Reducing the Burden of Malaria in HIV-uninfected Pregnant Women and Infants

Summary

This will be a double-blinded randomized controlled phase III trial of 300 HIV uninfected pregnant women and the children born to them. The study interventions will be divided into two phases. In the first phase, HIV uninfected women at 12-20 weeks gestation will be randomized in equal proportions to one of three intermittent preventive therapy in pregnancy (IPTp) treatment arms: 1) 3 doses of sulfadoxine-pyrimethamine (SP), 2) 3 doses of dihydroartemisinin-piperaquine (DP), or 3) monthly DP. All three interventions arms will have either SP or DP placebo to ensure adequate blinding is achieved. Follow-up for the pregnant women will end approximately 6 weeks after giving birth. In the second phase of the study, all children born to mothers enrolled in the study will be followed from birth until they reach 36 months of age. Children born to mothers randomized to receive 3 doses of SP during pregnancy will receive DP every 3 months between 2-24 months of age. Children born to mothers randomized to receive 3 doses of DP or monthly DP during pregnancy will receive either DP every 3 months or monthly DP between 2-24 months of age. To ensure adequate blinding, children who will receive DP every 3 months will be given DP placebo during the months they will not be taking DP. Children will then be followed an additional year between 24-36 months of age following the interventions. We will test the hypothesis that IPT with DP will significantly reduce the burden of malaria in pregnancy and infancy and improve the development of naturally acquired antimalarial immunity.

Timeline

Start

2014-06-23

Primary completion

2018-05-14

Completion

2018-05-14

Publications

• Results Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Opira B, Olwoch P, Ategeka J, Nayebare P, Clark TD, Feeney ME, Charlebois ED, Rizzuto G, Muehlenbachs A, Havlir DV, Kamya MR, Dorsey G. Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med. 2016 Mar 10;374(10):928-39. doi: 10.1056/NEJMoa1509150.
• Results Muhindo MK, Kakuru A, Natureeba P, Awori P, Olwoch P, Ategeka J, Nayebare P, Clark TD, Muehlenbachs A, Roh M, Mpeka B, Greenhouse B, Havlir DV, Kamya MR, Dorsey G, Jagannathan P. Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda. Malar J. 2016 Aug 26;15(1):437. doi: 10.1186/s12936-016-1489-x.
• Results Conrad MD, Mota D, Foster M, Tukwasibwe S, Legac J, Tumwebaze P, Whalen M, Kakuru A, Nayebare P, Wallender E, Havlir DV, Jagannathan P, Huang L, Aweeka F, Kamya MR, Dorsey G, Rosenthal PJ. Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Uganda. J Infect Dis. 2017 Nov 15;216(8):1008-1017. doi: 10.1093/infdis/jix421.
• Results Kapisi J, Kakuru A, Jagannathan P, Muhindo MK, Natureeba P, Awori P, Nakalembe M, Ssekitoleko R, Olwoch P, Ategeka J, Nayebare P, Clark TD, Rizzuto G, Muehlenbachs A, Havlir DV, Kamya MR, Dorsey G, Gaw SL. Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malar J. 2017 Oct 5;16(1):400. doi: 10.1186/s12936-017-2040-4.
• Results Jagannathan P, Kakuru A, Okiring J, Muhindo MK, Natureeba P, Nakalembe M, Opira B, Olwoch P, Nankya F, Ssewanyana I, Tetteh K, Drakeley C, Beeson J, Reiling L, Clark TD, Rodriguez-Barraquer I, Greenhouse B, Wallender E, Aweeka F, Prahl M, Charlebois ED, Feeney ME, Havlir DV, Kamya MR, Dorsey G. Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. PLoS Med. 2018 Jul 17;15(7):e1002606. doi: 10.1371/journal.pmed.1002606. eCollection 2018 Jul.
• Results Muhindo MK, Jagannathan P, Kakuru A, Opira B, Olwoch P, Okiring J, Nalugo N, Clark TD, Ruel T, Charlebois E, Feeney ME, Havlir DV, Dorsey G, Kamya MR. Intermittent preventive treatment with dihydroartemisinin-piperaquine and risk of malaria following cessation in young Ugandan children: a double-blind, randomised, controlled trial. Lancet Infect Dis. 2019 Sep;19(9):962-972. doi: 10.1016/S1473-3099(19)30299-3. Epub 2019 Jul 12.
• Results Conroy AL, Bangirana P, Muhindo MK, Kakuru A, Jagannathan P, Opoka RO, Liechty EA, Nakalembe M, Kamya MR, Dorsey G, John CC. Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins. Am J Trop Med Hyg. 2019 Mar;100(3):552-555. doi: 10.4269/ajtmh.18-0659.
• Wallender E, Ali AM, Hughes E, Kakuru A, Jagannathan P, Muhindo MK, Opira B, Whalen M, Huang L, Duvalsaint M, Legac J, Kamya MR, Dorsey G, Aweeka F, Rosenthal PJ, Savic RM. Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children. Nat Commun. 2021 Nov 18;12(1):6714. doi: 10.1038/s41467-021-27051-8.
• Hughes E, Imperial M, Wallender E, Kajubi R, Huang L, Jagannathan P, Zhang N, Kakuru A, Natureeba P, Mwima MW, Muhindo M, Mwebaza N, Clark TD, Opira B, Nakalembe M, Havlir D, Kamya M, Rosenthal PJ, Dorsey G, Aweeka F, Savic RM. Piperaquine Exposure Is Altered by Pregnancy, HIV, and Nutritional Status in Ugandan Women. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01013-20. doi: 10.1128/AAC.01013-20. Print 2020 Nov 17.
• Whalen ME, Kajubi R, Chamankhah N, Huang L, Orukan F, Wallender E, Kamya MR, Dorsey G, Jagannathan P, Rosenthal PJ, Mwebaza N, Aweeka FT. Reduced Exposure to Piperaquine, Compared to Adults, in Young Children Receiving Dihydroartemisinin-Piperaquine as Malaria Chemoprevention. Clin Pharmacol Ther. 2019 Dec;106(6):1310-1318. doi: 10.1002/cpt.1534. Epub 2019 Jul 22.
• Savic RM, Jagannathan P, Kajubi R, Huang L, Zhang N, Were M, Kakuru A, Muhindo MK, Mwebaza N, Wallender E, Clark TD, Opira B, Kamya M, Havlir DV, Rosenthal PJ, Dorsey G, Aweeka FT. Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis. 2018 Sep 14;67(7):1079-1088. doi: 10.1093/cid/ciy218.

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