Review: Intermittent preventive treatment--a new approach to the prevention of malaria in children in areas with seasonal malaria transmission

Intermittent preventive treatment, the administration of a full course of an anti-malarial treatment to a population at risk at specified time points regardless of whether or not they are known to be infected, is now a recommended approach to the prevention of malaria in pregnancy and is being explored as a potential way of preventing malaria in infants. However, in many malaria endemic areas, the main burden of malaria is in older children and increasing use of insecticide treated bednets is likely to increase further the proportion of episodes of malaria that occur in older children. Recently, it has been shown in Senegal and in Mali that intermittent preventive treatment given to older children during the malaria transmission season can be remarkably effective in preventing malaria. This approach to malaria control is likely to be most effective in areas with a high level of malaria transmission concentrated in a short period of the year. However, several issues need to be addressed before intermittent preventive treatment in children can be advocated for use in malaria control programmes. These include: (1) determination of whether intermittent preventive treatment adds to the protection afforded by other control measures such as insecticide-treated bednets; (2) whether an effective and sustainable delivery system can be found; (3) choice of drug to be used; (4) optimum timing of drug administration; (5) the requisite interval between treatments. The potential benefits of intermittent preventive treatment in children are substantial; more research is needed to determine if this is a practical approach to malaria control.     

Use of antenatal care services and intermittent preventive treatment for malaria among pregnant women in Blantyre District, Malawi

Malaria in pregnancy contributes to low birth weight and increased infant mortality. As part of WHO's Roll Back Malaria initiative, African heads of state pledged that by 2005, 60% of pregnant women will receive malaria chemoprophylaxis or intermittent preventive treatment (IPT). We performed a cluster sample survey to study the use of sulfadoxine-pyrimethamine (SP) for IPT among recently pregnant women in February 2000 in Blantyre District, Malawi. Among 391 women in the sample, 98.6% had attended antenatal clinic at least once and 90.2% knew that SP/IPT was recommended during pregnancy. Overall, only 36.8% received the full recommended two-dose regimen of SP/IPT. Using data from 187 women with antenatal clinic cards, we found that residence location, housing type and gender/age/education of the head of household were not associated with failure to receive SP/IPT. Adjusting for education, multigravid women were more likely not to receive the recommended SP/IPT regimen (RR 1.2, 95% CI 1.02-1.5, P=0.03). A substantial effort to improve the delivery and use of SP/IPT in Malawi will be necessary, but the Roll Back Malaria 2005 goal appears achievable.     

Intermittent preventive treatment of malaria in pregnancy: the effect of new delivery approaches on access and compliance rates in Uganda

OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilizers can administer intermittent preventive treatment (IPT) with sulfadoxine-pyremethamine to pregnant women, and reach those most at risk of malaria and increase access and compliance to it. METHODS: The study was designed to assess new approaches of delivering IPT through these groups and compare it with IPT at health units. The primary outcome measures were: the proportion of adolescents and primigravidae accessed; gestational age at recruitment and the proportion of women who completed two doses of sulfadoxine-pyremethamine. RESULTS: Two thousand seven hundred and eighty-five pregnant women (78% of those in the study area) participated. With new approaches, 92.4% of the women received IPT during the second trimester as recommended by the policy, vs. 76.1% at health units, P < 0.0001. Of the women who received two doses of sulfadoxine-pyremethamine, 39.9% were at health units (control) vs. 67.5% through new approaches (P < 0.0001). Women using the new approaches also accessed IPT early: the mean gestational age when receiving the first dose of sulfadoxine-pyremethamine was 21.0 weeks vs. 23.1 weeks at health units (P < 0.0001). However, the health units were used by a higher proportion of primigravidae (23.6% vs. 20.0%, P < 0.04), and this was also the case for adolescents (28.4% vs. 25.0%, P < 0.03). This intervention was acceptable with 89.1% of the women at the new approaches intending to use IPT in future. CONCLUSIONS: The new approaches increased access to and compliance with IPT. We recommend a review of the policy to allow the provision of IPT through the new approaches.     

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment

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.     

Implementation of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in Kisumu, western Kenya

OBJECTIVE: In 1998, the Kenyan Ministry of Health introduced intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP), one treatment dose in the second trimester (16-27 weeks) and one treatment dose between 28 and 34 weeks of gestational age, for the control of malaria in pregnancy. We evaluated the coverage and determinants of receipt of IPT after its introduction in the Provincial Hospital in Kisumu, western Kenya. METHODS: Information on the use of IPT in pregnancy was collected from women who attended the antenatal clinic (ANC) and delivered in the same hospital. In exit interviews, we assessed patterns of IPT use in the ANC. RESULTS: Of 1498 women who delivered between June 1999 and June 2000, 23.7%, 43.4% and 32.9% received > or =2, 1 or no dose of SP, respectively. Late first ANC attendance was the most important factor contributing to incomplete IPT; 45% of the women started attending ANC in the third trimester. More women received at least one tetanus toxoid immunization than at least one dose of IPT (94%vs. 67%, P < 0.05). In exit interviews, 74% correctly associated IPT with treatment of malaria; however, knowledge on the need for the second dose was poor. Three per cent of the administrations were given despite contraindications. The agreement between gestational age by date of last menstrual period and by palpation was low (kappa = 0.1). CONCLUSIONS: Education of pregnant women and ANC staff to increase earlier attendance for ANC has the potential to substantially increase the proportion of women receiving two doses of IPT with SP.     

Intermittent preventive treatment of malaria in pregnancy: at the crossroads of public health policy

The intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) has been a key component of the focused antenatal care package for nearly a decade, reducing the burden of low birthweight attributable to malaria in sub-Saharan Africa. However, SP has lost parasite sensitivity in many sub-Saharan locations during the same period, rendering its beneficial effect in IPTp debatable. Malaria transmission has also declined in some epidemiological settings. There is no evidence to suggest, however, that the risk of malaria in pregnancy without preventive measures has declined in the same locations. Thus, the urgency to identify efficacious drugs and/or new strategies to prevent malaria in pregnancy remains as great as ever. We summarise the results of recently published SP-IPTp studies from areas of high drug resistance and/or low malaria transmission. We also present the evidence for mefloquine and azithromycin-based combinations (ABCs), two leading drug options to replace SP in IPTp. We discuss optimal dosing for ABCs and their likely protection against several sexually transmitted and reproductive tract infections. We also summarise data from a diagnosis-based alternative to IPTp known as the intermittent screening and treatment (IST) for malaria. Clinical and operational research is urgently needed to compare birth outcomes achieved by IPTp with ABCs vs. IST using an efficacious antimalarial therapy.     

The clinical impact of combining intermittent preventive treatment with home management of malaria in children aged below 5 years: cluster randomised trial

Objective To investigate the impact of seasonal intermittent preventive treatment (IPTc) on malaria‐related morbidity in children <5 years of age who already had access to home‐based management of malaria (HMM) for presumptive treatment of fevers. Method Thirty community‐based drug distributors (CDDs) from all 13 communities of a rural subdistrict in Ghana were trained to provide prompt treatment for presumptive malaria using artesunate‐amodiaquine (AS+AQ) to all children under 5 years of age. Six communities were randomised to also receive bimonthly courses of seasonal IPTc with AS+AQ in May, July and September of 2007. The primary outcome was the incidence rate of febrile episodes diagnosed presumptively as malaria by the CDDs in the communities in each intervention group. Cross‐sectional surveys were conducted to determine the prevalence of parasitaemia and anaemia among the study children. Results During the 6 months in which IPTc was delivered, incidence of fevers in communities given HMM+IPTc was lower than in communities given HMM alone, but this difference was not statistically significant (protective efficacy: 37.0%(95% CI: ?9.7 to 63.8; P = 0.14). However, incidence of presumptive malaria was significantly lower in IPTc communities when only children who received all three courses of IPTc were included in the analysis: protective efficacy 61.5% (95% CI:31.2–78.5; P = 0.018). Protection with IPTc was not followed by rebound morbidity in the following year. At the end of the intervention period, prevalence of asymptomatic parasitaemia was lower in communities that had received IPTc, but there were no differences in anaemia or haemoglobin concentration. Conclusion In this study area, incidence of fevers was lower in communities given three courses of IPTc during the time of peak transmission than in communities that received only HMM. However, high levels of coverage for IPTc will be necessary for maximum impact.     

Reaching the Abuja target for intermittent preventive treatment of malaria in pregnancy in African women: a review of progress and operational challenges

OBJECTIVE: To review progress with the implementation of intermittent preventive treatment (IPT) for the control of malaria in pregnancy in sub-Saharan Africa (SSA), in order to identify facilitating factors and operational challenges for scaling up IPT delivery. METHODS: Information on the status of IPT policy, programme and coverage indicators was extracted from published sources. Information on country experiences from both published and unpublished literature was supplemented with semi-structured interviews with malaria programme managers. RESULTS: Whilst countries in SSA have made important progress with IPT implementation, coverage levels remain low. High antenatal clinic (ANC) attendance alone is not sufficient to ensure high IPT coverage. Staff shortages, poor drug supply, poor ANC access and poor health worker practices are some of the operational challenges in delivering IPT. CONCLUSION: Country experiences show that IPT can be introduced and scaled up relatively quickly and effectively where there is political will, effective integration between malaria and reproductive health programmes, adequate funding and drug supply, high ANC attendance and community receptiveness. There is however urgent need to better document best practices and lessons as a basis for developing simplified guidelines for dissemination to countries embarking on IPT implementation.     

Adherence to artesunate–amodiaquine combination therapy for uncomplicated malaria in children in Zanzibar, Tanzania

Objectives  To estimate caretaker adherence to co-blistered, but not co-formulated, artesunate-amodiaquine (AsAq) for uncomplicated malaria and identify factors associated with caretaker adherence.
Methods  Cross sectional household survey of caretakers of 210 children under 5 years of age who had been prescribed and dispensed AsAq at 21 public health facilities (HFs). The caretakers were interviewed in their homes on the 4th day of receiving the 3 day treatment. Adherence of caretakers was assessed by self report and pill count.
Results  Caretaker adherence to AsAq was 77% (95% CI: 67%–87%). Non-adherence resulted in under-dosing ¾ of the time and was most often in the form of wrong daily doses due to misunderstanding or forgetting the correct dose regimens. Predictors of adherence were education exceeding 7 years (OR = 5.08, P  = 0.008) and receiving the exact number of pills to complete the treatment regimen (OR = 4.09, P  = 0.006). All caretakers of children who were administered the first dose at the HF had adhered to the treatment.
Conclusion  We found moderate levels of caretaker adherence to AsAq. Further improvement could be achieved by producing dose-specific packaging for infants, providing clear instructions and giving the first dose under observation at the HF.     

Immune responses after single-dose sulphadoxine-pyrimethamine indicate underestimation of protective efficacy of intermittent preventive treatment in infants

OBJECTIVE: To assess how intermittent preventive treatment in infants (IPTi) with sulphadoxine-pyrimethamine (SP) affects Immunoglobulin (IgG) immune responses against Plasmodium falciparum in infants from rural Ghana. METHODS: Randomized, placebo-controlled and double-blinded clinical trial with participants randomized in blocks of 10 to receive either 250 mg sulphadoxine/2.5 mg pyrimethamine or placebo at the age of 3 (IPTi-1), 9 (IPTi-2) and 15 (IPTi-3) months and followed-up for 21 months. (i) Anti-P. falciparum IgG levels were measured in 180 children at the age of 9 months. (ii) Longitudinal study of the relationship between IgG levels and P. falciparum infections and/or clinical malaria in 17 naive children until they reached the age of 2 years. RESULTS: IgG antibody levels against crude P. falciparum lysate were dependent on the frequency of preceding infections and significantly lower in children treated with SP. CONCLUSION: Placebo-treated children had an indifferentially higher incidence of P. falciparum infections than clinically observed, which implicates an underestimation of the protective efficacy of IPTi. IgG profiles in 17 children followed up until the age of 2 years provided no evidence for impaired immune responses after a single dose of SP within the framework of IPTi.     

A randomized, placebo-controlled trial of intermittent preventive treatment with sulphadoxine-pyrimethamine in Gambian multigravidae

We investigated the ability of intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine/pyrimethamine to prevent anaemia and low birthweight in Gambian multigravidae. Between July 2002 and February 2004, 2688 multigravidae living in a rural area of The Gambia received SP (1346 women) or placebo (1342 women) up to four times during pregnancy and were followed until 6-weeks post-partum. Shortly after delivery, 10.7% of women in the intervention group and 8.8% in the control group were severely anaemic [Hb < 7 g/dl, risk difference = 0.02 (95% CI -0.01, 0.04), P = 0.17]. The overall mean birthweight of infants born to women who had received SP (3103 g) was very similar to that observed in infants born to women in the control group [3075 g; difference = 28 g (95% CI -11 g, 67 g), P = 0.16]. However, among women who did not use a bednet (either insecticide treated or untreated), infants born to women who had received SP weighed more than infants born to women in the control group [3147 g vs. 3044 g; difference 143 g (95% CI 53 g, 232 g), interaction test P < 0.001]. This study did not show that IPTp with SP benefited Gambian multigravidae overall but that it may benefit a sub-group of women who do not use a bednet. In areas such as The Gambia, provision of insecticide-treated bednets to multigravidae may provide an adequate means of protection against malaria in pregnancy without the need for additional IPTp.     

The effect of health care worker training on the use of intermittent preventive treatment for malaria in pregnancy in rural western Kenya

BACKGROUND: In 1998, Kenya adopted intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) for malaria prevention during pregnancy. We conducted a survey in 2002 among women who had recently delivered in the rural neighbouring areas Asembo and Gem and reported coverage of 19% of at least one dose and 7% of two or more doses of SP. Health care workers (HCW) in Asembo were retrained on IPTp in 2003. OBJECTIVES: To evaluate if IPTp coverage increased and if the training in Asembo led to better coverage than in Gem, and to identify barriers to the effective implementation of IPTp. METHODS: Community-based cross-sectional survey among a simple random sample of women who had recently delivered in April 2005, interviews with HCW of antenatal clinics (ANC) in Asembo and Gem. RESULTS: Of the 724 women interviewed, 626 (86.5%) attended the ANC once and 516 (71.3%) attended two or more times. Overall IPTp coverage was 41% for at least one dose, and 21% for at least two doses of SP. In Asembo, coverage increased from 19% in 2002 to 61% in 2005 for at least one dose and from 7% to 17% for two doses of SP. In Gem, coverage increased from 17% to 28% and 7% to 11%, respectively. Interviews of HCW in both Asembo and Gem revealed confusion about appropriate timing, and lack of direct observation of IPTp. CONCLUSION: Training of HCW and use of simplified IPTp messages may be a key strategy in achieving Roll Back Malaria targets for malaria prevention in pregnancy in Kenya.     

Artemisinin-based combination therapy reduces expenditure on malaria treatment in KwaZulu Natal, South Africa

INTRODUCTION: There is growing international evidence that artemisinin-based combination therapy (ACT) is one of the few effective measures available to 'Roll Back Malaria'. However, concerns about the costs and affordability of ACT are obstacles to its widespread implementation. This paper explores some economic aspects of the implementation of artemether-lumefantrine (AL) to replace sulphadoxine-pyrimethamine (SP) in the KwaZulu Natal (KZN) province, South Africa. METHODS: Recurrent and capital costs for malaria treatment were compared at baseline and post-intervention for nine clinics and a sentinel rural district hospital. Changes in the unit costs of, and total expenditure on, malaria services were calculated and the cost effectiveness of AL relative to SP was assessed. RESULTS: The number of outpatient malaria cases and inpatient admissions both declined by 94% between 2000 and 2002. After accounting for the role of concurrent improvements in vector control, it was conservatively estimated that 36% of the decline in outpatient cases and 46% for inpatient admissions was attributable to changing the first-line drug to AL. Although AL is considerably more expensive than SP, its improved cure rate and reduced malaria transmission resulted in an estimated 201,065 US dollars cost saving in 2002 alone for the subdistrict studied. DISCUSSION: In the context of effective vector control and low efficacy of existing monotherapy, ACT can reduce total expenditure on malaria services. However, the relevance of these findings requires careful consideration in countries with currently effective treatment policies and higher intensity malaria transmission.     

Early treatment of childhood fevers with pre-packaged antimalarial drugs in the home reduces severe malaria morbidity in Burkina Faso

In rural, malaria-endemic Burkina Faso, we evaluated the impact of the use of pre-packaged antimalarial drugs (PPAM), by mothers in the home, on the progression of disease in children from uncomplicated fever to severe malaria. In each village of one province, a core group of opinion leaders (mainly older mothers) was trained in the management of uncomplicated malaria, including the administration of PPAM. Full courses of antimalarial (chloroquine) and antipyretic (aspirin) drugs were packaged in age-specific bags and made widely available through community health workers who were supplied through the existing drug distribution system. Drugs were sold under a cost-recovery scheme. Local schoolteachers conducted surveys in a random sample of 32 villages at the end of the high transmission seasons in 1998 and 1999. Disease history and the treatment received were investigated for all children under the age of 6 years having suffered from a fever episode in the previous 4 weeks. 'Uncomplicated malaria' was defined as every episode of fever and 'severe malaria' as every episode of fever followed by convulsions or loss of consciousness. During the study period, 56%[95% confidence interval (CI) 50-62%] of 3202 fever episodes in children under 6 years of age were treated promptly by mothers with the pre-packaged drugs made available by the study. A total of 59% of children receiving PPAM were reported to have received the drugs over the prescribed 3-day period, while 52% received the correct age-specific dose. PPAM use was similar among literate (61%) and non-literate mothers (55%) (P = 0.08). The overall reported risk of developing severe malaria was 8%. This risk was lower in children treated with PPAM (5%) than in children not treated with PPAM (11%) (risk ratio = 0.47; 95% CI 0.37, 0.60; P < 0.0001). This estimate of the impact of PPAM was largely unchanged when account was taken of potential confounding by age, sex, maternal literacy status, year or village. Our findings support the view that, after appropriate training and with adequately packaged drugs made available, mothers can recognize and treat promptly and correctly malarial episodes in their children and, by doing so, reduce the incidence of severe disease.     

Revaccination with Bacillus Calmette-Guerin (BCG) vaccine does not reduce morbidity from malaria in African children

BACKGROUND: Studies in West Africa and elsewhere have suggested that Bacillus Calmette-Guérin (BCG) vaccine given at birth is beneficial for child survival. It is possible that this effect is mediated partly through an effect on malaria, a hypothesis supported by animal studies. We investigated whether revaccination with BCG at 19 months of age reduced morbidity from malaria. METHOD: In the capital of Guinea-Bissau, between January and November 2003, children who had previously received BCG vaccination and who did not have a strong reaction to tuberculin were individually randomised to either receive revaccination with BCG at the age of 19 months or to be a control. Episodes of malaria were recorded during the 2003 malaria transmission season through passive case detection at health centres in the study area and at the national hospital. Cross-sectional surveys were carried out at the beginning and at the end of the rainy season. RESULTS: Incidence rates of first episodes of malaria associated with any level of parasitaemia were 0.16 episodes per child-year among 713 revaccinated children and 0.12 among 720 control children [incidence rate ratio (IRR) = 1.37; 95% confidence intervals (CI): 0.84-2.25]. Results were similar when the diagnosis of malaria was based on the presence of parasitaemia >5000 parasites/microl (IRR = 1.30; 95% CI: 0.61-2.77). The incidence of all-cause hospitalisation was higher among BCG-revaccinated children than among controls (IRR = 2.13; 95% CI: 1.10-4.13). There were no significant differences in the prevalence of parasitaemia between the two groups of children at cross-sectional surveys. CONCLUSION: We found no evidence that BCG revaccination reduces morbidity from malaria.     

Mother-to-child transmission of HIV-1: association with malaria prevention, anaemia and placental malaria

Objectives

Malaria infection may impact on mother‐to‐child transmission (MTCT) of HIV‐1. Prevention of malaria in pregnancy could thus potentially affect MTCT of HIV. We studied the impact of intermittent preventive treatment during pregnancy (IPTp) on HIV‐1 MTCT in southern Mozambique.

Methods

A total of 207 HIV‐positive Mozambican pregnant women were enrolled in the study as part of a randomized placebo‐controlled trial of two‐dose sulfadoxine‐pyrimethamine (SP) IPTp in women receiving single‐dose nevirapine to prevent MTCT of HIV. HIV RNA viral load, maternal anaemia and peripheral and placental malaria were assessed at delivery. Infant HIV status was determined by DNA polymerase chain reaction (PCR) at 1 month of age.

Results

There were 19 transmissions of HIV in 153 mother–infant pairs. IPTp with SP did not have a significant impact on MTCT (11.8% in the SP group vs. 13.2% in the placebo group; P=0.784) or on maternal HIV RNA viral load [16 312 (interquartile range {IQR} 4076–69 296) HIV‐1 RNA copies/mL in the SP group vs. 18 274 (IQR 5471–74 104) copies/mL in the placebo group; P=0.715]. In multivariate analysis, maternal HIV RNA viral load [adjusted odds ratio (AOR) 19.9; 95% confidence interval (CI) 2.3–172; P=0.006] and anaemia (haematocrit <33%; AOR 7.5; 95% CI 1.7–32.4; P=0.007) were independent risk factors for MTCT. Placental malaria was associated with a decrease in MTCT (AOR 0.23; 95% CI 0.06–0.89; P=0.034).

Conclusions

IPTp with SP was not associated with a significant impact on MTCT of HIV. Maternal anaemia was an independent risk factor for MTCT.     

Child malaria treatment practices among mothers in the district of Yanfolila, Sikasso region, Mali

We studied child malaria treatment practices among mothers living in the District of Yanfolila in southern Mali. For sampling, we first chose five of 13 health areas with probability proportional to size. Then villages, compounds and mothers with at least one child aged 1-5 years were randomly chosen. We assessed the spleen size of one 1-5 year-old child of each mother, collected a thick blood film and recorded the body temperature of every child whose mother thought he/she was sick. 399 mothers in 28 villages were interviewed with a structured questionnaire divided into two parts. If the child had had soumaya (a term previously associated with uncomplicated malaria) during the past rainy season, we asked about signs and symptoms, health-seeking behaviour (who the mother consulted first) and treatment. If not, information about knowledge of the disease and treatment to be given was collected. 86% of the mothers interviewed stated that their child had been sick and almost half of them had had soumaya. All mothers named at least one sign by which they recognized the disease. Vomiting, fever and dark urine/yellow eyes/jaundice were the three most common signs mentioned. 75.8% managed their child's disease at home and used both traditional and modern treatment. The most common anti-malarial drug was chloroquine, often given at inappropriate dosage. The sensitivity and specificity of the mothers' diagnosis was poor, although this might be explained by the large percentage of children who had already been treated at the time of the interview. The results of our survey call for prompt educational action for the correct treatment of uncomplicated malaria/soumaya, particularly for mothers and possibly for shopkeepers. The high spleen rate (58.1%) among randomly selected children confirms that malaria is a common disease in this area. Improved case-management at home could only be beneficial.