Richard Kajubi1, Teddy Ochieng1, Abel Kakuru1, Prasanna Jagannathan2, Miriam Nakalembe3, Theodore Ruel4, Bishop Opira1, Harriet Ochokoru1, John Ategeka1, Patience Nayebare1, Tamara D Clark5, Diane V Havlir5, Moses R Kamya6, Grant Dorsey7. 1. Infectious Diseases Research Collaboration, Kampala, Uganda. 2. Department of Medicine, Stanford University, Stanford, CA, USA. 3. Department of Obstetrics and Gynecology, Makerere University College of Health Sciences, Kampala, Uganda. 4. Department of Pediatrics, University of California, San Francisco, CA, USA. 5. Department of Medicine, University of California, San Francisco, CA, USA. 6. School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda. 7. Department of Medicine, University of California, San Francisco, CA, USA. Electronic address: grant.dorsey@ucsf.edu.
Abstract
BACKGROUND: Intermittent treatment with sulfadoxine-pyrimethamine, recommended for prevention of malaria in pregnant women throughout sub-Saharan Africa, is threatened by parasite resistance. We assessed the efficacy and safety of intermittent preventive treatment with dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine. METHODS: We did a double-blind, randomised, controlled, superiority trial at one rural site in Uganda with high malaria transmission andsulfadoxine-pyrimethamine resistance. HIV-uninfected pregnant women between 12 and 20 weeks gestation were randomly assigned (1:1) to monthly intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine. The primary endpoint was the risk of a composite adverse birth outcome defined as low birthweight, preterm birth, or small for gestational age in livebirths. Protective efficacy was defined as 1-prevalence ratio or 1-incidence rate ratio. All analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02793622. FINDINGS:Between Sept 6, 2016, and May 29, 2017, 782 women were enrolled and randomly assigned to receive sulfadoxine-pyrimethamine (n=391) or dihydroartemisinin-piperaquine (n=391); 666 (85·2%) women who delivered livebirths were included in the primary analysis. There was no significant difference in the risk of our composite adverse birth outcome between the dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine treatment group (54 [16%] of 337 women vs 60 [18%] of 329 women; protective efficacy 12% [95% CI -23 to 37], p=0·45). Both drug regimens were well tolerated, with no significant differences in adverse events between the groups, with the exception of asymptomatic corrected QT interval prolongation, which was significantly higher in the dihydroartemisinin-piperaquine group (mean change 13 ms [SD 23]) than in the sulfadoxine-pyrimethamine group (mean change 0 ms [SD 23]; p<0·0001). INTERPRETATION: Monthly intermittent preventive treatment with dihydroartemisinin-piperaquine was safe but did not lead to significant improvements in birth outcomes compared with sulfadoxine-pyrimethamine. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Bill & Melinda Gates Foundation.
RCT Entities:
BACKGROUND: Intermittent treatment with sulfadoxine-pyrimethamine, recommended for prevention of malaria in pregnant women throughout sub-Saharan Africa, is threatened by parasite resistance. We assessed the efficacy and safety of intermittent preventive treatment with dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine. METHODS: We did a double-blind, randomised, controlled, superiority trial at one rural site in Uganda with high malaria transmission and sulfadoxine-pyrimethamine resistance. HIV-uninfected pregnant women between 12 and 20 weeks gestation were randomly assigned (1:1) to monthly intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine. The primary endpoint was the risk of a composite adverse birth outcome defined as low birthweight, preterm birth, or small for gestational age in livebirths. Protective efficacy was defined as 1-prevalence ratio or 1-incidence rate ratio. All analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02793622. FINDINGS: Between Sept 6, 2016, and May 29, 2017, 782 women were enrolled and randomly assigned to receive sulfadoxine-pyrimethamine (n=391) or dihydroartemisinin-piperaquine (n=391); 666 (85·2%) women who delivered livebirths were included in the primary analysis. There was no significant difference in the risk of our composite adverse birth outcome between the dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine treatment group (54 [16%] of 337 women vs 60 [18%] of 329 women; protective efficacy 12% [95% CI -23 to 37], p=0·45). Both drug regimens were well tolerated, with no significant differences in adverse events between the groups, with the exception of asymptomatic corrected QT interval prolongation, which was significantly higher in the dihydroartemisinin-piperaquine group (mean change 13 ms [SD 23]) than in the sulfadoxine-pyrimethamine group (mean change 0 ms [SD 23]; p<0·0001). INTERPRETATION: Monthly intermittent preventive treatment with dihydroartemisinin-piperaquine was safe but did not lead to significant improvements in birth outcomes compared with sulfadoxine-pyrimethamine. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Bill & Melinda Gates Foundation.
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