Intermittent Preventive Antimalarial Treatment Research Articles

Intermittent preventive antimalarial treatment for children with anaemia.

BackgroundAnaemia is a global public health problem. Children under five years of age living in developing countries (mostly Africa and South‐East Asia) are highly affected. Although the causes for anaemia are multifactorial, malaria has been linked to anaemia in children living in malaria‐endemic areas. Administering intermittent preventive antimalarial treatment (IPT) to children might reduce anaemia, since it could protect children from new Plasmodium parasite infection (the parasites that cause malaria) and allow their haemoglobin levels to recover.ObjectivesTo assess the effect of IPT for children with anaemia living in malaria‐endemic areas.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register, Cochrane Central of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and metaRegister of Controlled Trials (mRCT) for ongoing trials up to 4 December 2014.Selection criteriaRandomized controlled trials (RCTs) evaluating the effect of IPT on children with anaemia.Data collection and analysisTwo review authors independently extracted data and assessed risk of bias. We analysed data by conducting meta‐analyses, stratifying data according to whether participants received iron supplements or not. We used GRADE to assess the quality of evidence.Main resultsSix trials with 3847 participants met our inclusion criteria. Trials were conducted in areas of low malaria endemicity (three trials), and moderate to high endemicity (three trials). Four trials were in areas of seasonal malaria transmission. Iron was given to all children in two trials, and evaluated in a factorial design in a further two trials.IPT for children with anaemia probably has little or no effect on the proportion anaemic at 12 weeks follow‐up (four trials, 2237 participants, (moderate quality evidence).IPT in anaemic children probably increases the mean change in haemoglobin levels from baseline to follow‐up at 12 weeks on average by 0.32 g/dL (MD 0.32, 95% CI 0.19 to 0.45; four trials, 1672 participants, moderate quality evidence); and may improve haemoglobin levels at 12 weeks (MD 0.35, 95% CI 0.06 to 0.64; four trials, 1672 participants, low quality evidence). For both of these outcomes, subgroup analysis did not demonstrate a difference between children receiving iron and those that did not.IPT for children with anaemia probably has little or no effect on mortality or hospital admissions at six months (three trials, 3160 participants moderate quality evidence). Subgroup analysis did not show a difference between those children receiving iron supplements and those that did not.Authors' conclusionsTrials did show a small effect on average haemoglobin levels but this did not appear to translate into an effect on mortality and hospital admissions. Three of the six trials were conducted in low endemicity areas where transmission is low and thus any protective effect is likely to be modest.

Severe Anemia in Papua New Guinean Children from a Malaria-Endemic Area: A Case-Control Etiologic Study

BackgroundThere are few detailed etiologic studies of severe anemia in children from malaria-endemic areas and none in those countries with holoendemic transmission of multiple Plasmodium species.Methodology/Principal FindingsWe examined associates of severe anemia in 143 well-characterized Papua New Guinean (PNG) children aged 0.5–10 years with hemoglobin concentration <50 g/L (median [inter-quartile range] 39 [33]–[44] g/L) and 120 matched healthy children (113 [107–119] g/L) in a case-control cross-sectional study. A range of socio-demographic, behavioural, anthropometric, clinical and laboratory (including genetic) variables were incorporated in multivariate models with severe anemia as dependent variable. Consistent with a likely trophic effect of chloroquine or amodiaquine on parvovirus B19 (B19V) replication, B19V PCR/IgM positivity had the highest odds ratio (95% confidence interval) of 75.8 (15.4–526), followed by P. falciparum infection (19.4 (6.7–62.6)), vitamin A deficiency (13.5 (5.4–37.7)), body mass index-for-age z-score <2.0 (8.4 (2.7–27.0)) and incomplete vaccination (2.94 (1.3–7.2)). P. vivax infection was inversely associated (0.12 (0.02–0.47), reflecting early acquisition of immunity and/or a lack of reticulocytes for parasite invasion. After imputation of missing data, iron deficiency was a weak positive predictor (6.4% of population attributable risk).Conclusions/SignificanceThese data show that severe anemia is multifactorial in PNG children, strongly associated with under-nutrition and certain common infections, and potentially preventable through vitamin A supplementation and improved nutrition, completion of vaccination schedules, and intermittent preventive antimalarial treatment using non-chloroquine/amodiaquine-based regimens.

The impact of intermittent preventive treatment with sulfadoxine-pyrimethamine on the prevalence of malaria parasitaemia in pregnancy

The Roll Back Malaria initiatives were introduced to ensure that 60% of pregnant women receive intermittent preventive anti-malarial treatment by the end of 2005 in an attempt to halve the mortality from malaria by 2010. Our aim was to determine the prevalence of asymptomatic malaria parasitaemia in pregnant women on intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) compared with a control group. This comparative study involved testing the peripheral blood of pregnant women on IPT with SP and a control group that did not receive SP for the malaria parasite upon registration and at 34 weeks gestational age. The levels of parasitaemia in the intervention group upon registration (4.9%) and at 34 weeks (63.9%) were not significantly different (P > 0.05) from that of the control group (10%) and at 34 weeks gestation (68.3%). IPT with SP during pregnancy did not significantly reduce the prevalence of the malaria parasitaemia among the pregnant women in our environment.

Follow-up Survey of Children Who Received Sulfadoxine-Pyrimethamine for Intermittent Preventive Antimalarial Treatment in Infants

Recently, the World Health Organization emphasized the potential benefit of intermittent preventive treatment in infants (IPTi) to control malaria and officially recommended implementation of IPTi with sulfadoxine-pyrimethamine (SP) in areas with moderate and high transmission, where SP resistance is not high. As reported rebound effects make further observation mandatory, we performed a survey of participants of a former IPTi trial. Malariometric parameters were similar in the SP and the placebo group. In contrast, anti–Plasmodium falciparum lysate immunoglobulin G antibody levels, a proxy measure for preceding malaria episodes, remained lower in the SP arm. The most likely explanation is a lower overall exposure to parasitic antigens after IPTi.

Malaria Burden in Pregnancy at Mulago National Referral Hospital in Kampala, Uganda

Pregnancy-associated malaria is a major global health concern. To assess the Plasmodium falciparum burden in pregnancy we conducted a cross-sectional study at Mulago Hospital in Kampala, Uganda. Malaria prevalence by each of three measures—peripheral smear, placental smear, and placental histology was 9% (35/391), 11.3% (44/389), and 13.9% (53/382) respectively. Together, smear and histology data yielded an infection rate of 15.5% (59/380) of active infections and 4.5% (17/380) of past infections; hence 20% had been or were infected when giving birth. A crude parity dependency was observed with main burden being concentrated in gravidae 1 through gravidae 3. Twenty-two percent were afflicted by anaemia and 12.2% delivered low birthweight babies. Active placental infection and anaemia showed strong association (OR = 2.8) whereas parity and placental infection had an interactive effect on mean birthweight (P = .036). Primigravidae with active infection and multigravidae with past infection delivered on average lighter babies. Use of bednet protected significantly against infection (OR = 0.56) whilst increased haemoglobin level protected against low birthweight (OR = 0.83) irrespective of infection status. Albeit a high attendance at antenatal clinics (96.8%), there was a poor coverage of insecticide-treated nets (32%) and intermittent preventive antimalarial treatment (41.5%).

Community-Based Promotional Campaign to Improve Uptake of Intermittent Preventive Antimalarial Treatment in Pregnancy in Burkina Faso

Malaria preventive strategies in pregnancy were assessed in a health center randomized trial comparing intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) with and without community based promotional activities in rural Burkina Faso. The study involved 2,240 secundigravidae and secundigravidae and evaluated factors associated with antenatal clinic (ANC) attendance and uptake of IPTp-SP. With promotion, 64.2% completed > or = 3 ANC visits compared with 44.7% without (P = 0.05). Complete uptake of IPTp-SP was 71.8% with and 49.1% without promotion (P = 0.008). The IPTp-SP uptake was lowest in adolescents delivering during high malaria transmission with (29%) or without promotion (30%). Uptake of SP was higher during the low transmission season than in the high transmission season (adjusted odds ratio = 2.17, 95% confidence interval = 1.59-3.03). Community sensitization increased ANC attendance and IPTp-SP uptake. Adolescents were the most difficult to reach, particularly during the high malaria transmission period. The impact of IPTp-SP will be limited unless this high risk group is protected.

Therapeutic and prophylactic effect of intermittent preventive anti-malarial treatment in infants (IPTi) from Ghana and Gabon

BackgroundIntermittent preventive treatment in infants (IPTi) with sulphadoxine-pyrimethamine (SP) reduces the incidence of malaria episodes in young children. The exact mechanism by which the protective effect is mediated needs to be defined. This study aimed to investigate therapeutic, prophylactic, and possible exceeding effects of SP-based IPTi in two clinical trials.MethodsProtective efficacies from two IPTi trials performed in Kumasi, Ghana, and Lambaréné, Gabon, were assessed for overlapping time series of 61 days. For six-months periods after each of three IPTi doses a multivariate Poisson regression model with the respective cohort as co-variate was generated and effect modification of protective efficacy with time strata was evaluated by log-likelihood tests.ResultsProtective efficacies were not significantly different between the two study cohorts. Study-cohort corrected protective efficacy was highest for the first 61 days after each IPTi application and decreased continuously. For the first 61 days after IPTi-1, IPTi-2, and IPTi-3 the protective efficacy was 71%, 44%, and 43%, respectively. A reduction of the malaria incidence rate was detectable for the first 60, 30 and 40 days after IPTi-1, IPTi-2 and IPTi-3 drug application, respectively. After IPTi-3 a higher risk for malaria could be seen after day 60. This effect was mainly based on the overwhelming influence of the Kumasi cohort.ConclusionThe results suggest that SP-based IPTi mainly works through a therapeutic and prophylactic effect over 30 to 60 days after drug application and that a sustained effect beyond post-treatment prophylaxis might be very low.Trial registrationData analysis from clinical trials NCT ID # 00206739 (Kumasi Trial) and NCT ID # 00167843 (Lambaréné Trial), .

Response to Buffet et al: Intermittent preventive anti-malarial treatment to children (IPTc): firebreak or fire trap?

Buffet and colleagues have reviewed some of the potential benefits and drawbacks of intermittent preventive antimalarial treatment in children (IPTc). They acknowledge its efficacy but raise concerns about the feasibility of implementing this intervention, its safety, its impact on drug resistance, the possibility that IPTc might impair the development of naturally acquired immunity and its role in a changing environment. We believe that we can address some, although not all, of their concerns.

Intermittent preventive antimalarial treatment to children (IPTc): firebreak or fire trap?

Intermittent preventive treatment is the prescheduled administration of antimalarial drugs to at-risk patients in endemic areas. This approach, which is recommended for pregnant women, is being evaluated in children. Sulfadoxine-pyrimethamine plus amodiaquine recently proved to be more protective than artemisinin-containing regimens. Therefore, the use of artemisinin derivatives could potentially be restricted to symptomatic patients. Determinants of three pending issues: safety, efficacy throughout childhood, and effectiveness--the latter depending on the implementation of sustainable delivery mechanisms--are analyzed in this comment.

Impact of Intermittent Preventive Anti-Malarial Treatment on the Growth and Nutritional Status of Preschool Children in Rural Senegal (West Africa)

Negative consequences of malaria might account for seasonality in nutritional status in children in the Sahel. We report the impact of a randomized, double-blind, placebo-controlled trial of seasonal intermittent preventive anti-malarial treatment on growth and nutritional status in 1,063 Senegalese preschool children. A combination of artesunate and sulfadoxine-pyrimethamine was given monthly from September to November. In the intervention arm, mean weight gain was significantly greater (122.9 +/- 340 versus 42.9 +/- 344 [SD] g/mo, P < 0.0001) and losses in triceps and subscapular skinfold measurements were less (-0.39 +/- 1.01 versus -0.66 +/- 1.01 mm/mo, and -0.15 +/- 0.64 versus -0.36 +/- 0.62 mm/mo, respectively, P < 0.0001 for both). There was no difference in height increments. The prevalence of wasting increased significantly in the control arm (4.6% before versus 9.5% after, P < 0.0001), but remained constant in intervention children: 5.6% versus 7.0% (P = 0.62). The prevention of malaria would improve child nutritional status in areas with seasonal transmission.

Intermittent Preventive Antimalarial Treatment in Infants

Intermittent preventive antimalarial treatment in infants (IPTi) involves the administration of a curative dose of an antimalarial drug to infants at the time of routine immunization, without determining whether the infant is parasitemic. This approach to the prevention of malaria in infants was tried first by Schellenberg et al. [1] in Ifakara, Tanzania, in 1999. They found that administration of sulfadoxinepyrimethamine (SP) to infants when they presented for vaccination with diphtheria, pertussis, and tetanus or measles vaccines at 2, 3, and 9 months of age reduced the incidence of clinical attacks of malaria and anemia (packed cell volume, !25%) by 59% (95% CI, 41%‐72%) and 50% (95% CI, 8%‐73%), respectively. Remarkably, protection persisted throughout the second year of life, long after SP had disappeared from circulation [2]. A second trial conducted in Tanzania at approximately the same time found that administration of amodiaquine to infants at 3-month intervals during the first year of life had a similar impact on the incidence of clinical attacks of malaria and anemia [3]. These very promising results led to the creation of the IPTi Consortium [4], whose brief is to determine the efficacy, safety, relation of efficacy to drug sensitivity, cost-effectiveness, and acceptability of this promising new approach to the prevention of malaria. Since the results of the initial studies in Tanzania were reported, 5 additional trials of IPTi with SP have been completed, and the results of 3 of these studies have been published—the latest in this issue of Clinical Infectious Diseases [5‐7]. Preliminary results from 2 other trials have been presented at open meetings. A large effectiveness trial of IPTi with SP is underway in southern Tanzania, and the United Nations Children’s Fund is performing pilot implementation studies of IPTi with SP in several countries in Africa. The carefully conducted study reported by Kobbe et al. [7] in this issue of Clinical Infectious Diseases was performed in the Ashanti region of central Ghana. Rainfall in the area is high, and malaria transmission occurs throughout the year, although with seasonal peaks. The entomological inoculation rate is estimated to be ∼400 infectious bites per year. Local strains of Plasmodium falciparum are still moderately sensitive to SP. The design of this new trial did not mimic exactly that of the initial Tanzanian study, because SP was administered to infants aged 3, 9, and 15 months, and cases of malaria were detected predominantly through monthly home visits; in Ifakara, passive case detection was used. One thousand seventy infants were individually randomized to receive SP treatment or placebo, and the groups were matched at entry into the study. In infants and children aged 3‐18 months (including the period 3 months after the last administration of IPTi), the protective efficacy of IPTi against first or single episodes of clinical malaria was 18% (95% CI, 4%‐31%), and the protective efficacy of IPTi against all episodes of clinical malaria was 20% (95% CI, 11%,‐ 29%). No significant protection was ob

A Randomized Controlled Trial of Extended Intermittent Preventive Antimalarial Treatment in Infants

Intermittent preventive antimalarial treatment in infants (IPTi) with sulfadoxine-pyrimethamine reduces falciparum malaria and anemia but has not been evaluated in areas with intense perennial malaria transmission. It is unknown whether an additional treatment in the second year of life prolongs protection. A randomized, double-blinded, placebo-controlled trial with administration of sulfadoxine-pyrimethamine therapy at 3, 9, and 15 months of age was conducted with 1070 children in an area in Ghana where malaria is holoendemic. Participants were monitored for 21 months after recruitment through active follow-up visits and passive case detection. The primary end point was malaria incidence, and additional outcome measures were anemia, outpatient visits, hospital admissions, and mortality. Stratified analyses for 6-month periods after each treatment were performed. Protective efficacy against malaria episodes was 20% (95% confidence interval [CI], 11%-29%). The frequency of malaria episodes was reduced after the first 2 sulfadoxine-pyrimethamine applications (protective efficacy, 23% [95% CI, 6%-36%] after the first dose and 17% [95% CI, 1%-30%] after the second dose). After the third treatment at month 15, however, no protection was achieved. Protection against the first or single anemia episode was only significant after the first IPTi dose (protective efficacy, 30%; 95% CI, 5%-49%). The number of anemia episodes increased after the last IPTi dose (protective efficacy, -24%; 95% CI, -50% to -2%). In an area of intense perennial malaria transmission, sulfadoxine-pyrimethamine-based IPTi conferred considerably lower protection than reported in areas where the disease is moderately or seasonally endemic. Protective efficacy is age-dependent, and extension of IPTi into the second year of life does not provide any benefit.

Delayed cord clamping and haemoglobin levels in infancy: a randomised controlled trial in term babies

This study was carried out to assess whether delaying umbilical cord clamping is effective in improving the haematological status of term infants living in a malaria-endemic area, and whether this is associated with complications in infants and mothers. We randomly assigned women delivering term babies in Mpongwe Mission Hospital, Zambia, to delayed cord clamping (DCC, n = 46) or immediate cord clamping (controls, n = 45) and followed their infants on a bi-monthly basis until the age of 6 months. We compared the haemoglobin (Hb) change from cord values and the proportion of anaemic infants. Secondary outcomes related to infant and maternal safety. Throughout the observation period infant Hb levels in both groups declined, but more rapidly in controls than in the DCC group [difference in Hb change from baseline at 4 months 1.1 g/dl, 95% confidence interval (CI) 0.2; 2.1]. By 6 months, this difference had disappeared (0.0 g/dl, 95% CI -0.9; 0.8). The odds ratio for iron deficiency anaemia in the DCC group at 4 months was 0.3 (95% CI 0.1; 1.0), but no differences were found between the groups at 6 months. No adverse events were seen in infants and mothers. Our findings indicate that DCC could help improve the haematological status of term infants living in a malaria-endemic region at 4 months of age. However, the beneficial haematological effect disappeared by 6 months. This simple, free and safe delivery procedure might offer a strategy to reduce early infant anaemia risk, when other interventions are not yet feasible.

P775 Effects of intermittent preventive anti-malarial treatment of infants in a holoendemic area

P775 Effects of intermittent preventive anti-malarial treatment of infants in a holoendemic area

O65 Spatiotemporal variations of malaria incidence and protective efficacy of intermittent preventive antimalarial treatment of infants

O65 Spatiotemporal variations of malaria incidence and protective efficacy of intermittent preventive antimalarial treatment of infants

Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial

Stopping antimalarial chemoprophylaxis can be followed by increased risk of malaria, suggesting that it interferes with the development of antimalarial immunity. We report analysis of extended follow-up until age 2 years of a randomised, placebo-controlled double-blind trial of intermittent preventive antimalarial treatment in infants. The rate of clinical malaria (events per person-year at risk, starting 1 month after final dose of intermittent treatment) was 0.28 in the sulfadoxine-pyrimethamine group and 0.43 in the placebo group (protective effect 36%, 95% CI 11-53). Intermittent treatment produced a sustained reduction in the risk of clinical malaria extending well beyond the duration of the pharmacological effects of the drugs, excluding a so-called rebound effect and suggesting that such treatment could facilitate development of immunity against Plasmodium falciparum.