Two articles published Online First and in a future edition of The Lancet report that intermittent malaria treatment for African infants is both safe and effective in a variety of settings. However, potential drug resistance and consequently the choice of drug used is an essential issue in the strategy. In an associated note, the recent WHO decision to continue using sulfadoxine-pyrimethamine for this purpose, regardless of the drug’s risks, is considered ‘a close call’.
In sub-Saharan Africa, malaria is a major cause of disease and death in children. There is a vital need for improved control measures. Intermittent preventive treatment in infants (IPTi) is the administration of a full course of an anti-malarial drug at specific time points. This is done whether or not parasites are present, such as when the children receive vaccinations against other diseases. Earlier studies have shown that continuous rather than intermittent administration of anti-malaria drugs (prophylaxis) can reduce malaria while the drugs are given. However, when they discontinue treatment, there is a rebound in cases as the children do not develop immunity. On the other hand, the use of continuous prophylaxis can also increase the risk of developing drug resistance.
In the first article, Dr Clara Menendez, Hospital Clínic of Barcelona – Barcelona Centre for International Health Research (Universitat de Barcelona), Spain, and colleagues joined together six randomised controlled trials. The trials were from Tanzania, Mozambique, Gabon, and three were in Ghana. They assessed IPTi using the drug combination sulfadoxine-pyrimethamine. In these six trials, IPTi was given to infants at the time of routine vaccinations under WHO’s Expanded Program on Immunization.
They evaluated a total of 7,930 infants from which 3,958 received IPTi and 3,972 received placebo. Protective efficacy is the proportion or percentage that is currently protected as a result of the intervention. Findings showed that IPTi had a protective efficacy of 30 percent against clinical malaria; 21 percent against the risk of malaria-related anaemia; 38 percent against hospital admissions associated with malaria; and 23 percent against all-cause hospital admissions. The numbers of death were similar in both groups: 56 in the IPTi group and 53 in the placebo group.
The authors underline that resistance to sulfadoxine-pyrimethamine has spread throughout Africa. This could limit the effectiveness of the IPTi using this drug. But they note: “Sulfadoxine-pyrimethamine is the only antimalarial drug available for IPT in both pregnancy and infancy, in view of the combination’s long half-life and prophylactic effect, established safety profile, acceptability, and affordability. IPT seems to work by prophylaxis, with sulfadoxine-pyrimethamine providing protection for up to 6 weeks in infants. New long-acting antimalarial drugs are urgently needed for use in IPTi.”
They write in closing: “IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control.”
In the second article, Professor Brian Greenwood and Dr Roly Gosling, London School of Hygiene and Tropical Medicine, UK, and colleagues examined the effectiveness of both long-acting and short-acting anti-malarial drugs in IPTi. Their study was implemented in a region where there is high-resistance to sulfadoxine-pyrimethamine combination treatment.
The randomised controlled trial took place in Tanzania. There were sites of moderate intensity transmission (MIT) including 1,280 infants, and low intensity transmission (LIT) including 1,139 infants. The infants were aged 8 to 16 weeks. They were randomly assigned to sulfadoxine plus pyrimethamine, chlorproguanil plus dapsone, mefloquine, or placebo. Treatment was given at the second and third immunisations for diphtheria, whooping cough, and tetanus, and for measles. Because of low malaria incidence, recruitment was stopped early at the LIT site. The primary endpoint was protective efficacy against all episodes of clinical malaria at 2 to11 months of age.
The results showed that at the MIT sites, mefloquine had a protective efficacy of 38.1 percent against clinical malaria in infants aged 2 to11 months. However, neither sulfadoxine-pyrimethamine (- 6.7 percent) nor chlorproguanil-dapsone (10.8 percent) had a statistically significant protective effect. There was no regimen with any protective efficacy against anaemia or hospital admission. Mefloquine caused vomiting in 141 of 1,731 (8 percent) doses given on the first day. This means infants were 5.5 times more likely to vomit than with placebo. More infants died in the chlorproguanil-dapsone and mefloquine groups (18 and 15, correspondingly) than in the sulfadoxine-pyrimethamine or placebo groups (eight deaths in each group).
The authors explain: “IPTi with a longacting, efficacious drug such as mefloquine can reduce episodes of malaria in infants in a moderate-transmission setting. IPTi with sulfadoxine-pyrimethamine has no benefit in areas of very high resistance to this combination. The appropriateness of IPTi should be measured by the expected incidence of malaria and the efficacy, tolerability, and safety of the drug.”
They write in conclusion: “If IPT in infants, children, or pregnant women is to remain a key component of malaria control strategies, new long-acting and very safe antimalarial drugs are urgently needed.”
In an associated note, Rose McGready, Shoklo Malaria Research Unit, Thailand, remarks: “WHO has clearly struggled with these issues, and currently considers that the benefits of IPT with sulfadoxine – pyrimethamine exceed the risks. But it seems a close call. WHO does recommend IPT with this combination where resistance is not high and transmission not low, but precise definitions of these terms are awaited. As ever more information is needed to support these recommendations, to define thresholds, optimise dosing, and confirm safety at scale. Looking to the future, and hoping that current downward trends in malaria are sustained, we need to evaluate the newly introduced antimalarials (piperaquine and pyronaridine look promising) as well as mefloquine to determine whether and when is the best time to give IPT.”
“Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial”
Roly D Gosling, Samwel Gesase, Jacklin F Mosha, Ilona Carneiro, Ramadhan Hashim, Martha Lemnge, Frank W Mosha, Brian Greenwood, Daniel Chandramohan
“Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials”
John J Aponte, David Schellenberg, Andrea Egan, Alasdair Breckenridge, Ilona Carneiro, Julia Critchley, Ina Danquah, Alexander Dodoo, Robin Kobbe, Bertrand Lell, Jürgen May, Zul Premji, Sergi Sanz, Esperanza Sevene, Rachida Soulaymani-Becheikh, Peter Winstanley, Samuel Adjei, Sylvester Anemana, Daniel Chandramohan, Saadou Issifou, Frank Mockenhaupt, Seth Owusu-Agyei, Brian Greenwood, Martin P Grobusch, Peter G Kremsner, Eusebio Macete, Hassan Mshinda, Robert D Newman, Laurence Slutsker, Marcel Tanner, Pedro Alonso, Clara Menendez
Written by Stephanie Brunner (B.A.)