A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border
Authors: Saito Makoto , Carrara Verena I. , Gilder Mary Ellen , Min Aung Myat , Tun Nay Win , Pimanpanarak Mupawjay , Viladpai-nguen Jacher , Paw Moo Kho , Haohankhunnatham Warat , Konghahong Kamonchanok , Phyo Aung Pyae , Chu Cindy , Turner Claudia , Lee Sue J. , Duanguppama Jureeporn , Imwong Mallika , Bancone Germana , Proux Stephane , Singhasivanon Pratap , White Nicholas J. , Nosten François , McGready Rose 
Published: June 2021

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.