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Intermittent preventive treatment against malaria: an update Expert Rev. Anti Infect. Ther. 8(5), 589–606 (2010)
Roly D Gosling†1,2, Matthew E Cairns1, R Matthew Chico1 and Daniel Chandramohan1 Department of Tropical and Infectious Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK 2 Department of Medical Microbiology, Royal Free Hospital NHS Trust, Pond Street, London, NW3 2QG, UK † Author for correspondence:
[email protected] 1
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. Keywords : anemia • children • infants • intermittent preventive therapy • malaria • pregnancy • school children • seasonal
Malaria is a major cause of morbidity and mortality worldwide. Globally, it is estimated that some 2.37 billion people live at risk of Plasmodium falciparum infection, the most virulent of the human malaria parasites [1] . P. falciparum malaria causes 250 million clinical episodes and 850,000 deaths every year, the overwhelming majority of which occur in subSaharan Africa [2–4] . Malaria transmission has fallen recently in some parts of Africa, leading to localized reductions in the malaria burden [5–10] , but the incidence remains high in many other areas. Global malaria control strategies have changed over time. In the 1950s the focus of the WHO was on eradication of malaria, although formal campaigns never included Africa. By the mid1960s, eradication efforts were seen to have failed. The strategy then moved towards malaria control, prioritizing the reduction of disease burden in children and pregnant women. With historically high levels of funding in recent years, elimination and eradication of malaria have, again, become stated objectives of the WHO. These different goals require distinct operational approaches. Specifically, eliminating or eradicating transmission calls for reducing carriage of malaria in all individuals, whereas reducing disease burden necessitates a focus on treating www.expert-reviews.com
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clinical disease or preventing infections in highrisk groups. Intermittent preventive treatment (IPT) is one approach to reduce parasite carriage and disease burden amongst the most vulnerable individuals. Intermittent preventive treatment with s ulfadoxine–pyrimethamine (SP) was first investigated in pregnant women (IPT in pregnant women [IPTp]) as an alternative to weekly chloroquine (CQ) chemoprophylaxis, a preventive strategy challenged by poor compliance [11,12] and widespread CQ resistance [13] . SP was viewed as a safe alternative that could be directly administered during antenatal consultations. Relatively easy and cheap to implement, IPTp was quickly recommended by the WHO as policy for areas of high malaria transmission [14] , although adoption of the policy has taken some years. The success of IPTp led to adaptation of this approach in infants and children. Regular chemoprophylaxis was known to reduce malaria and increase hemoglobin concentrations in children less than 5 years of age. However, children who received regular chemoprophylaxis experienced an increase in malaria attacks the year after prophylaxis was discontinued [15–17] . Although poorly understood, it appears that continuous chemoprophylaxis hinders the development of host immunity in young children,
© 2010 Roly D Gosling
ISSN 1478-7210
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causing a ‘rebound effect’. Researchers hypothesized that SP provided to infants less often during scheduled vaccinations might clear asymptomatic infections and prevent anemia whilst interfering less with immune development. The first trial of IPT in infants (IPTi) showed an impressive protective effect of 59% against clinical malaria and 50% protection against severe anemia [18] . This prompted further investigation of IPTi as a control tool, and development of a research agenda to consider the possibility of extending IPT to protect children outside infancy. The use of IPT in children has since been studied using a variety of delivery methods. In recent years IPT research in children has been formalized into two broad themes: IPT in young children (IPTc) and IPT in school children (IPTsc). The objectives of these two strategies are different. IPTc attempts to prevent malaria episodes and other acute consequences of infection in young children who lack acquired immunity. To date, IPTc studies have predominantly involved monthly administration of antimalarial drugs to children less than 5 years of age in areas with seasonal malaria transmission [19] . Monthly SP has also been shown to be effective for management of anemia when given with iron supplementation [20–23] . Meanwhile, the primary objective of IPTsc is to reduce the consequences of chronic infection in older children who harbor asymptomatic parasitemia. Reducing anemia was the main benefit, although clearance of long-term infections may also improve cognitive abilities and school performance [24] . Although only IPTp is recommended by the WHO, IPT as a principle has become an accepted form of malaria control. It is thought to be preferable to continuous chemoprophylaxis for several reasons. First, fewer doses of drugs and fewer health-service contacts are required for implementation. Second, because IPT is normally given under supervision, rather than by self-administration, high compliance and correct dosing is more likely than with long-term chemoprophylaxis. Fewer treatments and correct doses may also increase tolerability. Third, as drugs are given intermittently and only to high-risk groups, the selection pressure that drives resistance may be minimized. Finally, because bloodstage malaria is not prevented between each treatment, IPT may be less likely to interfere with the development of antimalarial immunity when used in infants and children. This review examines the purpose, mechanism, drugs used, and controversies and new directions for each of the IPT strategies.
A characteristic unique to P. falciparum is that infected erythrocytes adhere to chondroitin sulphate A (CSA) molecules and sequester along the endothelial and syncytiotrophoblast cells of the human placenta [37] . For this reason, screening of peripheral blood may fail to detect infection of the placenta. Parasitemia triggers an inflammatory response, elevating levels of TNF-a and IL-10 [38] , but the mechanisms by which malaria initiates parturition are poorly understood. Chronic infection is associated with IUGR, whilst acute infection is more commonly the cause of miscarriage or stillbirth [39] . Placental insufficiency may compromise the exchange of vital nutrients between mother and fetus [40,41] . However, placental malaria does not appear to interfere with the transport of vitamin A [42] , iron [43] , folacin or cobalamin [44] . It is possible that parasitic invasion of the trophoblast has an effect similar to that of preeclampsia, decreasing placental circulation by undermining normal remodeling of spiral arteries into dilated utero-placental vessels [45] . Although not observed in other studies [46,47] , a recent trial found an increase in the risk of hypertension among primigravidae who also had chronic placental malaria. Hypertension could have been caused by the fetal response to placental inflammation [48] . In high-transmission settings, multigravidae exhibit anti-adhesion antibodies that target CSA-binding parasites [49] and are better able to control parasite densities compared with paucigravidae [37] . Placental and CSA-selected parasites selectively transcribe the var2csa gene [50–52] . Because var2csa-specific IgG is only found in women and is a positively associated parity [53] , a pre-erythrocytic vaccine that induces protection and is nonstrain-specific would be an appropriate candidate for vaccine development [54] . Infection with HIV removes the parity-specific pattern of malaria risk in pregnant women [55] and coinfection with malaria increases the risk of maternal anemia and LBW by as much as 35% [56] . Monthly IPTp with SP, however, has been shown to achieve similar protection in pregnant women who are HIV-positive as two courses taken by pregnant HIV-negative women [56] .
IPT in pregnancy
Resistance to SP
Purpose
Despite the considerable loss of parasite sensitivity in recent years, IPTp with SP remains efficacious in areas where SP treatment failure rates at day 14 among children under 5 years of age are as high as 40% [57] . However, because SP is no longer the firstline treatment for uncomplicated malaria in the region, a similar analysis would ideally establish the prevalence threshold of molecular markers specific to SP resistance above which IPTp with SP should no longer be used. The rapid reduction in SP use has reduced drug pressure for selection of resistant mutants but it is unknown if and how quickly this might translate into renewed parasite sensitivity. If there is a high fitness cost for SP resistance mutations in the absence of SP exposure, then drug
Each year 50 million pregnancies are at risk of malaria infection, the majority of these pregnancies occurring in sub-Saharan Africa [25] . Malaria in pregnancy is associated with intrauterine growth retardation (IUGR) [26,27] , preterm birth [28,29] , low birthweight (LBW) [30–32] and maternal anemia [33–35] . The purpose of IPTp is to reduce the risk of LBW and maternal anemia by clearing asymptomatic peripheral and placental parasitemia whilst providing pregnant women intermittent protection against malaria infection between antenatal consultations. The WHO recommends administration of two to three courses of SP (three tablets total, 500 mg sulfadoxine and 25 mg pyrimethamine per tablet) after 590
fetal quickening, with each course given no less than 1 month apart and all prior to the last month of pregnancy [36] . IPTp has been adopted as national policy in 37 countries worldwide, 33 of which are in the sub-Saharan region [2] . Mechanism
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sensitivity could return quickly as witnessed in Malawi with CQ. High in vitro sensitivity to CQ emerged within just 5 years of suspending it as the first-line treatment [58] . Establishing a new proxy threshold for policymakers would be important since there may be some locales where SP resistance is extremely high and the use of IPTp may actually increase parasitemia among pregnant women [59] . A prospective birth cohort of 880 Tanzanian women in an area of high resistance to SP showed that 112 (12.7%) had placental malaria at delivery. Data on IPTp exposure was available for 104 patients, of which 17 (16.4%) with placental infection had received no IPTp, 77 (74.0%) were given IPTp early in pregnancy, and ten (9.6%) had been given IPTp recently. Mean parasitemia across treatment groups was 6.7% with the lowest rate, 1.9%, among women who had not been administered IPTp, in contrast to 6.4% in women with early IPTp, and 14.1% among recent recipients. The difference in placental parasitemia between women exposed and unexposed to IPTp was highly significant (adjusted difference: 4.9%; p = 0.003) [59] . Nearby SP resistance levels in children under 5 years of age were very high with day 28 failures in excess of 80% associated with near saturation of the dhfr/dhps quintuple mutation and the appearance of a third mutation in the parasite dhps gene at codon 581 [60] . Pyrimethamine may be culpable. Women in Ghana were given prophylactic pyrimethamine during pregnancy, only to have parasite loads increase [61] . These findings are consistent with a model where the most highly resistant parasites repopulate more rapidly than less fit parasite populations when placed under drug pressure [62] . Despite these observations, the benefits of IPTp with SP continue to outweigh the risks and there are no recommendations to stop using SP in settings of high SP resistance. High priority must be given to identifying safe and affordable alternatives to SP [54,57] . Drugs for IPTp
Currently the WHO policy only recommends SP for IPTp. Owing to rising concerns about continuing efficacy of this drug combination, alternatives are being sought. Several reviews have described potential alternatives to SP [58,63–66] with mefloquine and azithromycin (AZ)-based combinations being the leading candidates under investigation. Having never been used before in the sub-Saharan region on any scale, mefloquine is likely to have good protective efficacy. A recent randomized clinical trial in Benin (n = 1601) showed mefloquine to be more efficacious than SP in preventing placental malaria (prevalence: 1.7 vs 4.4% of women; p = 0.005) and clinical malaria (incidence: 26 cases per 10,000 person-months vs 68 cases per 10,000 person-months; p = 0.007) [67] . Mefloquine also has appeal because it can be administered like SP, as a single observed-dose during antenatal consultations, although the dose of 15 mg per kg bodyweight may not be well tolerated. The Benin study found that 78% of subjects assigned to the mefloquine group experienced vomiting, dizziness, tiredness and/or nausea whilst one subject had severe neuropsychiatric symptoms. The authors suggest a split-dose regimen of 10 mg/kg, followed by 5 mg/kg given over 2 days, or 6–8 h apart may be better tolerated [67] . A Cochrane review of drugs for preventing malaria in travelers noted 22 published case reports of www.expert-reviews.com
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deaths, including five suicides, associated with mefloquine use at normal dosages. No other drugs reviewed had resulted in death when used as prescribed [68] . Azithromycin-based combinations may also be used in IPTp, offering antimalarial and antibacterial protection. Doses of AZ between 500 and 2000 mg have been used in all trimesters of human pregnancy for the treatment of upper and lower respiratory tract infections, skin diseases, Chlamydia trachomatis, mycoplasma and group B streptococci infections. Meta-analysis among pregnant women with C. trachomatis infection found AZ to be associated with significantly fewer gastrointestinal adverse events than erythromycin (odds ratio [OR]: 0.11; 95% CI: 0.07–0.18) and significantly fewer total adverse events (OR: 0.11; 95% CI: 0.07–0.18) [69] . However, AZ in a placebo-controlled trial produced three times more gastrointestinal effects among HIV-positive patients, 67 of 85 (78.9%), compared with 24 of 89 (27.5%) subjects who received placebo [70] . Case reports suggest that HIV-positive patients may also experience temporary ototoxicity with AZ use [71] . No evidence of teratogenicity has been observed in animal models with quantities equivalent to four-times a human treatment dose [72–74] . The potency of AZ, a translation inhibitor, is greatest against the progeny of malaria parasites that inherit a nonfunctioning apicoplast following drug exposure. This manifests as ‘delayed death’ among malaria parasites. AZ requires a 3-day course of daily doses of 1 g with a fast-acting partner drug that is pharmaco logically compatible [58] . A smaller dose, shorter course or an inappropriate partner drug can be expected to produce suboptimal results. AZ plus CQ has an additive-to-synergistic effect in vitro against P. falciparum whilst AZ–mefloquine and AZ–pyronaridine combinations are both additive [75] . By contrast, AZ and artesunate (AS) were found to have antagonistic effects when used against fresh P. falciparum samples [75] , a confirmation of earlier observations in which clones and culture-adapted malaria parasites were used [76] . In vivo antagonism between AZ and AS may explain the poor performance of the AZ–AS combination in a recent pediatric trial that suspended recruitment early [77] . In vivo synergy between AZ and CQ has been demonstrated in India against P. falciparum infection. After receiving 1 g of AZ for 3 days, 19% of subjects (three of 16) had eradicated parasites by day 28. Of subjects who received a daily dose of 600 mg CQ for 3 days, 27% (four of 15) were parasite-free at day 28. When coadministered, however, AZ and CQ produced 97% parasitological cure through to day 28 [78] . Azithromycin could be combined with piperaquine (PQ) to improve adherence; PQ is at least as effective as, and better tolerated than, CQ [79] . AZ plus SP is another option for IPTp in areas where SP resistance is not high; this combination would avoid the side effect of pruritus found with CQ. Controversies & new directions Changing transmission
Several malaria control tools have been scaled-up in recent years, altering local transmission rates. Indoor residual spraying (IRS) has provided protection for 9% of the general population at risk 591
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of infection, whilst 31% of households owned at least one insecticide-treated net (ITN) in 2008, compared with 17% in 2006, with ownership exceeding 50% in 13 countries [2] . An estimated 20% of pregnant women received two courses of IPTp with SP between 2007 and 2008, ranging from 3% in Angola to 66% in Zambia [2] . Rwanda reports that malaria transmission has reduced to such a point that parasitemia may no longer affect birthweight [80] . In the Benin study previously described, the superiority of mefloquine over SP in preventing placental and clinical infection did not translate into a statistically significant reduction in the rate of LBW: 8% of women who received mefloquine (n = 735) gave birth to LBW newborns, whilst 9.8% of those administered SP had LBW infants (difference: -1.8%; 95% CI: -4.8–1.1) [67] . At enrollment, 53% of women in both treatment groups said they had slept under an ITN the previous night. Thus, if ITN use continued throughout the trial, SP and mefloquine may have encountered fewer placental parasites upon which to act, diluting the protective effect that either treatment could have exerted on birthweight. Similar interaction between ITNs and IPTp may explain, in part, the results of a randomized placebo-controlled trial in Mozambique. With all participants having received a new ITN at enrollment, two antenatal courses of SP had no protective effect against LBW (relative risk [RR]: 0.99; 95% CI: 0.70–1.39) or overall placental infection (p = 0.964) [81] . SP did demonstrate protection against malaria parasitemia at 8 weeks postpartum (RR: 0.52; 95% CI: 0.27–0.99; p = 0.044). It is unknown if this resulted in protection over a longer time frame, but this observation is important since the maternal risk of infection in the early postpartum period is higher than at any time during pregnancy [82] . In areas where there may be high ITN or IRS coverage resulting in the risk of malaria infection being greatly declined, the protection of SP against LBW may be limited to the effect of sulfadoxine against several common reproductive tract and sexually transmitted infections (RTI/STIs). Sulfadoxine is part of the sulfonamide family, compounds which have been used since the 1930s for their antibacterial properties. Sulfadoxine may be active against Neisseria gonorrhoeae and C. trachomatis since sulfameth oxazole is curative against both [83–85] . Sulfadoxine may also inhibit the effects of bacterial vaginosis. In vitro testing of three sulfonamides, sulfacetamide, sulfathiazole and sulfabenzamide, has shown strong growth inhibition of Gardnerella vaginalis, the most abundant microbial flora found in bacterial vaginosis [86] . AZ-based combinations that contain 3 g of AZ are most likely to provide optimal protection against RTI/STIs whilst clearing P. falciparum. Trials that employ fewer than 3 g may fail to detect these benefits [87,88] . Increasing coverage of IPTp with SP should be encouraged while safe and affordable alternatives are identified, with the exception being localities where extreme SP resistance has been observed. Changing transmission patterns may also reduce parity-acquired immunity in endemic areas, thus making previously immune multigravidae vulnerable to placental parasitemia. Reducing transmission rates raises the question of whether a ‘malaria only’ 592
replacement for SP, such as mefloquine, can be justified if an AZ-based combination is capable of offering similar protection against the occasional P. falciparum infection whilst also offering broader benefits against RTI/STIs. Future research
Comprised of 40 partner institutions in 28 countries around the world, a collaborative approach to answering questions on IPTp has been undertaken under the auspices of the Malaria in Pregnancy (MiP) Consortium [201] . In sub-Saharan Africa, the MiP Consortium is focused on: identifying at least one safe and effective alternative to SP for use in IPTp in the region with an emphasis on mefloquine and AZ-based combinations; assessing the protective effect of providing seasonal IPTp; and determining the optimal use of IPTp where ITN protection is simultaneously used. Additional studies are being conducted by other investigators with similar objectives. Table 1 summarizes key IPTp trials involving mefloquine or AZ that have already been conducted as well as planned studies that have been registered with ClinicalTrials.gov. There has been some concern that AZ use might increase the prevalence of AZ- and erythromycin-resistant pneumococci. Trachoma eradication campaigns, having used AZ among targeted children in Australia and Nepal, found that treatment did select for macrolide-resistant pneumococcal strains in the nasopharynx [89,90] and conjunctiva [91] . Selection, however, was transient [89,92] . This needs to be demonstrated in IPTp trials and routinely monitored if an AZ-based combination is adopted as policy. Delivery strategies need to be investigated specific to mefloquine and AZ-based combinations. Since mefloquine will likely require a split-dose to be well tolerated and AZ-based combinations rely upon 3-day regimens, only the first day of treatment will be observed for certain. Operational research is needed to determine if home visits through an ‘active delivery’ strategy with community health workers, community reproductive health workers and traditional birth attendants are needed to achieve high levels of adherence. A nonrandomized community trial in Uganda found that IPTp provided through a similar network was able to reach 67.5% (1404 of 2081) of pregnant women with two courses of SP whist the formal health system was only able to achieve similar coverage for 39.9% (281 of 704) [93] . Another study of active delivery in Uganda yielded even more impressive results. Community-directed drug distributors of ivermectin for onchocerciasis control also provided at least two courses of IPTp with SP to 88.5% of pregnant women (401 of 473). Health facilities passively reached 52.3% (237 of 453) of participants [94] . Given the combined antimalarial and antimicrobial protection that AZ-based combinations are likely to provide, ethnographic studies should assess whether knowledge of such broad-spectrum protection might affect the motivation of pregnant women to remain compliant and seek at least two courses of IPTp. The combination of AZ–CQ has a unique advantage in that it can be safely administered in any trimester. Knowing this may increase Expert Rev. Anti Infect. Ther. 8(5), (2010)
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Table 1. Intermittent preventive treatment in pregnancy trials using mefloquine, azithromycin-based combinations, or intermittent screening and treatment with sulfadoxine–pyrimethamine alternative. Trial location
Seasonality
Drugs used
Subject profile and sample size
End points
Ouidah, Benin
Seasonal
SP IPTp MQ IPTp
All parities enrolled at 16–28 weeks of gestation (n = 1601)
Blantyre, Malawi
Perennial with SP IPTp seasonal peak AZ + SP IPTp AS + SP IPTp
All parities enrolled at 14–26 weeks of gestation (n = 141)
Mangoch, Malawi
Perennial with CQ seasonal peak MQ IPTp
All parities enrolled (n = 3380)
Thai–Burma border
Seasonal
Placebo MQ IPTp
Juaben, Ghana
Seasonal
IST with RDT and SP Rx + ITN AQ + AS IPTp SP IPTp + ITN
All parities enrolled at >20 weeks of gestation (n = 339) All parities enrolled at 16–20 weeks of gestation (n = 3330)
Primary: LBW: MQ = 8% (59 of 735); SP = 9.8% (72 of 730); difference between mean LBW = 1.8% (95% CI: -4.8–1.1%) Secondary: • Placental parasitemia: MQ = 1.7%; SP = 4.4%; p = 0.005 • Clinical malaria: MQ = 26 cases/10,000 personmonths vs SP = 68 cases/10,000 person-months; p = 0.007 • Maternal anemia (
