A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border

Makoto Saito, Verena I Carrara, Mary Ellen Gilder, Aung Myat Min, Nay Win Tun, Mupawjay Pimanpanarak, Jacher Viladpai-Nguen, Moo Kho Paw, Warat Haohankhunnatham, Kamonchanok Konghahong, Aung Pyae Phyo, Cindy Chu, Claudia Turner, Sue J Lee, Jureeporn Duanguppama, Mallika Imwong, Germana Bancone, Stephane Proux, Pratap Singhasivanon, Nicholas J White, François Nosten, Rose McGready, Makoto Saito, Verena I Carrara, Mary Ellen Gilder, Aung Myat Min, Nay Win Tun, Mupawjay Pimanpanarak, Jacher Viladpai-Nguen, Moo Kho Paw, Warat Haohankhunnatham, Kamonchanok Konghahong, Aung Pyae Phyo, Cindy Chu, Claudia Turner, Sue J Lee, Jureeporn Duanguppama, Mallika Imwong, Germana Bancone, Stephane Proux, Pratap Singhasivanon, Nicholas J White, François Nosten, Rose McGready

Abstract

Background: Artemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported.

Methods: Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL+). The primary endpoint for P. falciparum infections was the PCR-corrected cure rate and for P. vivax infections was recurrent parasitaemia, before delivery or day 63, whichever was longer, assessed by Kaplan-Meier estimate.

Results: Between February 2010 and August 2016, 511 pregnant women with malaria (353 P. vivax, 142 P. falciparum, 15 co-infections, 1 Plasmodium malariae) were randomized to either DP (n=170), ASMQ (n=169) or AL+ (n=172) treatments. Successful malaria elimination efforts in the region resulted in premature termination of the trial. The majority of women had recurrent malaria (mainly P. vivax relapses, which are not prevented by these treatments). Recurrence-free proportions (95% confidence interval [95% CI]) for vivax malaria were 20.6% (5.1-43.4) for DP (n=125), 46.0% (30.9-60.0) for ASMQ (n=117) and 28.7% (10.0-50.8) for AL+ (n=126). DP and ASMQ provided longer recurrence-free intervals. PCR-corrected cure rates (95% CI) for falciparum malaria were 93.7% (81.6-97.9) for DP (n=49), 79.6% (66.1-88.1) for AMSQ (n=55) and 87.5% (74.3-94.2) for AL+ (n=50). Overall 65% (85/130) of P. falciparum infections had Pfkelch13 propeller mutations which increased over time and recrudescence occurred almost exclusively in them; risk ratio 9.42 (95% CI 1.30-68.29). Among the women with falciparum malaria, 24.0% (95% CI 16.8-33.6) had P. vivax parasitaemia within 4 months. Nausea, vomiting, dizziness and sleep disturbance were more frequent with ASMQ. Miscarriage, small-for-gestational-age and preterm birth did not differ significantly among the treatment groups, including first trimester exposures (n=46).

Conclusions: DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum-infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area.

Trial registration: ClinicalTrials.gov identifier NCT01054248 , registered on 22 January 2010.

Keywords: Artemisinin-based combination therapy; Efficacy; Malaria; Pfkelch13; Plasmodium falciparum; Plasmodium vivax; Pregnancy; Safety; Tolerability; pfmdr1.

Conflict of interest statement

This study received partial financial support from the Holley Pharmacy (China). The authors declare that they have no other competing interests.

Figures

Fig. 1
Fig. 1
Participant flow in the randomized comparison of DP, ASMQ and AL+. Five hundred twelve did not meet eligibility criteria (underage n = 98, first trimester infection before amendment n = 155 or after amendment but no foetal heart beat visible n = 19, hyperparasitaemia n = 21, foetal demise at time of diagnosis n = 5, imminent labour n = 49, severe anaemia n = 3, very low parasitaemia n = 162). ANC: antenatal clinics, AL+: artemether-lumefantrine extended regimen, ASMQ: artesunate-mefloquine, CBC/biochem: complete blood count and biochemistry, DP: dihydroartemisinin-piperaquine, Pf: Plasmodium falciparum, Pm: Plasmodium malariae, PTB: preterm birth, Pv: Plasmodium vivax, SGA: small for gestational age
Fig. 2
Fig. 2
Cumulative proportions of treatment success over time for each arm stratified by malaria species estimated by Kaplan-Meier estimator. aPlasmodium falciparum PCR-corrected treatment success. bPlasmodium vivax treatment success. Black dotted line shows 95% and solid line 90%, which is the efficacy threshold set by the World Health Organization to replace the treatment [3]

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