title: Multi-Country Evaluation of Safety of Dihydroartemisinin/Piperaquine Post-Licensure in African Public Hospitals with Electrocardiograms.
abstract: The antimalarial drug piperaquine is associated with delayed ventricular depolarization, causing prolonged QT interval (time taken for ventricular de-polarisation and re-polarisation). There is a lack of safety data regarding dihydroartemisinin/piperaquine (DHA/PPQ) for the treatment of uncomplicated malaria, which has limited its use. We created a platform where electrocardiograms (ECG) were performed in public hospitals for the safety assessment of DHA/PPQ, at baseline before the use of dihydroartemisinin/piperaquine (Eurartesim®), and on day 3 (before and after administration of the final dose) and day 7 post-administration. Laboratory analyses included haematology and clinical chemistry. The main objective of the ECG assessment in this study was to evaluate the effect of administration of DHA/PPQ on QTc intervals and the association of QTc intervals with changes in blood biochemistry, full and differential blood count over time after the DHA/PPQ administration. A total of 1315 patients gave consent and were enrolled of which 1147 (87%) had complete information for analyses. Of the enrolled patients 488 (42%), 323 (28%), 213 (19%) and 123 (11%) were from Ghana, Burkina Faso, Tanzania and Mozambique, respectively. Median (lower-upper quartile) age was 8 (5-14) years and a quarter of the patients were children under five years of age (n = 287). Changes in blood biochemistry, full and differential blood count were temporal which remained within clinical thresholds and did not require any intervention. The mean QTcF values were significantly higher than on day 1 when measured on day 3 before and after administration of the treatment as well as on day 7, four days after completion of treatment (12, 22 and 4 higher, p < 0.001). In all age groups the values of QT, QTcF and QTcB were highest on day 3 after drug intake. The mean extreme QTcF prolongation from baseline was lowest on day 3 before drug intake (33 ms, SD = 19) and highest on day 3 after the last dose (60 ms, SD = 31). There were 79 (7%) events of extreme mean QTcF prolongation which were not clinically significant. Nearly a half of them (n = 37) were grade 3 and mainly among males (33/37). Patients in Burkina Faso, Mozambique and Tanzania had significantly lower mean QTcF than patients in Ghana by an average of 3, 4 and 11 ms, respectively. We found no evidence that Eurartesim® administered in therapeutic doses in patients with uncomplicated malaria and no predisposing cardiac conditions in Africa was associated with adverse clinically significant QTc prolongation.
authors.affiliation: Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Abdunoor M
authors.identifier: http://orcid.org/0000-0002-2980-0429
authors.initials: AM
authors.lastname: Kabanywanyi
authors.affiliation: INDEPTH Network, Accra, Ghana.
authors.forename: Rita
authors.initials: R
authors.lastname: Baiden
authors.affiliation: Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Ali
authors.affiliation: Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Muhidin K
authors.initials: MK
authors.lastname: Mahende
authors.affiliation: INDEPTH Network, Accra, Ghana.
authors.forename: Bernhards R
authors.initials: BR
authors.lastname: Ogutu
authors.affiliation: Navrongo Health Research Centre, Navrongo, Ghana.
authors.forename: Abraham
authors.initials: A
authors.lastname: Oduro
authors.affiliation: Nanoro Health Research Centre, Nanoro, Burkina Faso.
authors.forename: Halidou
authors.initials: H
authors.lastname: Tinto
authors.affiliation: Dodowa Health Research Centre, Dodowa, Ghana.
authors.forename: Margaret
authors.initials: M
authors.lastname: Gyapong
authors.affiliation: Nouna Health Research Centre, Nouna, Burkina Faso.
authors.forename: Ali
authors.initials: A
authors.lastname: Sie
authors.affiliation: Centro de Investigaçãoem Saúde de Manhiça(CISM), Manhiça, Mozambique.
authors.forename: Esperanca
authors.initials: E
authors.lastname: Sevene
authors.affiliation: Centro de Investigaçãoem Saúde de Manhiça(CISM), Manhiça, Mozambique.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Macete
authors.affiliation: Kintampo Health Research Centre, Kintampo, Ghana.
authors.forename: Seth
authors.initials: S
authors.lastname: Owusu-Agyei
authors.affiliation: Dodowa Health Research Centre, Dodowa, Ghana.
authors.forename: Alex
authors.initials: A
authors.lastname: Adjei
authors.affiliation: Nouna Health Research Centre, Nouna, Burkina Faso.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Compaoré
authors.affiliation: Nanoro Health Research Centre, Nanoro, Burkina Faso.
authors.forename: Innocent
authors.initials: I
authors.lastname: Valea
authors.affiliation: Navrongo Health Research Centre, Navrongo, Ghana.
authors.forename: Isaac
authors.initials: I
authors.lastname: Osei
authors.affiliation: Kintampo Health Research Centre, Kintampo, Ghana.
authors.forename: Abena
authors.initials: A
authors.lastname: Yawson
authors.affiliation: INDEPTH Network, Accra, Ghana.
authors.forename: Martin
authors.initials: M
authors.lastname: Adjuik
authors.affiliation: INDEPTH Network, Accra, Ghana.
authors.forename: Raymond
authors.initials: R
authors.lastname: Akparibo
authors.affiliation: Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Mwaka A
authors.initials: MA
authors.lastname: Kakolwa
authors.affiliation: Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdulla
authors.affiliation: University for Health and Allied Sciences, Ho, Ghana.
authors.forename: Fred
authors.initials: F
authors.lastname: Binka
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D044383:Black People; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D002050:Burkina Faso; D002648:Child; D002675:Child, Preschool; D003627:Data Interpretation, Statistical; D004562:Electrocardiography; D005260:Female; D005869:Ghana; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects*; D006779:Hospitals, Public; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D008297:Male; D009073:Mozambique; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013636:Tanzania; D018754:Ventricular Dysfunction / Q000209:etiology; D055815:Young Adult; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines