Intermittent preventive therapy or intermittent preventive treatment (IPT) is a public health intervention aimed at treating and preventing malaria episodes in infants (IPTi), children (IPTc), schoolchildren (IPTsc) and pregnant women (IPTp). The intervention builds on two tested malaria control strategies to clear existing parasites (treatment effect seen in mass drug administrations) and to prevent new infections (prophylaxis).
IPTi
IPTi using the antimalarial drug sulfadoxine/pyrimethamine (S/P) was pioneered in Ifakara, Tanzania in 1999.Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, et al. Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial. Lancet 2001;357(9267):1471-7 Infants received S/P at ages 3, 6, and 9 months in combination with their routine childhood (EPI) vaccinations. IPTi reduced clinical attacks of malaria by 59% (95% CI, 41%–72%) in Ifakara. Remarkably, protection persisted throughout the second year of life, long after SP had disappeared from circulation.Schellenberg D, Menendez C, Aponte JJ, Kahigwa E, Tanner M, Mshinda H, et al. Intermittent preventive antimalarial treatment for Tanzanian infants: follow-up to age 2 years of a randomised, placebo-controlled trial. Lancet 2005;365(9469):1481-3 A trial conducted in northern Tanzania using the antimalarial drug amodiaquine instead of S/P was similarly successful.Massaga JJ, Kitua AY, Lemnge MM, Akida JA, Malle LN, Ronn AM, et al. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Lancet 2003;361(9372):1853-60 Six subsequent trials showed less encouraging results.Chandramohan D, Owusu-Agyei S, Carneiro I, Awine T, Amponsa-Achiano K, Mensah N, et al. Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ 2005;331(7519):727-33Macete E, Aide P, Aponte JJ, Sanz S, Mandomando I, Espasa M, et al. Intermittent preventive treatment for malaria control administered at the time of routine vaccinations in Mozambican infants: a randomized, placebo-controlled trial. J Infect Dis 2006;194(3):276-85Grobusch MP, Lell B, Schwarz NG, Gabor J, Dornemann J, Potschke M, et al. Intermittent preventive treatment against malaria in infants in Gabon--a randomized, double-blind, placebo-controlled trial. J Infect Dis 2007;196(11):1595-602Kobbe R, Kreuzberg C, Adjei S, Thompson B, Langefeld I, Thompson PA, et al. A randomized controlled trial of extended intermittent preventive antimalarial treatment in infants. Clin Infect Dis 2007;45(1):16-25Mockenhaupt FP, Reither K, Zanger P, Roepcke F, Danquah I, Saad E, et al. Intermittent preventive treatment in infants as a means of malaria control: a randomized, double-blind, placebo-controlled trial in northern Ghana. Antimicrob Agents Chemother 2007;51(9):3273-81
The latest and so far largest IPTi study was an effectiveness study conducted in the South East of Tanzania.Armstrong Schellenberg, J.R., et al., Community effectiveness of Intermittent Preventive Treatment for infants (IPTi) in rural southern Tanzania. Am J Trop Med Hyg, 2010. 82(5): p. 772-81. A study area of approximately 250x180km2 with a population of about 900,000 people was subdivided into 24 similar clusters. Half of the 23,400 infants, those residing in 12 of 24 randomly selected clusters were invited in 2005 to receive IPTi. Between 47 and 76% of the eligible infants in each of the 12 selected clusters received IPT-SP. In the following year, 2006, the effect of IPTi on malaria and anaemia was assessed in a representative sample of 600 infants. An intention to treat analysis, which includes all eligible infants did not show a statistically significant benefit of IPTi-SP. Parasitaemia prevalence was 31% in the intervention and 38% in the comparison areas (p=0.06). In a ‘per protocol’ analysis, which only included infants who actually received IPTi there was a significant benefit: parasite prevalence was 22%, 19 percentage points lower than comparison children in the control group (p=0.01). This trial showed that IPTi has a protective effect at the individual level but is not effective at the community level. The study had followed up children for two years until 2007 but the findings from the surveillance in 2007 have not been reported.
IPTc Treating children with S/P and artesunate in Senegal where malaria is highly seasonal repeatedly during the malaria season reduced malaria attacks by 86% (95% CI 80-90)9..Cisse B, Sokhna C, Boulanger D, Milet J, Ba el H, Richardson K, et al. Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet 2006;367(9511):659-67 A subsequent trial in Mali showed a protective efficacy of 43% [95% CI 29–54%].Dicko A, Sagara I, Sissoko MS, Guindo O, Diallo AI, Kone M, et al. Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Malar J 2008;7:123
IPTsc Treating schoolchildren in Kenya with S/P and amodiaquine significantly improved anaemia (RR 0.52, 95% CI 0.29-0.93).Clarke SE, Jukes MC, Njagi JK, Khasakhala L, Cundill B, Otido J, et al. Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet 2008;372(9633):127-38
IPTp IPTp consists in the administration of a single curative dose of an efficacious anti-malarial drug at least twice during pregnancy – regardless whether or not the woman is infected. The drug is administered under supervision during antenatal care (ANC) visits. Sulfadoxine-pyrimethamine is the drug currently recommended by the WHO because of its safety and efficacy in pregnancy.WHO. A strategic framework for malaria prevention and control during pregnancy in the Africa Region. Geneva: WorldHealthOrganization, 2004 AFR/MAL/04/01 Several studies have shown the high efficacy of IPTp with SP, compared to placebo or CQ prophylaxis, on placental infection, LBW and/or severe maternal anaemia.Shulman CE, Dorman EK, Cutts F, Kawuondo K, Bulmer JN, Peshu N, et al. Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. Lancet 1999;353(9153):632-6Challis K, Osman NB, Cotiro M, Nordahl G, Dgedge M, Bergstrom S. Impact of a double dose of sulphadoxine-pyrimethamine to reduce prevalence of pregnancy malaria in southern Mozambique. Trop Med Int Health 2004;9(10):1066-73Kayentao K, Kodio M, Newman RD, Maiga H, Doumtabe D, Ongoiba A, et al. Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali. J Infect Dis 2005;191(1):109-16Njagi JK, Magnussen P, Estambale B, Ouma J, Mugo B. Prevention of anaemia in pregnancy using insecticide-treated bednets and sulfadoxine-pyrimethamine in a highly malarious area of Kenya: a randomized controlled trial. Trans R Soc Trop Med Hyg 2003;97(3):277-82Parise ME, Ayisi JG, Nahlen BL, Schultz LJ, Roberts JM, Misore A, et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg 1998;59(5):813-22Rogerson SJ, Chaluluka E, Kanjala M, Mkundika P, Mhango C, Molyneux ME. Intermittent sulfadoxine-pyrimethamine in pregnancy: effectiveness against malaria morbidity in Blantyre, Malawi, in 1997-99. Trans R Soc Trop Med Hyg 2000;94(5):549-53van Eijk AM, Ayisi JG, ter Kuile FO, Otieno JA, Misore AO, Odondi JO, et al. Effectiveness of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in western Kenya: a hospital-based study. Trop Med Int Health 2004;9(3):351-60Verhoeff FH, Brabin BJ, Chimsuku L, Kazembe P, Russell WB, Broadhead RL. An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treatment in pregnancy on parasite clearance and risk of low birth weight in rural Malawi. Ann Trop Med Parasitol 1998;92(2):141-50 More recent findings from Tanzania also suggest that IPTp using S/P has reached the end of its lifecycle.Harrington WE, Mutabingwa TK, Muehlenbachs A, Sorensen B, Bolla MC, Fried M, et al. Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment. Proc Natl Acad Sci U S A 2009;106(22):9027-32 The authors found that the "use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance". As for infants, there is no simple readily available replacement of S/P for malaria in pregnancy. Indeed, the fear of teratogenic effects add a layer of complexity how this intervention will evolve.
Controversy
While some controversial aspects e.g. the drug of choice are shared by all forms of intermittent preventive therapy, the controversy has been reported in greatest detail for IPTi (see also politics below). The reasons which make the large scale introduction of IPTi highly controversial include:Intermittent preventive antimalarial treatment in infancy. Lancet 2008;372(9647):1383-4
The six studies reported subsequent to the first 2 IPTi studies did not confirm the same degree of protection against malaria (59%) nor the protracted period of protective benefit (into the second year of life) seen in that initial study. Subsequent studies indicated that protection lasted about 35 days after each treatment dose, which translates into an overall protective efficacy in infancy of 20–33%. Effects on anaemia and hospital admission were inconsistent between study sites. There was no evidence of mortality reduction. In more than 8,000 children enrolled in IPTi studies, there were 152 deaths in the placebo groups and 157 deaths in the sulfadoxine-pyrimethamine groups: a protective efficacy of –2% (95% CI –22 to 21). There were concerns that any benefits shown in these IPTi-SP trials might be less now that resistance to sulfadoxine-pyrimethamine has worsened. A recent trial of S/P conducted in Tanzania had to be closed early because of high mortality in children receiving S/P.:Gesase S, Gosling RD, Hashim R, Ord R, Naidoo I, Madebe R, et al. High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581. PLoS ONE 2009;4(2):e4569 There was uncertainty over the true incidence of serious adverse effects, notably the cutaneous reactions that stopped the use of sulfadoxine pyrimethamine as prophylaxis.
An added theoretical concern is that the widespread use of antimalarial drugs for prophylaxis will add to the already considerable drug pressure and will facilitate the emergence and spread of drug resistance. McGready summarised IPTi as an intervention which uses the wrong drug, probably in the wrong dose in the wrong age group.McGready, R., Intermittent preventive treatment of malaria in infancy. Lancet, 2009. 9700(374): p. 1478-80.
Politics