Publication: A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border
Issued Date
2021-12-01
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17417015
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2-s2.0-85107488240
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Mahidol University
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SCOPUS
Bibliographic Citation
BMC Medicine. Vol.19, No.1 (2021)
Suggested Citation
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 A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border. BMC Medicine. Vol.19, No.1 (2021). doi:10.1186/s12916-021-02002-8 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/77575
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Title
A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border
Author(s)
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
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.