A trial conducted in northwest Thailand has found that it is safe to use artemisinin combination therapy (ACT) to treat pregnant women with malaria, but that efficacy is inferior to single-drug artesunate treatment. The study, published in next week's PLoS Medicine, suggests that the ACT evaluated in the trial, artemether-lumefantrine (AL), may have lower efficacy because drug concentrations were seen to be reduced during pregnancy. The authors suggest that longer, or more frequent, regimens of the drug combination should be evaluated for treatment of pregnant women.
ACT - the combination of two antimalarial drugs to reduce the chance of malaria becoming resistant to either - is now the primary form of treatment for Plasmodium falciparum malaria, which kills nearly one million people per year. ACT may soon be the only effective treatment for malaria, given that the disease has become resistant to many of the older antimalarial drugs, and it has shown to be safe and effective in non-pregnant women. For pragmatic reasons the World Health Organisation (WHO) also recommends that ACT is also used to treat malaria in mid-late pregnancy, despite the fact that little is known about how well it works in pregnant women. This trial was conducted on the Thai-Burmese border, an area where malaria transmission is low but highly drug-resistant, meaning that pregnant women who contract the disease are at risk of developing severe malaria that can be fatal to both the mother and her unborn child.
Rose McGready, of the Shoklo Malaria Research Unit in Thailand, and colleagues sought to compare the safety and efficacy of the most widely used ACT, artemether-lumefantrine (AL), with artesunate, a single artemisinin-derived drug. The 253 women enrolled in the trial had uncomplicated malaria - the stage before the patient needs treatment with intravenous drugs - and were in the second and third trimesters of pregnancy. Using a measure called the PCR adjusted cure rate to assess how each type of treatment cured new infections, they found that artesunate outperformed AL (89.7% compared to 81.2%), although neither course of treatment achieved the 95% cure rate recommended by the WHO. Few side effects were found with either type of treatment, and the health and development of infants at birth and at one-year of age were similar irrespective of the type of treatment their mothers received.
This is the first trial that examined the use of ACT to treat pregnant women and the finding that it is safe and well-tolerated in the second and third trimesters of pregnancy is significant and welcome. Despite the fact that ACT did not perform as well as in studies of non-pregnant women with uncomplicated malaria, the researchers are careful to warn that this does not mean it cannot be used to treat pregnant women effectively in other endemic regions. Low drug blood levels were observed in the women seven days after treatment, which may explain the reduced efficacy of ACT in this area of Thailand with highly drug-resistant parasites. The researchers conclude by suggesting a higher-dose ACT regimen should now be evaluated for the treatment of pregnant women with uncomplicated malaria.
This study received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Medicine (TDR) and was part of the Mahidol University Oxford Tropical Medicine Research Programme funded by the Wellcome Trust.
Citation: McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-nguen J, et al. (2008) A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum treatment in pregnancy. PLoS Med 5(12): e253. doi:10.1371/journal.pmed.0050253
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