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Mefloquine not recommended as alternative drug for malaria prevention treatment in pregnancy

24 September 2014

The results of two large randomised controlled trials conducted in Africa that tested mefloquine, a drug for malaria prevention in HIV-negative and HIV-positive pregnant women, were published in the PLOS Medicine on 23 September 2014. The results showed that mefloquine could reduce rates of malaria infection and improve maternal health; however, it was not better at preventing low birth weight in newborns when compared to current WHO-recommended antimalarial regimens. In addition, the drug presented poor tolerability among the trial participants. These trials are part of the EDCTP-funded Malaria in Pregnancy Preventive Alternative Drugs (MiPPAD) study and were led by Professor Clara Menéndez (Barcelona Centre for International Health Research, Spain).

In areas where malaria is endemic, pregnant women are at high risk of morbidity and mortality. Malaria infection in pregnancy is associated with increased risk of anaemia in the mother and with low birth weight, which is a major determinant of infant mortality. Finding new antimalarial options for treatment is critical as the malaria parasites are increasingly resistant to sulphadoxine-pyrimethamine (SP), the WHO-recommended treatment for prevention of malaria. Moreover, SP is not recommended in HIV-positive women receiving cotrimoxazole prophylaxis or antiretroviral drugs to avoid any possible increased incidence of adverse drug reactions.

MIPPAD study

The MiPPAD study aimed to evaluate the safety, tolerability and efficacy of mefloquine (MQ) as an alternative to SP used for Intermittent Preventive Treatment in pregnancy (IPTp) in combination with Long Lasting Insecticide Treated Nets (LLITNs). It also involved HIV-infected pregnant women to provide a better understanding of the interactions between antimalarial treatment and HIV.

The first trial compared the currently recommended IPTp regime with two different formulations of MQ in 4,749 HIV-negative pregnant women. The main outcome of this trial was the frequency of children born with low birth weight.

The second trial compared three doses of MQ with a placebo in 1,017 HIV-positive pregnant women who also received cotrimoxazole. It compared the rates of women with malaria parasites in their blood or placenta at delivery. The trials also measured adverse pregnancy outcomes, such as miscarriage or stillbirth, as well as other indicators of maternal health during pregnancy and drug tolerability.

Both trials reported that MQ reduced malaria infections and improved overall health in pregnant women, compared to either SP (first trial) or placebo (second trial). However, results of the first trial indicated that neither of the two MQ regimens was better than SP at preventing low birth weight. In addition, tolerability for MQ was poorer than for SP, with more participants in the MQ groups reporting nausea and dizziness.

The second trial showed no difference in adverse pregnancy outcomes or in low birth weight between the two groups. It also showed poorer tolerability in the MQ group than the placebo group. Moreover, the second trial found that women in the MQ group had higher HIV viral loads at delivery than women in the placebo group, and were more likely to transmit HIV to their child around the time of birth. This result was based on an unplanned exploratory analysis and needs further investigation before drawing definitive conclusions as to whether MQ interferes with HIV suppression.

Based on these findings, the study concluded that MQ cannot be recommended as an alternative to SP in HIV-negative pregnant women nor for malaria prevention during pregnancy in HIV-positive women.

The trials were conducted in Benin (Allada, Sékou and Attogon), Gabon (Fougamou and Lambaréné), Kenya (Kisumu), Mozambique (Manhiça and Maragra), and in Tanzania (Makole and Chambwino). The study has also strengthened capacity development at institutional and individual levels for antimalarial research in all participating sites.

Funding

MiPPAD is one of the studies under the umbrella of the global Malaria in Pregnancy (MiP) Consortium that evaluates new and improved existing interventions for the prevention and treatment of malaria in pregnancy.

The study was supported by EDCTP, with cofunding from the Institute of Health Carlos III (Spain), the University of Tübingen and German Aerospace Center (Germany); the Institut de Recherche pour le Développement (France); the Austrian Federal Ministry of Science (Austria); and the MiP Consortium, which is funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine.

Registration
The trials of the MiPPAD study are registered with ClinicalTrials.gov under number NCT 00811421 and with the Pan African Clinical Trials Registry under numbers PACTR 2010020001813440 and PACTR 2010020001429343.