Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial

Dicko, Alassane; Diallo, Abdoulbaki I; Tembine, Intimbeye; Dicko, Yahia; Dara, Niawanlou; Sidibé, Yoro; Gaoussou, Santara; Diawara, Halimatou; Conaré, Toumani; Djimdé, Abdoulaye; Chandramohan, Daniel; Cousens, Simon; Milligan, Paul; Diallo, Diadier; Doumbo, Ogobara K.; Greenwood, Brian

doi:10.1371/journal.pmed.1000407

Cited by 133 publications

(160 citation statements)

References 28 publications

(44 reference statements)

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“…By contrast, the post-intervention prevalence of quadruple mutants in Mali was significantly higher in the SP + amodiaquine-IPTc group than the placebo group, and prevalence also increased from baseline in the IPTc group but not in the placebo group 70 . In Senegal, post-intervention prevalence of triple Pfdhfr and Pfdhps A437G mutants was also significantly higher in the SP + artesunate treatment arm than the placebo arm, despite an increase in both groups from baseline 69 .…”

Section: Children and Smc/iptcmentioning

confidence: 68%

Monitoring antifolate resistance in intermittent preventive therapy for malaria

Venkatesan

Alifrangis

Roper

et al. 2013

Trends in Parasitology

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Mutations in the Plasmodium falciparum genes Pfdhfr and Pfdhps have rendered sulfadoxine-pyrimethamine (SP) ineffective for malaria treatment in most regions of the world. Yet, SP is efficacious as intermittent preventive therapy in pregnant women (IPTp) and infants (IPTi) and as seasonal malaria control in children (SMC). SP-IPTp is being widely implemented in sub-Saharan Africa. SP-IPTi is recommended where the prevalence of SP-resistant malaria parasites is low, while SMC is recommended for areas of intense seasonal malaria transmission. The continuing success of these interventions depends largely on the prevalence of Pfdhfr and Pfdhps resistance mutations in the target population. Here we review the relationship between resistance mutations and SP-IPT within target populations in the context of monitoring and informing implementation of this intervention.

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Section: Children and Smc/iptcmentioning

confidence: 68%

Monitoring antifolate resistance in intermittent preventive therapy for malaria

Venkatesan

Alifrangis

Roper

et al. 2013

Trends in Parasitology

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“…The inoculation dose dependency seen in this study definitely seems to suggest so. Perhaps a more practical application of our findings for a P. berghei clone that had been selected for highlevel pyrimethamine resistance in the blood stage but that remained partially susceptible to pyrimethamine during liverstage development is to help explain the somewhat surprising protective efficacy of IPT with SP in infants and children despite a high prevalence of antifolate resistance (4,14). These findings also indicate that an adjustment of the currently inappropriate SP dose (5) may entail a disproportional increase in the chemoprophylactic efficacy after each IPT dose.…”

Section: Vol 55 2011mentioning

confidence: 96%

“…First, only a single, though very visible, study demonstrated sustained protection during 1 year of follow-up in children who had received IPT in their first year of life (35). Subsequent studies were unable to replicate this intriguing finding and, in some instances, even suggested a rebound effect (4,14). Second, it is controversial whether homologous challenge in the P. berghei-C57BL/6 model reflects the effect of protective immune responses in human infections with P. falciparum.…”

Section: Vol 55 2011mentioning

confidence: 99%

Induction of Antimalaria Immunity by Pyrimethamine Prophylaxis during Exposure to Sporozoites Is Curtailed by Parasite Resistance

Friesen

Borrmann

Matuschewski

2011

Antimicrob Agents Chemother

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Each year, infections with the protozoan parasite Plasmodium falciparum kill 1 million people, mostly children in Africa. Intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) reduces the incidence of malaria and aims to prevent mortality in infants, children, and pregnant women. There is contradictory evidence as to whether this strategy may generate additional protection against reinfection beyond the limited duration of the intervention. Previous work established that ablation of either liver-stage maturation or subsequent life cycle conversion by causal prophylactic drugs elicits protective immune responses against reinfections when drugs are no longer present. Here we show in the rodent malaria model that pyrimethamine, a component of SP, inhibits liver-stage development in vitro and in vivo, confirming the causal prophylactic activity of pyrimethamine. Repeated exposure to high doses of Plasmodium berghei sporozoites during pyrimethamine prophylaxis induced complete protection in C57BL/6 mice against challenge with high doses of sporozoites delivered intravenously 35 to 199 days later. Immunizations by infectious mosquito bites induced limited, inoculation-dependent protection against subsequent challenge by infected mosquito bites but provided partial protection against experimental cerebral malaria. Short-term pyrimethamine prophylaxis during intravenous transmission of sporozoites from a pyrimethamine-resistant strain delayed, but did not prevent, blood-stage infection. Our data provide a rationale for the notion of sustained protective efficacy of IPT based on the capacity of arrested, drug-sensitive liver-stage and/or suppressed blood-stage parasites to mount lasting protection.

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“…Of the two trials, which considered severe anemia as a separate outcome, both also found a significant reduction as a result of IPT (Dicko et al, 2011; Konate et al, 2011). This is consistent with the findings of a previous Cochrane review, which had also concluded that IPT in pregnant women was similarly associated with decreased rates of both severe anemia and all anemia (Garner and Gulmezoglu, 2006).…”

Section: Malaria Prevention Efforts Reduce Anemia Prevalencementioning

confidence: 98%

Iron, anemia and hepcidin in malaria

Spottiswoode¹,

Duffy²,

Drakesmith³

2014

Front. Pharmacol.

104

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Malaria and iron have a complex but important relationship. Plasmodium proliferation requires iron, both during the clinically silent liver stage of growth and in the disease-associated phase of erythrocyte infection. Precisely how the protozoan acquires its iron from its mammalian host remains unclear, but iron chelators can inhibit pathogen growth in vitro and in animal models. In humans, iron deficiency appears to protect against severe malaria, while iron supplementation increases risks of infection and disease. Malaria itself causes profound disturbances in physiological iron distribution and utilization, through mechanisms that include hemolysis, release of heme, dyserythropoiesis, anemia, deposition of iron in macrophages, and inhibition of dietary iron absorption. These effects have significant consequences. Malarial anemia is a major global health problem, especially in children, that remains incompletely understood and is not straightforward to treat. Furthermore, the changes in iron metabolism during a malaria infection may modulate susceptibility to co-infections. The release of heme and accumulation of iron in granulocytes may explain increased vulnerability to non-typhoidal Salmonella during malaria. The redistribution of iron away from hepatocytes and into macrophages may confer host resistance to superinfection, whereby blood-stage parasitemia prevents the development of a second liver-stage Plasmodium infection in the same organism. Key to understanding the pathophysiology of iron metabolism in malaria is the activity of the iron regulatory hormone hepcidin. Hepcidin is upregulated during blood-stage parasitemia and likely mediates much of the iron redistribution that accompanies disease. Understanding the regulation and role of hepcidin may offer new opportunities to combat malaria and formulate better approaches to treat anemia in the developing world.

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Intermittent Preventive Treatment of Malaria Provides Substantial Protection against Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali: A Randomised, Double-Blind, Placebo-Controlled Trial

Abstract: A randomized trial reported by Alassane Dicko and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes by insecticide-treated bednets provides substantial protection from malaria.

Cited by 133 publications

References 28 publications

Monitoring antifolate resistance in intermittent preventive therapy for malaria

Monitoring antifolate resistance in intermittent preventive therapy for malaria

Induction of Antimalaria Immunity by Pyrimethamine Prophylaxis during Exposure to Sporozoites Is Curtailed by Parasite Resistance

Iron, anemia and hepcidin in malaria

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