Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial

Prasanna Jagannathan, Abel Kakuru, Jaffer Okiring, Mary K Muhindo, Paul Natureeba, Miriam Nakalembe, Bishop Opira, Peter Olwoch, Felistas Nankya, Isaac Ssewanyana, Kevin Tetteh, Chris Drakeley, James Beeson, Linda Reiling, Tamara D Clark, Isabel Rodriguez-Barraquer, Bryan Greenhouse, Erika Wallender, Francesca Aweeka, Mary Prahl, Edwin D Charlebois, Margaret E Feeney, Diane V Havlir, Moses R Kamya, Grant Dorsey, Prasanna Jagannathan, Abel Kakuru, Jaffer Okiring, Mary K Muhindo, Paul Natureeba, Miriam Nakalembe, Bishop Opira, Peter Olwoch, Felistas Nankya, Isaac Ssewanyana, Kevin Tetteh, Chris Drakeley, James Beeson, Linda Reiling, Tamara D Clark, Isabel Rodriguez-Barraquer, Bryan Greenhouse, Erika Wallender, Francesca Aweeka, Mary Prahl, Edwin D Charlebois, Margaret E Feeney, Diane V Havlir, Moses R Kamya, Grant Dorsey

Abstract

Background: Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP.

Methods and findings: We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68-3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87-10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp-SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy.

Conclusions: Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy.

Trial registration: ClinicalTrials.gov number NCT02163447.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: (1) EC declared NIH research grants to institution; (2) DVH declared that they received grant funding from NIH. For studies outside of submitted work, they received antiretroviral therapy for NIH funded study from Gilead Sciences; (3) JB is a member of the Editorial Board of PLOS Medicine.

Figures

Fig 1. Trial profile.
Fig 1. Trial profile.
DP, dihydroartemisinin-piperaquine; IPTp-DP4w, IPTp-DP every 4 weeks; IPTp-DP8w, IPTp-DP given every 8 weeks; IPTp-SP8w, IPTp-SP given every 8 weeks.
Fig 2. Time to parasitemia following DP…
Fig 2. Time to parasitemia following DP administration in infancy.
Repeated measures analysis performed, using multilevel mixed-effects survival model, account for clustering within individuals and mothers, both overall (A) and stratified by infant sex (B–C) and adjusted for maternal age, gravidity, and LAMP status at enrolment. *aHR and p-values comparing IPTp-DP4w versus IPTp-SP8w. aHR, adjusted hazard ratio; DP, dihydroartemisinin-piperaquine; IPTp, intermittent preventive treatment of malaria in pregnancy; IPTp-DP4w, IPTp-DP every 4 weeks; IPTp-DP8w, IPTp-DP every 8 weeks; IPTp-SP8w, IPTp-SP given every 8 weeks; LAMP, loop-mediated isothermal amplification.
Fig 3
Fig 3
Antibody levels stratified by maternal IPTp assignment (IPTp-SP8w versus IPTp-DP4w) measured in maternal blood at delivery (A) and infant cord blood (B). *p < 0.05; **p < 0.01. AMA1, Apical membrane antigen 1; CSP, circumsporozoite protein; EBA, erythrocyte binding antigen; Etramp4, Early transcribed membrane protein 4; GEXP, gametocyte export protein; GST, Glutathione S-transferase; H103/MSP11, merozoite surface protein 11; HSP40, Heat shock protein 40; Hyp2, Plasmodium exported protein; IPTp, intermittent preventive treatment of malaria in pregnancy; IPTp-DP4w, IPTp-DP every 4 weeks; IPTp-SP8w; IPTp-SP every 8 weeks; MSP1, merozoite surface protein 1; MSP2Ch150 and MSP2Dd2, merozoite surface protein 2 of Ch150/90 and Dd2 alleles; Rh2, Reticulocyte-binding protein homologue 2; Rh4, Reticulocyte-binding protein homologue 4; SBP1, skeleton-binding protein 1; SEA, Schizont egress antigen; TT, tetanus toxoid.
Fig 4
Fig 4
Mean PQ levels measured 28, 56, and 84 days posttreatment among children whose mothers were randomized to IPTp-SP8w (A), IPTp-DP8w (B), and IPTp-DP4w (C). Marginal estimates obtained using generalized estimating observations with log link and robust standard errors, accounting for repeated measurements in children. *p < 0.05. **p < 0.01. DP, dihydroartemisinin-piperaquine; IPTp, intermittent preventive treatment of malaria in pregnancy; DP4w, IPTp-DP given every 4 weeks; DP8w, IPTp-DP given every 8 weeks; SP8w, IPTp-SP given every 8 weeks; PQ, piperaquine; SP, sulfadoxine-pyrimethamine.

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