Factors affecting haemoglobin dynamics in African children with acute uncomplicated Plasmodium falciparum malaria treated with single low-dose primaquine or placebo.
Male
Female
Humans
Child
Child, Preschool
Primaquine
Antimalarials
/ adverse effects
alpha-Thalassemia
/ drug therapy
Artemether, Lumefantrine Drug Combination
/ therapeutic use
Artemether
/ therapeutic use
Malaria, Falciparum
/ drug therapy
Hemoglobins
/ analysis
Glucosephosphate Dehydrogenase Deficiency
Plasmodium falciparum
Anaemia
Children
Glucose-6-phosphate dehydrogenase deficiency
Haemoglobin
Plasmodium falciparum
Primaquine
Journal
BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723
Informations de publication
Date de publication:
20 10 2023
20 10 2023
Historique:
received:
05
07
2023
accepted:
05
10
2023
medline:
23
10
2023
pubmed:
20
10
2023
entrez:
19
10
2023
Statut:
epublish
Résumé
Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa. The trial is registered at ISRCTN 11594437.
Sections du résumé
BACKGROUND
Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.
METHODS
This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.
RESULTS
One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo).
CONCLUSIONS
In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.
TRIAL REGISTRATION
The trial is registered at ISRCTN 11594437.
Identifiants
pubmed: 37858129
doi: 10.1186/s12916-023-03105-0
pii: 10.1186/s12916-023-03105-0
pmc: PMC10588240
doi:
Substances chimiques
Primaquine
MVR3634GX1
Antimalarials
0
Artemether, Lumefantrine Drug Combination
0
Artemether
C7D6T3H22J
artenimol
6A9O50735X
Hemoglobins
0
Types de publication
Randomized Controlled Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
397Subventions
Organisme : Medical Research Council
ID : MR/P006973/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 202800/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203077/Z/16/Z
Pays : United Kingdom
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Br J Haematol. 2009 Sep;146(6):675-82
pubmed: 19650883
EBioMedicine. 2023 Oct;96:104805
pubmed: 37757570
Antimicrob Agents Chemother. 2015 Aug;59(8):4719-26
pubmed: 26014949
Malar J. 2016 Jun 10;15:316
pubmed: 27287612
Am J Prev Med. 2011 Dec;41(6 Suppl 4):S398-405
pubmed: 22099364
Lancet Infect Dis. 2014 Feb;14(2):130-9
pubmed: 24239324
Clin Transl Sci. 2020 Jan;13(1):116-124
pubmed: 31647186
J Clin Pathol. 2009 Jan;62(1):35-8
pubmed: 19103857
BMC Med. 2022 Sep 16;20(1):350
pubmed: 36109733
Nat Commun. 2022 Oct 26;13(1):6353
pubmed: 36289202
BMC Infect Dis. 2019 Mar 12;19(1):250
pubmed: 30871496
PLoS One. 2016 Mar 24;11(3):e0151898
pubmed: 27010542
Antimicrob Agents Chemother. 2020 May 21;64(6):
pubmed: 32179526
N Engl J Med. 2021 Sep 23;385(13):1163-1171
pubmed: 34551228
Lancet Infect Dis. 2023 Apr;23(4):471-483
pubmed: 36462528
Antimicrob Agents Chemother. 2014 Sep;58(9):5528-36
pubmed: 25001306
Eur J Hum Genet. 2009 Aug;17(8):1080-5
pubmed: 19223928
Malar J. 2013 Sep 23;12:343
pubmed: 24060207
Malar J. 2018 Oct 19;17(1):371
pubmed: 30340592
N Engl J Med. 2008 Dec 11;359(24):2619-20
pubmed: 19064625
PLoS One. 2018 Jan 11;13(1):e0190272
pubmed: 29324864
J Infect Dis. 2022 Apr 19;225(8):1411-1414
pubmed: 34216470
Biotechniques. 2005 Oct;39(4):571-4
pubmed: 16235570
N Engl J Med. 2023 Sep 28;389(13):1191-1202
pubmed: 37754284
BMC Med Genet. 2017 Nov 23;18(1):139
pubmed: 29169341
Nat Med. 2020 Oct;26(10):1602-1608
pubmed: 32747827
Nature. 2022 Feb;602(7895):106-111
pubmed: 34883497
BMC Infect Dis. 2017 Jun 23;17(1):443
pubmed: 28645255
J Infect Dis. 2022 Apr 1;225(7):1215-1226
pubmed: 32778875
Lancet Child Adolesc Health. 2022 Sep;6(9):606-613
pubmed: 35785794
Lancet Infect Dis. 2018 Jun;18(6):627-639
pubmed: 29422384
BMC Med. 2018 Jan 18;16(1):11
pubmed: 29347975
Malar J. 2013 May 28;12:171
pubmed: 23714236
BMC Med. 2022 Mar 7;20(1):85
pubmed: 35249546
PLoS One. 2008;3(12):e4031
pubmed: 19112496
N Engl J Med. 2019 Aug 1;381(5):407-419
pubmed: 31365799
Blood. 2005 Jul 1;106(1):368-71
pubmed: 15769889
Malar J. 2014 Apr 17;13:148
pubmed: 24742291
J Infect Dis. 2018 Mar 28;217(8):1298-1308
pubmed: 29342267
Clin Infect Dis. 2017 Aug 15;65(4):535-543
pubmed: 28605472
Antimicrob Agents Chemother. 2017 Apr 24;61(5):
pubmed: 28289025
PLoS One. 2013 Jul 12;8(7):e68800
pubmed: 23874768
Am J Trop Med Hyg. 2001 Nov;65(5):614-22
pubmed: 11716124
Malar J. 2022 Mar 12;21(1):84
pubmed: 35279143
Malar J. 2013 Jun 19;12:209
pubmed: 23777546
Nat Genet. 2014 Nov;46(11):1197-204
pubmed: 25261933
Lancet Glob Health. 2016 Mar;4(3):e195-200
pubmed: 26833239
N Engl J Med. 2009 Jul 30;361(5):455-67
pubmed: 19641202
Malar J. 2018 Nov 15;17(1):427
pubmed: 30442143
Malar J. 2012 Dec 14;11:418
pubmed: 23237606
Nucleic Acids Res. 2001 Dec 1;29(23):E119
pubmed: 11726702
Infect Genet Evol. 2017 Nov;55:281-287
pubmed: 28939159
Antimicrob Agents Chemother. 2010 May;54(5):1762-8
pubmed: 20194698
Ann Trop Med Parasitol. 1983 Jun;77(3):239-46
pubmed: 6354114
Blood. 2012 Nov 15;120(20):4123-33
pubmed: 22993389
Lancet Infect Dis. 2016 Jun;16(6):674-684
pubmed: 26906747