and their offspring. The risk of malaria is also high during the postpartum period, although mechanisms underlying this susceptibility are not known. Here, we aimed to identify host factors contributing to the risk of postpartum infections and to determine the origin of postpartum parasites by comparing their genotypes with those present at the time of delivery. To address this, blood samples were collected at delivery (n = 402) and postpartum (n = 354) from Mozambican women enrolled in a trial of intermittent preventive treatment in pregnancy (IPTp). P. falciparum was detected by real-time quantitative PCR (qPCR), and the parasite merozoite surface protein 1 (msp-1) and msp-2 genes were genotyped. Fifty-seven out of 354 (16%) women were infected postpartum as assessed by qPCR, whereas prevalence by optical microscopy was only 4%. Risk of postpartum infection was lower in older women (odds ratio [OR] = 0.34, 95% confidence interval [CI] = 0.15 to 0.81) and higher in women with a placental infection at delivery (OR = 4.20, 95% CI = 2.19 to 8.08). Among 24 women with matched infections, 12 (50%) were infected postpartum with at least one parasite strain that was also present in their placentas. These results suggest that parasites infecting pregnant women persist after delivery and increase the risk of malaria during the postpartum period. Interventions that reduce malaria during pregnancy may translate into a lower risk of postpartum infection.

Background: Intermittent preventive treatment in children (IPTc) is a promising strategy to control malaria morbidity. A significant concern is whether IPTc increases children's susceptibility to subsequent malaria infection by altering their anti-Plasmodium acquired immunity., Methods: To investigate this concern, IgG antibody (Ab) responses to Plasmodium falciparum schizont extract were measured in Senegalese children (6 months-5 years old) who had received three rounds of IPTc with artesunate + sulphadoxine-pyrimethamine (or placebo) at monthly intervals eight months earlier. Potential confounding factors, such as asexual malaria parasitaemia and nutritional status were also evaluated., Results: Firstly, a bivariate analysis showed that children who had received IPTc had lower anti-Plasmodium IgG Ab levels than the non-treated controls. When epidemiological parameters were incorporated into a multivariate regression, gender, nutritional status and haemoglobin concentration did not have any significant influence. In contrast, parasitaemia, past malaria morbidity and increasing age were strongly associated with a higher specific IgG response., Conclusions: The intensity of the contacts with P. falciparum seems to represent the main factor influencing anti-schizont IgG responses. Previous IPTc does not seem to interfere with this parasite-dependent acquired humoral response eight months after the last drug administration.

Preterm delivery, which is associated with infections during pregnancy, is common in sub-Saharan Africa. We enrolled 1,320 pregnant women into a randomized, controlled trial in Malawi to study whether preterm delivery and low birth weight (LBW) incidence can be reduced by intermittent preventive treatment of maternal malaria and reproductive tract infections. The participants received either sulfadoxine-pyrimethamine (SP) twice (controls), monthly SP, or monthly SP and two doses of azithromycin (AZI-SP). The incidence of preterm delivery was 17.9% in controls, 15.4% in the monthly SP group (P = 0.32), and 11.8% in AZI-SP group (risk ratio = 0.66, P = 0.01). Compared with controls, those in AZI-SP group had a risk ratio of 0.61 (P = 0.02) for LBW. Incidence of serious adverse events was low in all groups. In conclusion, the incidence of preterm delivery and LBW can in some conditions be reduced by treating pregnant women with monthly SP and two azithromycin doses.

For monitoring efficacy of sulfadoxine/pyrimethamine intermittent preventive treatment for malaria during pregnancy, data obtained from studies of children seemed inadequate. High prevalence of triple and quadruple mutants in the dihydropteroate synthase and dihydrofolate reductase genes of Plasmodium falciparum parasites contrasts with the efficacy of sulfadoxine/pyrimethamine in reducing low birthweights and placental infection rates. In light of this discrepancy, emphasis on using molecular markers for monitoring efficacy of intermittent preventive treatment during pregnancy appears questionable. The World Health Organization recently proposed conducting in vivo studies in pregnant women to evaluate molecular markers for detecting resistance precociously. Other possible alternative strategies are considered.

Objectives: To evaluate the effects of pre-season treatment with single dose of sulfadoxine-pyrimethamine (SP) or artemether-lumefantrine (AL) on subsequent malaria morbidity in under-fives., Methods: A cohort of 156 children was enrolled for longitudinal follow-up. Children received curative therapy with SP or AL, and a third group received no treatment. Participants were home-visited twice a week with blood smears taken from children with fever (axillary T° ≥ 37.5 °C) or history of fever. To assess the time to re-infection, a blood film was also systematically obtained from pre-treated children every 2 weeks., Results: The mean time to the first malaria infection was 36 days in the SP arm and 26 days in the AL arm (P=0.006). The incidence density of malaria infection was similar in both groups (86.5%vs. 92.3%, P=0.52). The mean time to the first malaria episode was 47 days in the SP arm and 32 days in the AL arm (P<0.001). The incidence of malaria episodes was significantly higher in the group pre-treated with AL (45.7 per 1000 child days-at-risk CI 95% [35-56]) than in the control group (10.7 per 1000 child days-at-risk CI 95% [7-15]); P<0.001)., Conclusions: Our findings suggest that the radical clearance of parasitemia with AL may increase susceptibility to malaria infection and clinical malaria episodes., (© 2010 Blackwell Publishing Ltd.)

Background: Intermittent preventive treatment (IPT) of malaria involves administration of curative doses of antimalarials at specified time points to vulnerable populations in endemic areas, regardless whether a subject is known to be infected. The effect of this new intervention on the development and maintenance of protective immunity needs further understanding. We have investigated how seasonal IPT affects the genetic diversity of Plasmodium falciparum infections and the risk of subsequent clinical malaria., Material and Methods: The study included 2227 Ghanaian children (3-59 months) who were given sulphadoxine-pyrimethamine (SP) bimonthly, artesunate plus amodiaquine (AS+AQ) monthly or bimonthly, or placebo monthly for six months spanning the malaria transmission season. Blood samples collected at three post-interventional surveys were analysed by genotyping of the polymorphic merozoite surface protein 2 gene. Malaria morbidity and anaemia was monitored during 12 months follow-up., Results: Monthly IPT with AS+AQ resulted in a marked reduction in number of concurrent clones and only children parasite negative just after the intervention period developed clinical malaria during follow-up. In the placebo group, children without parasites as well as those infected with ≥2 clones had a reduced risk of subsequent malaria. The bimonthly SP or AS+AQ groups had similar number of clones as placebo after intervention; however, diversity and parasite negativity did not predict the risk of malaria. An interaction effect showed that multiclonal infections were only associated with protection in children without intermittent treatment., Conclusion: Molecular typing revealed effects of the intervention not detected by ordinary microscopy. Effective seasonal IPT temporarily reduced the prevalence and genetic diversity of P. falciparum infections. The reduced risk of malaria in children with multiclonal infections only seen in untreated children suggests that persistence of antigenically diverse P. falciparum infections is important for the maintenance of protective malaria immunity in high transmission settings.

Concern has been raised that iron supplementation for treatment of acute malaria may worsen the severity of malaria. We compared the effect of iron and folate with folate alone on hematologic recovery in children treated for acute malaria. We randomized 82 children 6-60 months of age from Nigeria with smear-positive malaria and anemia (hematocrit < 33%) to receive iron (2 mg/kg/day) plus folate (5 mg/day) or folate alone in addition to antimalarial drugs. The mean ± SD hematocrit at baseline was 28.5% ± 2.9%. At four weeks, the mean hematocrit increased by 2.5% ± 1.6% in the iron plus folate group and by 1.4% ± 1.0% in the folate alone group (P = 0.001). Baseline hematocrit, iron supplementation, weight for height, and weekly meat intake were significant predictors of final hematocrit. The effect of iron was not significantly modified by baseline hematocrit, weekly meat intake, nutritional status, mother's education, sex, or age of the child. Iron supplementation improved hematologic recovery in children with malarial anemia.

Background: Intermittent preventive treatment in infants with sulphadoxine-pyrimethamine (IPTi-SP) reduces malaria morbidity by 20% to 33%. Potentially, however, this intervention may compromise the acquisition of immunity, including the tolerance towards multiple infections with Plasmodium falciparum., Methods: Plasmodium falciparum isolates were obtained from children participating in two Ghanaian IPTi-SP trials (Tamale, Afigya Sekyere) at 15 months of age, i.e., six months after they had received the second dose of IPTi-SP or placebo. By typing the polymorphic merozoite surface protein 1 (msp1) and msp2 genes, multiplicity of infection (MOI) was assessed in 389 isolates. A total of additional 133 samples were collected in Tamale at 3, 6, 9, and 12 months of age. Comparisons of MOI between groups were done by non-parametric statistical tests., Results: The number of distinguishable P. falciparum clones (MOI) ranged between one and six. Mean MOI in Tamale was stable at 2.13 - 2.17 during the first year of life, and increased to 2.57 at age 15 months (P = 0.01). At no age did MOI differ between the IPTi-SP and placebo groups (each, P ≥ 0.5). At 15 months of age, i.e., six months after the second dose, MOI was very similar for children who had received IPTi or placebo (means, 2.25 vs. 2.33; P = 0.55) as was the proportion of polyclonal infections (69.6% vs. 69.7%; P = 0.99). Adjusting for study site, current and prior malaria, parasite density, and season did not change this finding., Conclusions: IPTi-SP appears to have no impact on the multiplicity of infection during infancy and thereafter. This suggests that tolerance of multiple infections, a component of protective immunity in highly endemic areas, is not affected by this intervention.

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 NCT00131716.

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.

Intermittent preventive treatment (IPT) against malaria is a malaria control strategy aimed at reducing the burden of malaria in certain high-risk groups, namely pregnant women and children. Three strategies - IPT in pregnancy (IPTp), infants (IPTi) and children (IPTc) - are reviewed here focusing on the mechanism of action, choice of drugs available, controversies and future research. Drugs for IPT need to be co-formulated, long acting, safe and preferably administered as a single dose. There is no obvious replacement for sulfadoxine-pyrimethamine, the most commonly utilized drug combination. All strategies face similar problems of rising drug resistance, falling malaria transmission and a policy shift from controlling disease to malaria elimination and eradication. IPT is an accepted form of malaria control, but to date only IPTp has been adopted as policy.

The current interest in malaria elimination has led to a renewed interest in drugs that can be used for mass administration to minimize malaria transmission. Primaquine (PQ) is the only generally available drug with a strong activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for transmission. Despite concerns about PQ-induced hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, a single dose of PQ may be safe and efficacious in clearing gametocytes that persist after conventional treatment. As part of a mass drug intervention, we determined the hemolytic effect of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) plus a single dose of primaquine (PQ; 0.75 mg/kg of body weight) in children aged 1 to 12 years. Children were randomized to receive SP+AS+PQ or placebo; those with a hemoglobin (Hb) level below 8 g/dl were excluded from receiving PQ and received SP+AS. The Hb concentration was significantly reduced 7 days after SP+AS+PQ treatment but not after placebo or SP+AS treatment. This reduction in Hb was most pronounced in G6PD-deficient (G6PD A-) individuals (-2.5 g/dl; 95% confidence interval [95% CI], -1.2 to -3.8 g/dl) but was also observed in heterozygotes (G6PD A) (-1.6 g/dl; 95% CI, -0.9 to -2.2 g/dl) and individuals with the wild-type genotype (G6PD B) (-0.5 g/dl; 95% CI, -0.4 to -0.6 g/dl). Moderate anemia (Hb level of <8 g/dl) was observed in 40% (6/15 individuals) of the G6PD A-, 11.1% (3/27 individuals) of the G6PD A, and 4.5% (18/399 individuals) of the G6PD B individuals; one case of severe anemia (Hb level of <5 g/dl) was observed. PQ may cause moderate anemia when coadministered with artemisinins, and excluding individuals based on G6PD status alone may not be sufficient to prevent PQ-induced hemolysis.

Background: Plasmodium falciparum parasites that cause malaria in pregnancy express unique variant surface antigens (VSAs). Levels of immunoglobulin G (IgG) antibody to pregnancy-associated VSAs measured at delivery are gravidity dependent, and they have been associated with protection from disease. It is not known how these IgG responses develop in pregnant women receiving intermittent preventive treatment during pregnancy (IPTp) or whether IgG levels in early pregnancy predict pregnancy outcomes., Methods: We performed longitudinal measurements of IgG antibody to VSAs by flow cytometric analysis of serum samples obtained from 549 Malawian women receiving IPTp. We examined fluctuations in IgG levels over time and associated the IgG levels noted at study enrollment with clinical outcomes., Results: Levels of IgG antibody to pregnancy-associated VSAs were gravidity dependent. Overall, levels decreased while women were receiving IPTp, but the levels of the individuals were highly dynamic. Primigravidae developed low levels of pregnancy-specific IgG, which were often boosted during second pregnancies. The prevalence of parasites was low (8.4% at enrollment and 2.4% in late pregnancy). Antibody levels at enrollment did not predict birth weight, duration of gestation at delivery, or the maternal hemoglobin level in late pregnancy., Conclusion: Levels of IgG antibody to pregnancy-specific VSAs decrease during receipt of IPTp. Antibody levels in early pregnancy did not predict clinical outcome. IPTp and decreasing malaria prevalence pose challenges for the evaluation of novel interventions for malaria during pregnancy.

In this paper, we introduce a deterministic malaria model for determining the drug administration protocol that leads to the smallest first malaria episodes during the wet season. To explore the effects of administering the malaria drug on different days during the wet season while minimizing the potential harmful effects of drug overdose, we define 40 drug administration protocols. Our results fit well with the clinical studies of Coulibaly et al. at a site in Mali. In addition, we provide protocols that lead to smaller number of first malaria episodes during the wet season than the protocol of Coulibaly et al.

Background: Intermittent preventive treatment in infants (IPTi) with sulphadoxine-pyrimethamine (SP) for the prevention of malaria has shown promising results in six trials. However, resistance to SP is rising and alternative drug combinations need to be evaluated to better understand the role of treatment versus prophylactic effects., Methods: Between March 2004 and March 2008, in an area of western Kenya with year round malaria transmission with high seasonal intensity and high usage of insecticide-treated nets, we conducted a randomized, double-blind placebo-controlled trial with SP plus 3 days of artesunate (SP-AS3), 3 days of amodiaquine-artesunate (AQ3-AS3), or 3 days of short-acting chlorproguanil-dapsone (CD3) administered at routine expanded programme of immunization visits (10 weeks, 14 weeks and 9 months)., Principal Findings: 1,365 subjects were included in the analysis. The incidence of first or only episode of clinical malaria during the first year of life (primary endpoint) was 0.98 episodes/person-year in the placebo group, 0.74 in the SP-AS3 group, 0.76 in the AQ3-AS3 group, and 0.82 in the CD3 group. The protective efficacy (PE) and 95% confidence intervals against the primary endpoint were: 25.7% (6.3, 41.1); 25.9% (6.8, 41.0); and 16.3% (-5.2, 33.5) in the SP-AS3, AQ3-AS3, and CD3 groups, respectively. The PEs for moderate-to-severe anaemia were: 27.5% (-6.9, 50.8); 23.1% (-11.9, 47.2); and 11.4% (-28.6, 39.0). The duration of the protective effect remained significant for up to 5 to 8 weeks for SP-AS3 and AQ3-AS3. There was no evidence for a sustained beneficial or rebound effect in the second year of life. All regimens were well tolerated., Conclusions: These results support the view that IPTi with long-acting regimens provide protection against clinical malaria for up to 8 weeks even in the presence of high ITN coverage, and that the prophylactic rather than the treatment effect of IPTi appears central to its protective efficacy.

Background: The development of Plasmodium falciparum resistance to chloroquine (CQ) has limited its use in many malaria endemic areas of the world. However, despite recent drug policy changes to adopt the more effective artemisinin-based combination (ACT) in Africa and in the Southern African region, in 2007 Swaziland still relied on CQ as first-line anti-malarial drug., Methods: Parasite DNA was amplified from P. falciparum isolates from Swaziland collected in 1999 (thick smear blood slides) and 2007 (filter paper blood spots). Markers of CQ and sulphadoxine-pyrimethamine (SP) resistance were identified by probe-based qPCR and DNA sequencing., Results: Retrospective microscopy, confirmed by PCR amplification, found that only six of 252 patients treated for uncomplicated malaria in 2007 carried detectable P. falciparum. The pfcrt haplotype 72C/73V/74I/75E/76T occurred at a prevalence of 70% (n = 64) in 1999 and 83% (n = 6) in 2007. Prevalence of the pfmdr1-86N allele was 24% in 1999 and 67% in 2007. A novel substitution of phenylalanine for asparagine at codon 86 of pfmdr1 (N86F) occurred in two of 51 isolates successfully amplified from 1999. The pfmdr1-1246Y allele was common in 1999, with a prevalence of 49%, but was absent among isolates collected in 2007. The 86N/184F/1246D pfmdr1 haplotype, associated with enhanced parasite survival in patients treated with artemether-lumefantrine, comprised 8% of 1999 isolates, and 67% among 2007 isolates. The pfdhfr triple-mutant 16C/51I/59R/108N/164I haplotype associated with pyrimethamine resistance was common in both 1999 (82%, n = 34) and 2007 (50%, n = 6), as was the wild-type 431I/436S/437A/540K/581A/613A haplotype of pfdhps (100% and 93% respectively in 1999 and 2007). The quintuple-mutant haplotype pfdhfr/pfdhps-CIRNI/ISGEAA, associated with high-level resistance to SP, was rare (9%) among 1999 isolates and absent among 2007 isolates., Conclusions: The prevalence of pfcrt and pfmdr1 alleles reported in this study is consistent with a parasite population under sustained CQ drug pressure. The low prevalence of dhps-437G and dhps-540E mutations (ISGEAA) and the rarity of quintuple-mutant haplotype pfdhfr/pfdhps-CIRNI/ISGEAA suggest that SP retains some efficacy in Swaziland. Anti-malarial policy changes in neighbouring countries may have had an impact on the prevalence of molecular markers of anti-malarial resistance in Swaziland, and it is hoped that this new information will add to understanding of the regional anti-malarial resistance map.

Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child's age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.

Malaria during pregnancy is associated with maternal and fetal morbidity and mortality. In order to minimize the burden, sulfadoxine-pyrimethamine (SP) is widely used in Africa as an intermittent preventive treatment of malaria in pregnancy (IPTp). However, only limited data are available on the pharmacokinetics of sulfadoxine and pyrimethamine during pregnancy. We conducted a prospective, self-matched, multicenter study of 98 pregnant women in four African countries in order to determine the effects of pregnancy on SP pharmacokinetics. After adjusting for the effects of potential confounders, blood concentrations (associated with therapeutic efficacy) of pyrimethamine were higher (geometric mean ratio (GMR) 1.33; 95% confidence interval (CI) 1.18-1.51; P < 0.001) and those of sulfadoxine were lower (GMR 0.91; 95% CI 0.84-0.98; P = 0.013) on day 7 after SP administration during pregnancy than after the postpartum period. SP pharmacokinetic parameters differed significantly among the study sites. Given the inconsistency of changes in pharmacokinetic parameters between sulfadoxine and pyrimethamine as well as among the study sites, it is not possible to recommend any dose adjustment to prolong the therapeutic life span of the fixed dose combination of SP for IPTp on the basis of our study findings.

Pregnant women are at particularly high risk for morbidity and mortality from malaria, and pregnancy can markedly affect drug pharmacokinetics, yet the pharmacokinetics of antimalarial drugs in pregnancy has been little studied. An important malaria-control measure in Africa is intermittent preventive therapy (IPT) with sulfadoxine-pyrimethamine (SP) during pregnancy. We discuss IPT with SP in light of several concerns and highlight recent findings from a pharmacokinetic study of SP in this population.

Less than a year after the introduction of amodiaquine (AQ)/sulfadoxine-pyrimethamine (SP) as the first-line antimalarial treatment in Senegal, our study aimed to assess patients' drug intake and check its correspondence with nurses' prescription-adherence, the national guidelines regimen and theoretical dosage. The study was conducted at five health centers. Children aged 2-10 years who were prescribed AQ/SP by the nurse were recruited. At day 3, caregivers were questioned about treatment adherence. We collected information about nurses' prescriptions and conducted in-depth interviews on prescription patterns. Among the 289 children who were recruited, 35.3% took less than 80% of the prescribed doses. Nevertheless, 47.7% and 83.7% respectively for AQ and SP received a dosage higher than the theoretical dosage. Age-weight discrepancy leads to overprescribing drugs: nurses acknowledged using the child's age more often than weight to determine the dosage if the child has a low weight. Under and overdosing are not only due to patient practices but causes related to national guidelines and health staff practices. For successful implementation and utilization of antimalarial combinations in Africa, countries should really focus on nurses' training. National guidelines should also be based on national average weight instead of international tables., (Copyright 2009 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.)

The new recommendations to prevent malaria in pregnant women have recently been implemented in Gabon. There is little information on the pregnancy indicators that are useful for their evaluation. A cross-sectional study for the assessment of the prevalence of peripheral, placental, and cord malaria and anemia among delivering women was performed at the largest public hospital of Gabon. Malaria prevalence was 34.4%, 53.6%, and 18.2% for maternal peripheral, placental, and cord blood respectively, with no difference between primigravidae and multigravidae. Submicroscopic infections were frequent and concerned all the positive cord samples. Maternal peripheral, late placental, and cord infections were all associated with a reduced mean birth weight in primigravidae (P = 0.02). Anemia prevalence was 53%, low birth rate was 13%, and prematurity was 25%. The use of intermittent preventive treatment with sulfadoxine-pyrimethamine (greater than or equal to one dose) combined with bed net was associated with a reduction in infection only in multigravidae and with a reduced risk of maternal anemia.

This study aimed to evaluate the impact of intermittent preventive treatment (IPT) and the associated adverse effects in pregnant women living in hyperendemic area of Sélingué in Mali on pregnancy outcome. Pharmacovigilance aims, monitoring the risk of adverse effects resulting from the use of drugs and products for human use licensees of marketing. IPT with sulfadoxine-pyrimethamine (SP) is based on the administration of 2 doses of SP treatment in pregnant women at defined intervals after about 18-20 weeks of pregnancy. The survey on attitudes and behavioural practices (KAP) has allowed us to interview 210 pregnant women attending antenatal clinics at the health district of Sélingué. Almost all women (99%) affirm to know malaria and 84.8% to know clinical signs of malaria. Self medication was practiced by 40% of the expectant mothers. A small proportion of women affirm to have mosquito nets (8.6%) while 14.3% affirm to use impregnated insecticide mosquito nets. The rate of severe anaemia was 30.5% (Hb < 7 g/dl) after the first dose and 13.3% after the second dose of S-P. In parallel, the rate of moderate anaemia (Hb 7-9g /dl) decreased by 54.8% after the first dose to 26.2% after the second dose. Anaemia was higher within multigestes (32.1%) compared with the primigestes (21.7%). We did not observe any case of therapeutic failure with S-P nor infection in our study. The rate of prematurity was 3% while the rate low birth weight was 17.6%. Observed adverse reactions were primarily nauseas and stomach upset (1.9% after first S-P dose and 1% after the 2nd dose of S-P). No case of severe side effects or malformations was observed within new-born babies. In conclusion, IPT with S-P was well tolerated by pregnant women living in Sélingué and presents very few minor secondary reactions. The S-P is currently the only antimalarial drug with a single-dose which has a prolonged action and which also has ideal properties (low cost, several data on its tolerance and its facility of use) for a better use during the pregnancy in Africa.

Background: Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in sub-Saharan Africa. However, studies reporting the effect of IPTp on malaria-specific immunity are scarce and are based on findings in human immunodeficiency virus (HIV)-negative primigravidae., Methods: Plasma samples obtained from 302 pregnant women (177 who were HIV negative, 88 who were HIV positive, and 37 who were of unknown HIV status) participating in a placebo-controlled trial of IPTp with SP (IPTp-SP) were analyzed for the presence of antibodies against merozoite antigens, whole asexual parasites, and variant surface antigens from chondroitin sulfate A-binding and nonbinding lines. Antibody levels were compared between intervention groups, and their association with morbidity outcomes was assessed., Results: HIV-positive mothers receiving SP had lower levels of peripheral antibodies against apical membrane antigen-1 and variant surface antigens, as well as lower levels of cord antibodies against erythrocyte-binding antigen-175 and parasite lysate, than did HIV-positive placebo recipients. No difference between intervention groups was observed among HIV-negative mothers. High antibody levels were associated with maternal infection and an increased risk of a first malaria episode in infants. Antibody responses were not consistently associated with reduced maternal anemia, prematurity, or low birth weight., Conclusions: The IPTp-associated reduction in antibodies in HIV-infected women, but not in HIV-uninfected women, may reflect a higher efficacy of the intervention in preventing malaria among HIV-positive mothers. This reduction did not translate into an enhanced risk of malaria-associated morbidity in mothers and infants. Trial registration. Clinicaltrials.gov identifier NCT00209781.

Background: Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy., Methods: We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized for treatment with AQ-SP, AS-AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro susceptibility to monodesethylamodiaquine (MDAQ) was measured with a histidine-rich protein 2-based enzyme-linked immunosorbent assay, and potential resistance-mediating polymorphisms in pfmdr1 were evaluated., Results: Parasites collected from patients treated with AQ-SP or AS-AQ within the prior 12 weeks were less susceptible to MDAQ (n = 18; mean of the median inhibitory concentration [IC(50)], 62.9 nmol/L; range, 12.7-158.3 nmol/L) than were parasites from those not treated within 12 weeks (n = 43; mean IC(50), 37.5 nmol/L; range, 6.3-184.7 nmol/L; P=.009) or only from those patients in the treatment arm that did not receive AQ (n = 12; mean IC(50), 28.8 nmol/L; range, 6.3-121.8 nmol/L; P = .004). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr1 86Y and 1246Y) increased after AQ therapy, although differences were not statistically significant., Conclusions: Prior therapy selected for diminished response to MDAQ, which suggests that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr1.

Background: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal., Methods: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events., Results: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season., Conclusions: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites., Trial Registration: ClinicalTrials.gov NCT00529620.

Background: The use of anti-malarial drug combinations with artemisinin or with one of its derivatives is now widely recommended to overcome drug resistance in falciparum as well as vivax malaria. The fixed oral dose artemisinin-naphthoquine combination (ANQ, ARCO) is a newer artemisinin-based combination (ACT) therapy undergoing clinical assessment. A study was undertaken to assess the safety, efficacy and tolerability of ANQ combination in areas of multi-drug resistance to generate preliminary baseline data in adult population of Papua New Guinea., Methods: The clinical assessment was an open-labeled, two-arm, randomized study comparing ANQ combination as a single dose regimen and three days regimen (10 mg/kg/day) of chloroquine plus single dose sulphadoxine-pyrimethamine (CQ+SP) for the treatment of uncomplicated falciparum malaria with 28 days follow-up in an adult population. The primary outcome measures for efficacy were day 1, 2, 3 7, 14 and 28-day cure rates. Secondary outcomes included parasite clearance time, fever clearance time, and gametocyte carriage. The main outcome measures for safety were incidences of post-treatment clinical and laboratory adverse events., Results: Between June 2005 and July 2006, 130 patients with confirmed uncomplicated P. falciparum were randomly assigned to receive ANQ and CQ+SP, only 100 patients (51 in ANQ group and 49 in CQ+SP group) were evaluated for clinical and parasitological outcomes. All the patients treated with ANQ and CQ+SP showed adequate clinical and parasitological response with 28 days follow-up. The cure rate for ANQ on day 1, 2, 3, 7, 14, and 28 was 47%, 86%, 92%, 94%, 94% and 94%, respectively. Recrudescence account for 6%; all were cleared on day 21. For CQ+SP treated group the cure rates were 24%, 67%, 82%, 82%, 84% and 88%, respectively. Recrudescence accounted for 10%; all were cleared on day 28 except for one patient. Both regimens were well tolerated with no serious adverse events. The proportion of gametocyte carriers was higher in CQ+SP treated group than ANQ treatment (41% versus 12%; p < 0.05)., Conclusion: While these data are not themselves sufficient, it strongly suggests that the ANQ combination as a single dose administration is safe and effective for the treatment of uncomplicated P. falciparum malaria in the adult population of Papua New Guinea and deserves further clinical evaluation.

Background: The introduction of new anti-malarial treatment that is effective, but more expensive, raises questions about whether the high level of effectiveness observed in clinical trials can be found in a context of family use. The objective of this study was to determine the factors related to adherence, when using the amodiaquine/sulphadoxine-pyrimethamine (AQ/SP) association, a transitory strategy before ACT implementation in Senegal., Methods: The study was conducted in five rural dispensaries. Children, between two and 10 years of age, who presented mild malaria were recruited at the time of the consultation and were prescribed AQ/SP. The child's primary caretaker was questioned at home on D3 about treatment compliance and factors that could have influenced his or her adherence to treatment. A logistic regression model was used for the analyses., Results: The study sample included 289 children. The adherence rate was 64.7%. Two risks factors for non-adherence were identified: the children's age (8-10 years) (ORa = 3.07 [1.49-6.29]; p = 0.004); and the profession of the head of household (retailer/employee versus farmer) (ORa = 2.71 [1.34-5.48]; p = 0.006). Previously seeking care (ORa = 0.28 [0.105-0.736], p=0.001] satisfaction with received information (ORa = 0.45 [0.24-0.84]; p = 0.013), and the quality of history taking (ORa = 0.38 [0.21-0.69]; p = 0.001) were significantly associated with good compliance., Conclusion: The results of the study show the importance of information and communication between caregivers and health center staff. The experience gained from this therapeutic transition emphasizes the importance of information given to the patients at the time of the consultation and drug delivery in order to improve drug use and thus prevent the emergence of rapid drug resistance.

Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.

The aim of this study was to determine the therapeutic success of the medical treatment of pyometra with the antigestagen aglepristone and to document the recurrence rate in relation to the time interval after treatment with antigestagens in cats. Ten cats, 2-13 years of age and nulliparous were used in the study. The cats were treated with aglepristone at a dose of 10mg/kg body weight subcutaneously on days 1, 2, 7 and 14 (if not cured). In addition, trimethoprim/sulphadoxine was also administered at a dose of 15mg/kg body weight subcutaneously once a day for 7 days. Nine out of the 10 cats responded well to treatment. No recurrence was observed in a follow-up period of 2 years. No side effects were observed. The data suggest that aglepristone treatment is a promising approach for the medical treatment of pyometra in cats.

Both malaria and intestinal helminths are endemic in sub-Saharan Africa, and their co-infection occurs commonly. This cross-sectional study assessed the prevalence of malaria and intestinal helminth co-infection in a sample of > 700 pregnant women in Ghana and identified risk factors for co-infection. The prevalence of malaria infection, intestinal helminth infection(s), and co-infection was 36.3%, 25.7%, and 16.6%, respectively. Women with intestinal helminth infection(s) were 4.8 times more likely to have malaria infection. Young age, low income, being single, and being primigravid were each associated with increased odds of co-infection. These associations were present when assessed separately for primi- and multigravid women, but the strength of associations varied considerably for the two groups of women. Young age had the strongest association among both primigravid (odds ratio = 5.2) and multigravid (odds ratio = 3.2) women. This study shows relatively high prevalence rates of malaria, intestinal helminths, and co-infection in pregnant women in Ghana.

Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], -7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%; P = 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.

Background: A study carried out in 2003-2005 in Southern Benin showed a day-28 sulphadoxine-pyrimethamine (SP) monotherapy failure rate greater than 40%, while for SP combined with artesunate (SP-AS) the failure rate was 5.3%. Such a large difference could be explained by the relatively short 28-day follow-up period, with a substantial number of recurrent infections possibly occurring after day 28. This paper reports the treatment outcome observed in the same study cohort beyond the initial 28-day follow-up., Methods: After the 28-day follow-up, children treated with either chloroquine alone (CQ), SP or SP-AS, were visited at home twice a week until day 90 after treatment. A blood sample was collected if the child had fever (axillary temperature > or =37.5 degrees C). Total clinical failure for each treatment group was estimated by combining all the early treatment failures and late clinical failures that occurred over the whole follow-up period, i.e. from day 0 up to day 90. Pre-treatment randomly selected blood samples were genotyped for the dhfr gene (59) and the dhps gene (437 and 540) point mutations related to SP resistance., Results: The PCR-corrected clinical failure at day 90 was significantly lower in the SP-AS group (SP-AS: 2.7%, SP alone: 38.2%; CQ: 41.1%) (Log-Rank p < 0,001). The most prevalent haplotype was dhfr Arg-59 with the dhps Gly-437 mutant and the dhps 540 wild type (85.5%). The dhps 540 mutation could be found in only three (8.3%) samples., Conclusion: Combining artesunate to SP dramatically increased the treatment efficacy, even when extending the follow-up to day 90 post-treatment, and despite the high percentage of failures following treatment with SP alone. Such a good performance may be explained by the low prevalence of the dhps 540 mutation, by the rapid parasite clearance with artesunate and by the level of acquired immunity.

Background: Improved control efforts are reducing the burden of malaria in Africa but may result in decreased antimalarial immunity., Methods: A cohort of 129 children aged 1-10 years in Kampala, Uganda, were treated with amodiaquine plus sulfadoxine-pyrimethamine for 396 episodes of uncomplicated malaria over a 29-month period as part of a longitudinal clinical trial., Results: The risk of treatment failure increased over the course of the study from 5% to 21% (hazard ratio [HR], 2.4 per year [95% confidence interval {CI}, 1.3-4.3]). Parasite genetic polymorphisms were associated with an increased risk of failure, but their prevalence did not change over time. Three markers of antimalarial immunity were associated with a decreased risk of treatment failure: increased age (HR, 0.5 per 5-year increase [95% CI, 0.2-1.2]), living in an area of higher malaria incidence (HR, 0.26 [95% CI, 0.11-0.64]), and recent asymptomatic parasitemia (HR, 0.06 [95% CI, 0.01-0.36]). In multivariate analysis, adjustment for recent asymptomatic parasitemia, but not parasite polymorphisms, removed the association between calendar time and the risk of treatment failure (HR, 1.5 per year [95% CI, 0.7-3.4]), suggesting that worsening treatment efficacy was best explained by decreasing host immunity., Conclusion: Declining immunity in our study population appeared to be the primary factor underlying decreased efficacy of amodiaquine plus sulfadoxine-pyrimethamine. With improved malaria-control efforts, decreasing immunity may unmask resistance to partially efficacious drugs.

Background: To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria., Methods: During the malaria transmission seasons of 2002 and 2003, 455 children--between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. In vivo outcomes were assessed using WHO standard protocols. Genotyping of msp1, msp2 and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction)., Results: Day 28 adequate clinical and parasitological responses (ACPR) were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR) were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of dhfr triple mutant and dhfr/dhps quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with dhps 540E was found., Conclusion: In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy.

Background: The use of most anti-malarial medications is restricted during pregnancy, but two doses of sulphadoxine-pyrimethamine are recommended after the first trimester as intermittent preventive treatment in pregnancy (IPTp). In The Gambia, only 32% of women receive two doses and very little research has been conducted on women's awareness of drug safety during pregnancy. The objective of this paper was to assess whether rural Gambian women were aware of the importance of the timing of the two-dose IPT dose schedule and its relevance to drug safety., Methods: This was a qualitative study in which 41 interviews and 16 focus group discussions with women, adolescents, men and traditional birth attendants were conducted. A generic qualitative approach was used to generate a theory as to why women might not participate in IPTp as recommended., Results: Although most women used calendar months to count their stage of pregnancy, these months did not correlate with their concept of foetal development. Foetal growth was described following Islamic tradition as water, clot, piece of meat and human being, although there was little consensus about the order or timing in which these stages occurred. Common signs and conditions of malaria were known. Women were anxious about miscarriage and recognized that some medicines should not be taken in the first trimester, but were urged by men and traditional birth attendants to attend for antenatal care in the first trimester to "start treatment." General knowledge about the purpose of pregnancy medications and when they should be taken was poor among both men and women. One important result was that women relied entirely on health workers to provide safe drugs, at the correct time., Conclusion: Women did not have relevant information to judge the safety and appropriate timing of pregnancy drugs, which made them over-reliant on health workers. They should be encouraged to date their own pregnancies in culturally relevant terms and to anticipate when and which medications they should receive.

Background: Because of the emergence of chloroquine resistance in Mali, artemether-lumefantrine (AL) or artesunate-amodiaquine (AS+AQ) are recommended as first-line therapy for uncomplicated malaria, but have not been available in Mali until recently because of high costs., Methods: From July 2005 to January 2006, a randomized open-label trial of three oral antimalarial combinations, namely AS+AQ, artesunate plus sulphadoxine-pyrimethamine (AS+SP), and amodiaquine plus sulphadoxine-pyrimethamine (AQ+SP), was conducted in Faladje, Mali. Parasite genotyping by polymerase chain reaction (PCR) was used to distinguish new from recrudescent Plasmodium falciparum infections., Results: 397 children 6 to 59 months of age with uncomplicated Plasmodium falciparum malaria were enrolled, and followed for 28 days to assess treatment efficacy. Baseline characteristics were similar in all three treatment groups. The uncorrected rates of adequate clinical and parasitologic response (ACPR) were 55.7%, 90.8%, and 97.7% in AS+AQ, AS+SP, and AQ+SP respectively (p < 0.001); after PCR correction ACPR rates were similar among treatment groups: 95.4%, 96.9%, and 99.2% respectively (p = 0.17). Mean haemoglobin concentration increased across all treatment groups from Day 0 (9.82 +/- 1.68 g/dL) to Day 28 (10.78 +/- 1.49 g/dL) (p < 0.001), with the greatest improvement occurring in children treated with AQ+SP. On Day 2, the prevalence of parasitaemia was significantly greater among children treated with AQ+SP (50.8%) than in children treated with AS+AQ (10.5%) or AS+SP (10.8%) (p < 0.001). No significant difference in gametocyte carriage was found between groups during the follow-up period., Conclusion: The combination of AQ+SP provides a potentially low cost alternative for treatment of uncomplicated P. falciparum infection in Mali and appears to have the added value of longer protective effect against new infection.

Febrile children in low-income countries receive care from multiple sources, and caretakers' ability to report drug intake is crucial for appropriate prescription of drugs when reaching health facilities. This study describes and validates caretakers' reported use of sulfamethoxazole, chloroquine and sulfadoxine in their children. We performed a cross-sectional study in 139 children diagnosed with severe pneumonia at hospital in Kampala, Uganda. Caretakers were interviewed regarding treatments given prior to arrival at the hospital. Reported drug intake was compared to drug levels in blood sampled on filter paper, analyzed by HPLC methods. Caretakers under-reported intake of the studied drugs. Positive and negative predictive values were 67 and 64% for sulfamethoxazole, 69 and 52% for chloroquine and 85 and 62% for sulfadoxine. Many caretakers were unaware of what drug had been given to the child, and more so if treated outside the home (risk ratio 2.6, 95% CI 1.2-5.6). We conclude that caretakers' reports of drug intake have limited validity. Health workers need to improve counseling of caretakers during drug dispensing, especially for antibiotics. The roles and names of different drugs should be emphasized during counseling, and existing information systems such as immunization cards should be considered for record-keeping of treatment given.

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 NCT00361114.

Background: Malaria in pregnancy is serious, and drug resistance in Africa is spreading. Drugs have greater risks in pregnancy and determining the safety and efficacy of drugs in pregnancy is therefore a priority. This study set out to determine the efficacy and safety of several antimalarial drugs and combinations in pregnant women with uncomplicated malaria., Methods: Pregnant women with non-severe, slide proven, falciparum malaria were randomised to one of 4 regimes: sulfadoxine-pyrimethamine [SP]; chlorproguanil-dapsone [CD]; SP+amodiaquine [SP+AQ] or amodiaquine+artesunate [AQ+AS]. Randomisation was on a 1ratio2ratio2ratio2 ratio. Women were admitted for treatment, and followed at days 7, 14, 21, 28 after the start of treatment, at delivery and 6 weeks after delivery to determine adverse events, clinical and parasitological outcomes. Primary outcome was parasitological failure by day 28., Results: 1433 pregnant women were screened, of whom 272 met entry criteria and were randomised; 28 to SP, 81 to CD, 80 to SP+AQ and 83 to AQ+AS. Follow-up to day 28 post treatment was 251/272 (92%), and to 6 weeks following delivery 91%. By day 28 parasitological failure rates were 4/26 (15%, 95%CI 4-35) in the SP, 18/77 (23%, 95%CI 14-34) in the CD, 1/73 (1% 95%CI 7-0.001) in the SP+AQ and 7/75 (9% 95%CI 4-18) in the AQ+AS arms respectively. After correction by molecular markers for reinfection the parasitological failure rates at day 28 were 18% for CD, 1% for SP+AQ and 4.5% for AQ+AS. There were two maternal deaths during the trial. There was no apparent excess of stillbirths or adverse birth outcomes in any arm. Parasitological responses were strikingly better in pregnant women than in children treated with the same drugs at this site., Conclusions: Failure rates with monotherapy were unacceptably high. The two combinations tested were efficacious and appeared safe. It should not be assumed that efficacy in pregnancy is the same as in children., Trial Registration: ClinicalTrials.gov NCT00146731.

Background: Delivery of two doses of intermittent preventive treatment of malaria during pregnancy (IPTp) is a key strategy to reduce the burden of malaria in pregnancy in sub-Saharan Africa. However, different settings have reported coverage levels well below the target 80%. Antenatal implementation guidelines in Tanzania recommend IPTp first dose to be given at the second antenatal visit, and second dose at the third visit. This investigation measured coverage of IPTp at national level in Tanzania and examined the role of individual, facility, and policy level influences on achieved coverage., Methods: Three national household and linked reproductive and child health (RCH) facility surveys were conducted July-August 2005, 2006, and 2007 in 210 clusters sampled using two-stage cluster sampling from 21 randomly selected districts. Female residents who reported a livebirth in the previous year were asked questions about malaria prevention during that pregnancy and individual characteristics including education, pregnancy history, and marital status. The RCH facility serving each cluster was also surveyed, and information collected about drug stocks, health education delivery, and the timing of antenatal care delivery by clinic users., Results: The national IPTp coverage had declined over the survey period being 71% for first dose in 2005 falling to 65% in 2007 (chi2 2.9, p = 0.05), and 38% for second dose in 2005 but 30% in 2007 (chi2 4.4, p = 0.01). There was no evidence of any individual factors being associated with second dose coverage beyond living in an urban area. Availability of sulphadoxine-pyrimethamine at RCH had decreased year on year from 85% of clinics in stock in 2005 to 60% in 2007 (chi2 20.6, p < 0.001). This reduction was evident in rural but not urban clinics. If safety recommendations and national antenatal care guidelines for IPTp delivery were followed, in 2007 only 76% of pregnant women could have received IPTp first dose and only 46% could have received second dose., Conclusion: There is scope to improve IPTp first and second dose coverage at national scale within existing systems by improving stock at RCH, and by revising the existing guidelines to recommend delivery of IPTp after quickening, rather than at a pre-defined antenatal visit.

Background: Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) is recommended for reducing the risk of malaria in pregnancy and its consequences on mothers and babies (IPTp-SP). Indicators of implementation and effects of IPTp-SP were collected in a rural clinic in Southern Senegal., Methods: Women seen routinely at the antenatal clinic (ANC) of a rural dispensary during 2000-2007. Deployment of IPTp-SP started in January 2004. Inspection of antenatal and outpatient clinic registries of the corresponding period., Results: Between 1st January 2000 and 30th April 2007, 1,781 women of all gravitidities and parities attended the ANC with 965 deliveries (606 and 398 respectively since 1st January 2004, when IPTp-SP was started.) 69% of women were seen > or = 3 times; 95% received at least one dose and 70% two doses of SP (from 61% in 2004 to 86% in 2007). The first visit, first and second dose of SP occurred at a median week 20, 22 and 31. The probability of receiving two doses was > 80% with > or = 3 antenatal visits and a first dose of SP by week 20.The prevalence of maternal malaria was low and similar pre- (0.7%) and during IPTp (0.8%). Effects on of low birth weight (LBW, < 2.5 kg) were non-statistically significant. The prevalence of LBW was 10.8% pre- and 7.7% during IPTp deployment (29% risk reduction, p = 0.12).Unfavourable pregnancy outcomes numbered 72 (7.5% of pregnancies with known outcome), including 30 abortions and 42 later deaths (late foetal deaths, stillbirth, peri-natal) of which 13 with one or more malformations (1.35% of all recorded deliveries)., Conclusion: The implementation of IPTp-SP was high. Early attendance to ANC favours completion of IPTp-SP. The record keeping system in place is amenable to data extraction and linkage. A model was developed that predicts optimal compliance to two SP doses, and could be tested in other settings. Maternal malaria was infrequent and unaffected by IPTp-SP. The risk of LBW was lower during IPT implementation but the difference was non-significant and could have other explanations.

Objectives: This preliminary study sought to investigate the response of uncomplicated falciparum infections to semi-supervised drug administration with quinine and two adjunctive schizontocidal drugs in infected patients in Guyana. Quinine and chloroquine cross-sensitivity was also assessed in vitro., Methods: Patients were treated with quinine 10mg/kg for 7 days followed by sulfadoxine/pyrimethamine 25mg/kg single dose (in children) or doxycycline 100mg daily for 7 days (in adults). Independently, falciparum-infected blood-medium mixtures were cultured in standardized pre-dosed quinine and chloroquine test plates, according to the protocol of the World Health Organization Mark III in vitro test system, for analysis., Results: The quinine/doxycycline regimen (N=12) produced 100% clinical cure (12/12) at day 14 and 100% parasitological cure (11/11) at day 28. However, with the quinine/sulfadoxine/pyrimethamine scheme, 1/12 therapeutic failure (on day 14) and 2/9 parasitological failures (on day 28) were observed. In vitro, parasite development beyond the cut-off concentrations and high IC(50) values (geometric mean IC(50) quinine 504.65nM and IC(50) chloroquine 506.69nM), confirmed diminished Plasmodium falciparum sensitivity to both drugs., Conclusion: These findings suggest P. falciparum resistance to both quinine and chloroquine, and support either the use of antibiotics as adjuncts to quinine therapy or drugs with alternate pharmacodynamics as first-line therapy.