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Intermittent preventive treatment: efficacy and safety of sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine plus piperaquine regimens in schoolchildren of the Democratic Republic of Congo: a study protocol for a randomized controlled trial.

ABSTRACT: In malaria endemic areas, schoolchildren usually have asymptomatic malaria infections and consequently remain untreated. Therefore, intermittent preventive treatment with sulfadoxine-pyrimethamine in schoolchildren would be a plausible strategy in malaria stable transmission areas to prevent anaemia and malnutrition. However, in contrast to infancy and pregnancy, antimalaria intermittent preventive treatment in children has been barely investigated. As the implementation of intermittent preventive treatment may be challenged by sulfadoxine-pyrimethamine resistance, sulfadoxine-pyrimethamine combined with piperaquine may be a better alternative than sulfadoxine-pyrimethamine monotherapy. A clinical trial is being conducted to assess the efficacy and safety of intermittent preventive treatments versus controls in Democratic Republic of Congo (DRCongo) schoolchildren and their impact on sulfadoxine-pyrimethamine resistance.A phase IIIb, randomised, controlled trial will enroll asymptomatic schoolchildren. For interventions, sulfadoxine-pyrimethamine is compared to sulfadoxine-pyrimethamine plus piperaquine and to a control group. The two treatments are given four-monthly from baseline for a year as a single dose for sulfadoxine-pyrimethamine and two doses at 24-hour intervals for piperaquine. All participants receive praziquantel and albendazole as mass-treatment for helminthiasis at enrolment. The primary endpoint is haemoglobin concentration change at 12 months follow-up. Secondary endpoints are malaria parasite load and malaria prevalence, at baseline and at month 12. Malaria and helminthiasis incidence will be monitored throughout the study. Statistical analysis will use multilevel modelling due to repeated measurements and clustering effect of participants.The very few studies on intermittent preventive treatment in schoolchildren in malaria stable transmission areas have contradictory results. This randomised controlled trial is unique in comparing efficacy and safety of a prophylactic combination therapy to monotherapy or a control group after 12 months follow-up. Resistance markers for sulfadoxine-pyrimethamine (including break through parasitaemias) will also be recorded. Its uniqueness lies also in the fact that we use piperaquine, a long acting antimalarial, in combination with sulfadoxine-pyrimethamine. Artemisinin derivatives have been excluded as it is part of the treatment policies in virtually all malaria endemic countries. Our findings may, therefore, contribute to the public health of youngsters who fail to thrive and grow due to multiple morbidities.NCT01722539; PACTR201211000449323.

SUBMITTER: Doua JY

PROVIDER: S-EPMC4015766 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Intermittent preventive treatment: efficacy and safety of sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine plus piperaquine regimens in schoolchildren of the Democratic Republic of Congo: a study protocol for a randomized controlled trial.

Doua Joachim Yorokpa JY Matangila Junior J Lutumba Pascal P Van Geertruyden Jean-Pierre JP

Trials 20130924

<h4>Background</h4>In malaria endemic areas, schoolchildren usually have asymptomatic malaria infections and consequently remain untreated. Therefore, intermittent preventive treatment with sulfadoxine-pyrimethamine in schoolchildren would be a plausible strategy in malaria stable transmission areas to prevent anaemia and malnutrition. However, in contrast to infancy and pregnancy, antimalaria intermittent preventive treatment in children has been barely investigated. As the implementation of in ...[more]

PMID: 24063608

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Project description:BACKGROUND:Point mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes which confer resistance to sulfadoxine-pyrimethamine (SP) occur at increasing rates. The present study aimed to identify Pfdhfr and Pfdhps mutations in P. falciparum isolates recovered from women who received two doses of SP during pregnancy in Bandundu, the Democratic Republic of Congo (DRC). METHODS:A total of 48 women with confirmed P. falciparum infection were enrolled in the study. Finger-prick blood samples that were collected on filter paper at the time of delivery were used for DNA isolation. Pfdhfr and Pfdhps genes were amplified by a nested PCR protocol. DNA sequencing was performed on both strands, and the point mutations were analysed. RESULTS:All of the 48 (100.0%) P. falciparum isolates carried at least one polymorphism in both genes. The wild-type haplotypes of Pfdhfr (CNCSI [C50, N51, C59, S108, I164]) and Pfdhps (SAKAA [S436, A437, K540, A581, A613]) were not observed in the study. In Pfdhfr, N51I (85.4%), C59R (60.4%), and S108N (100.0%) polymorphisms were detected. Triple mutation (CIRNI) (mutant amino acids are underlined) was the most prevalent (47.9%) Pfdhfr haplotype. In the study, all P. falciparum isolates (100.0%) harboured the A437G allele in Pfdhps gene. Also, K540E and A581G polymorphisms were observed in one (2.1%) isolate. Single mutant haplotype (SGKAA) was detected in 97.9% of the isolates. Mutant Pfdhfr and Pfdhps allele combinations revealed quintuple (CICNI-SGEGA; 2.1%), quadruple (CIRNI-SGKAA; 47.9%), triple (CICNI-SGKAA; 35.4%, CNRNI-SGKAA; 12.5%), and double (CNCNI-SGKAA; 2.1%) haplotypes. CONCLUSIONS:In the study, the rate of SGEGA haplotype was low (2.1%). Although K540E and A581G alleles are more common in Eastern Africa, a distinct lineage of SGEGA is also present in the DRC, which is located in Central Africa. This haplotype is associated with decreased efficacy of SP in pregnant women and infants, therefore, it should be carefully considered in the DRC and SP resistance should be routinely monitored.

Project description:BackgroundSulfadoxine-pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap.MethodsDried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays.ResultsAcross populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5-25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3-87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7-47.2%). The dhfr I164L mutation was found in one sample.ConclusionsThe prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.

Project description:BackgroundIntermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown.MethodsWe conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4 weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12 months of life. All analyses were done by modified intention to treat.ResultsOf the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12 months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p = 0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p = 0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p = 0.93).ConclusionDespite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants.Trial registrationClinicalTrials.gov, NCT02793622 . Registered on June 8, 2016.

Project description:BackgroundIn Africa, most plasmodium infections during pregnancy remain asymptomatic, yet are associated with maternal anemia and low birthweight. WHO recommends intermittent preventive therapy in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, sulfadoxine-pyrimethamine (SP) efficacy is threatened by high-level parasite resistance. We conducted a trial to evaluate the efficacy and safety of scheduled intermittent screening with malaria rapid diagnostic tests (RDTs) and treatment of RDT-positive women with dihydroartemisinin-piperaquine (DP) as an alternative strategy to IPTp-SP.Methods and findingsThis was an open-label, two-arm individually randomized superiority trial among HIV-seronegative women at three sites in Malawi with high SP resistance. The intervention consisted of three or four scheduled visits in the second and third trimester, 4 to 6 wk apart. Women in the IPTp-SP arm received SP at each visit. Women in the intermittent screening and treatment in pregnancy with DP (ISTp-DP) arm were screened for malaria at every visit and treated with DP if RDT-positive. The primary outcomes were adverse live birth outcome (composite of small for gestational age, low birthweight [<2,500 g], or preterm birth [<37 wk]) in paucigravidae (first or second pregnancy) and maternal or placental plasmodium infection at delivery in multigravidae (third pregnancy or higher). Analysis was by intention to treat. Between 21 July 2011 and 18 March 2013, 1,873 women were recruited (1,155 paucigravidae and 718 multigravidae). The prevalence of adverse live birth outcome was similar in the ISTp-DP (29.9%) and IPTp-SP (28.8%) arms (risk difference = 1.08% [95% CI -3.25% to 5.41%]; all women: relative risk [RR] = 1.04 [95% CI 0.90-1.20], p = 0.625; paucigravidae: RR = 1.10 [95% CI 0.92-1.31], p = 0.282; multigravidae: RR = 0.92 [95% CI 0.71-1.20], p = 0.543). The prevalence of malaria at delivery was higher in the ISTp-DP arm (48.7% versus 40.8%; risk difference = 7.85%, [95% CI 3.07%-12.63%]; all women: RR = 1.19 [95% CI 1.07-1.33], p = 0.007; paucigravidae: RR = 1.16 [95% CI 1.04-1.31], p = 0.011; multigravidae: RR = 1.29 [95% CI 1.02-1.63], p = 0.037). Fetal loss was more common with ISTp-DP (2.6% versus 1.3%; RR = 2.06 [95% CI 1.01-4.21], p = 0.046) and highest among non-DP-recipients (3.1%) in the ISTp-DP arm. Limitations included the open-label design.ConclusionsScheduled screening for malaria parasites with the current generation of RDTs three to four times during pregnancy as part of focused antenatal care was not superior to IPTp-SP in this area with high malaria transmission and high SP resistance and was associated with higher fetal loss and more malaria at delivery.Trial registrationPan African Clinical Trials Registry PACTR201103000280319; ISRCTN Registry ISRCTN69800930.

Dataset Information

Intermittent preventive treatment: efficacy and safety of sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine plus piperaquine regimens in schoolchildren of the Democratic Republic of Congo: a study protocol for a randomized controlled trial.

Publications

Intermittent preventive treatment: efficacy and safety of sulfadoxine-pyrimethamine and sulfadoxine-pyrimethamine plus piperaquine regimens in schoolchildren of the Democratic Republic of Congo: a study protocol for a randomized controlled trial.

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