Dataset Information

Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy.

ABSTRACT: Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria.The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events.The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.).

SUBMITTER: Kakuru A

PROVIDER: S-EPMC4847718 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy.

Kakuru Abel A Jagannathan Prasanna P Muhindo Mary K MK Natureeba Paul P Awori Patricia P Nakalembe Miriam M Opira Bishop B Olwoch Peter P Ategeka John J Nayebare Patience P Clark Tamara D TD Feeney Margaret E ME Charlebois Edwin D ED Rizzuto Gabrielle G Muehlenbachs Atis A Havlir Diane V DV Kamya Moses R MR Dorsey Grant G

The New England journal of medicine 20160301 10

<h4>Background</h4>Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.<h4>Methods</h4>We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly ass ...[more]

PMID: 26962728

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Project description:BackgroundAnti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure.MethodsChildren were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored.ResultsThe incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001).ConclusionsThe protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.Trial registrationCurrent Controlled Trials Identifier NCT00948896.

Project description:BackgroundIntermittent 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 findingsWe 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.ConclusionsContrary 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 registrationClinicalTrials.gov number NCT02163447.

Project description:One promising new Artemisinin-based combination therapies (ACTs) is dihydroartemisinin-piperaquine (DHA-PQ). However, the pharmacokinetics of piperaquine and the relationship between drug levels and clinical efficacy are incompletely characterized, particularly in children.We performed a single-arm open-label trial in Bobo-Dioulasso, Burkina Faso. A total of 379 participants aged 6 months or more with uncomplicated falciparum malaria were enrolled. Each participant received daily dose of DHA-PQ for three days and followed for 42 days. Parasitological efficacy was analyzed, considering rates of recrudescence and overall recurrence. PK was an exploratory endpoint and a priori, no sample size had been determined. Day 7 capillary and venous plasma concentrations of piperaquine were measured in children aged 2-10 years.Of the 379 participants, 365 (96.3%) completed 42 days of follow-up. The median daily dose of PQ was 18.5 mg/kg [6.5-24]. Treatment with DHA-PQ was well tolerated with fever and parasitemia resolution within 48 hours in nearly all children. Recurrent malaria within 42 days of follow-up occurred in 31.3% (10/34) of children less than 2 years old, 16.0% (16/106) of those aged 2-5 years, 9.4% (15/160) of those aged 5-10 years, and none (0/68) of those over 10 years old. After genotyping, 3 of 41 recurrent episodes were recrudescence. An exploratory analysis shows that children with successful treatment outcomes had significantly higher median plasma concentrations of PQ compared to those with recurrent malaria within 42 days after therapy, considering either capillary samples (68 ng/ml [50-85] compared to 48 ng/ml [36-55], p<0.001) or venous samples (42 ng/ml [29-59] compared to 25 ng/ml [19-44], p<0.001).DHA-PQ was effective for uncomplicated P. falciparum malaria treatment and offers an alternative to other ACTs. Recurrent malaria was mainly due to new infections after treatment and was correlated with low day 7 PQ concentration in the youngest patients.Controlled-Trials.com ISRCTN59761234.

Dataset Information

Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy.

Publications

Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy.

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