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Intermittent Preventive Treatment in Infants (IPTi)

Approximately three quarters of preschool children in eastern Africa suffer from anemia. In 2000 a team in Tanzania demonstrated that an antimalarial drug (sulfadoxine-pyrimethamine, or SP) could be administered to children at 2,3, and 9 months of age attending vaccination visits, resulting in a nearly 60% reduction in rates of clinical malaria and a 50% reduction in the rate of severe anemia compared to those receiving placebo.

In 2003, CDC joined a large group of European and African partners to form the Intermittent Preventive Treatment in Infants (IPTi) Consortium. The IPTi Consortium aims to conduct a comprehensive slate of research with the following aims:

IPTi Consortium's Research Aims

1. Determine the efficacy of IPTi in settings with different intensities of malaria transmission
2. Broaden the database on the safety of IPTi
3. Evaluate potential interactions with vaccinations administered at the same time as IPTi
4. Determine whether other antimalarial drugs (particularly those that are more short acting than SP) are as efficacious in preventing anemia and malaria when administered as IPTi
5. Explain the impact of IPTi on the development of immunity to Plasmodium falciparum
6. Evaluate the acceptability of IPTi by parents and guardians of infants receiving the intervention and impact of IPTi on vaccination coverage
7. Estimate the cost of delivering IPTi as a routine part of a child health package, as well as its cost effectiveness
8. Investigate whether an infant dose of effective antimalarial drugs can be formulated for easy and safe administration during visits for routine vaccinations
9. Determine community effectiveness of IPTi when introduced into vaccination programs on a large scale
10. Develop strategies within countries to ensure that drugs for IPTi are available in health facilities, staff are trained, and district health management teams have tools to plan for IPTi (human and financial resources, drug supply, training, supervision)

Study of IPTi in Kenya

As part of the IPTi Consortium, CDC, in collaboration with the Kenya Medical Research Institute (KEMRI) has just been conducting a randomized double blind placebo-controlled trial to estimate the efficacy of IPTi with 3 different antimalarial drug combinations:

• sulfadoxine-pyrimethamine (SP) in combination with artesunate
• amodiaquine in combination with artesunate
• chlorproguanil-dapsone

These will be given to infants at routine immunization visits (10 weeks, 14 weeks, and 9 months), and their efficacy in preventing clinical malaria and moderate-to-severe anemia in the first 2 years of life will be assessed. All infants will also receive iron supplementation from 10 weeks to 6 ½ months of age.

Use of Results of the Kenya Study

This trial, scheduled to conclude in 2007, will generate important public health information on the efficacy of IPTi in preventing anemia and clinical malaria among infants in an area with intense malaria transmission and ongoing prevention efforts through the use of insecticide-treated bed nets (ITNs).

This trial will contribute towards understanding IPTi's mechanism of action (i.e., through intermittent clearance of parasites vs. a chemoprophylactic effect afforded through the use of an antimalarial with a long half-life).

The information gained will be useful to determine the safety of IPTi, to decide what sort of antimalarials are appropriate for IPTi, and ultimately to help to direct child survival and malaria control policy in African countries.

If alternative drug regimens to SP prove effective, that information will be valuable to policymakers as levels of P. falciparum resistance to SP rise with increased usage in east Africa.

Recent Results from Other IPTi Trials

Since the publication of the original trial of IPTi in Tanzania, two other trials using SP for IPTi have been completed in Africa. 

• An IPTi trial in Ghana that delivered 4 doses of SP or placebo (at the time of the second and third diphtheria-pertussus-tetanus [DTP] vaccinations, at the time of measles vaccination, and at 12 months of age) demonstrated a 25% reduction in clinical malaria in the first 15 months of life, and a 35% reduction in hospitalizations with anemia. This same study did note a 20% increase in the risk of high-density malaria during the same period. 
• A trial in Mozambique that delivered SP or placebo at 3,4, and 9 months of age found a 22% reduction in the incidence of clinical malaria in the first year of life and a 19% reduction in the rate of all-cause hospital admissions. 

Other trials on IPTi using SP from Ghana and Gabon will be published in the near future.

Programmatic Future of IPTi

The dossier of evidence regarding IPTi with SP, including efficacy, safety, and interactions with vaccines delivered by the Expanded Program on Immunizations (EPI), is currently being reviewed by the World Health Organization (WHO).  It is expected that WHO will decide in early 2007 whether or not to recommend IPTi with SP for use in malaria-endemic areas in Africa.