Mefloquine not suitable as intermittent preventive treatment of malaria, in pregnant women living with HIV

Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial.

Gonzalez R, Desai M, Macete E, Ouma P, Kakolwa MA, Abdulla S, Aponte JJ, Bulo H, Kabanywanyi AM, Katana A, Maculuve S, Mayor A, Nhacolo A, Otieno K, Pahlavan G, Ruperez M, Sevene E, Slutsker L, Vala A, Williamsom J, Menendez C. PLoS Med. 2014 Sep 23;11(9):e1001735. doi: 10.1371/journal.pmed.1001735. eCollection 2014.

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).

Methods and findings: A total of 1071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p = 0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p = 0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p = 0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p = 0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p = 0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.

Conclusions: An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.

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Editor’s notes: The gold standard for intermittent preventive treatment of malaria in pregnancy (IPTp) is at least three doses of sulfadoxine-pyrimethamine, along with the use of insecticide-treated nets. In resource-limited, high HIV prevalent areas, all HIV-positive pregnant women are recommended to take co-trimoxazole prophylaxis. This rules out the concomitant use of sulfadoxine-pyrimethamine because of the increased risk of drug toxicity. However, the effectiveness of co-trimoxazole alone to prevent malaria in pregnant women living with HIV has not been established.   

This article reports a randomised double-blind placebo-controlled trial. The trial compares the efficacy of three-monthly doses of mefloquine (a long-acting efficacious antimalarial, considered to be safe throughout pregnancy) with placebo, in pregnant women living with HIV taking daily co-trimoxazole. Women in the mefloquine arm had a reduced risk of maternal malarial parasitaemia, a reduced rate of placental malaria and reduced incidence of non-obstetric hospital admissions. However, mefloquine was poorly tolerated. Unexpectedly, women in the mefloquine arm had a higher HIV viral load at delivery and were more likely to transmit HIV to their child. Since this finding was based on an exploratory, rather than a pre-planned analysis, its validity is uncertain. If other data support this finding, a better understanding of the underlying mechanism (biological/immunological) will be important to inform future alternative drug regimens for pregnant women living with HIV. 

This trial suggests that an effective antimalarial drug combined with co-trimoxazole can offer additional protection against malaria in pregnant women living with HIV, but mefloquine is not the drug of choice for this purpose. 

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