Clinical and In Vitro Resistance of Plasmodium falciparum to Artesunate-Amodiaquine in Cambodia.
Plasmodium falciparum
Cambodia
artemisinin
artesunate-amodiaquine
drug resistance
Journal
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213
Informations de publication
Date de publication:
02 08 2021
02 08 2021
Historique:
received:
21
12
2019
pubmed:
28
5
2020
medline:
7
8
2021
entrez:
28
5
2020
Statut:
ppublish
Résumé
Artesunate-amodiaquine is a potential therapy for uncomplicated malaria in Cambodia. Between September 2016 and January 2017, artesunate-amodiaquine efficacy and safety were evaluated in a prospective, open-label, single-arm observational study at health centers in Mondulkiri, Pursat, and Siem Reap Provinces, Cambodia. Adults and children with microscopically confirmed Plasmodium falciparum malaria received oral artesunate-amodiaquine once daily for 3 days plus single-dose primaquine, with follow-up on days 7, 14, 21, and 28. The primary outcome was day-28 polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR). An amodiaquine parasite survival assay (AQSA) was developed and applied to whole genome sequencing results to evaluate potential amodiaquine resistance molecular markers. In 63 patients, day-28 PCR-adjusted ACPR was 81.0% (95% confidence interval [CI], 68.9-88.7). Day 3 parasite positivity rate was 44.4% (28/63; 95% CI, 31.9-57.5). All 63 isolates had the K13(C580Y) marker for artemisinin resistance; 79.4% (50/63) had Pfpm2 amplification. The AQSA resistance phenotype (≥45% parasite survival) was expressed in 36.5% (23/63) of isolates and was significantly associated with treatment failure (P = .0020). Pfmdr1 mutant haplotypes were N86/184F/D1246, and Pfcrt was CVIET or CVIDT at positions 72-76. Additional Pfcrt mutations were not associated with amodiaquine resistance, but the G353V mutant allele was associated with ACPR compared to Pfmdr1 haplotypes harboring F1068L or S784L/R945P mutations (P = .030 and P = .0004, respectively). For uncomplicated falciparum malaria in Cambodia, artesunate-amodiaquine had inadequate efficacy owing to amodiaquine-resistant P. falciparum. Amodiaquine resistance was not associated with previously identified molecular markers.
Sections du résumé
BACKGROUND
Artesunate-amodiaquine is a potential therapy for uncomplicated malaria in Cambodia.
METHODS
Between September 2016 and January 2017, artesunate-amodiaquine efficacy and safety were evaluated in a prospective, open-label, single-arm observational study at health centers in Mondulkiri, Pursat, and Siem Reap Provinces, Cambodia. Adults and children with microscopically confirmed Plasmodium falciparum malaria received oral artesunate-amodiaquine once daily for 3 days plus single-dose primaquine, with follow-up on days 7, 14, 21, and 28. The primary outcome was day-28 polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR). An amodiaquine parasite survival assay (AQSA) was developed and applied to whole genome sequencing results to evaluate potential amodiaquine resistance molecular markers.
RESULTS
In 63 patients, day-28 PCR-adjusted ACPR was 81.0% (95% confidence interval [CI], 68.9-88.7). Day 3 parasite positivity rate was 44.4% (28/63; 95% CI, 31.9-57.5). All 63 isolates had the K13(C580Y) marker for artemisinin resistance; 79.4% (50/63) had Pfpm2 amplification. The AQSA resistance phenotype (≥45% parasite survival) was expressed in 36.5% (23/63) of isolates and was significantly associated with treatment failure (P = .0020). Pfmdr1 mutant haplotypes were N86/184F/D1246, and Pfcrt was CVIET or CVIDT at positions 72-76. Additional Pfcrt mutations were not associated with amodiaquine resistance, but the G353V mutant allele was associated with ACPR compared to Pfmdr1 haplotypes harboring F1068L or S784L/R945P mutations (P = .030 and P = .0004, respectively).
CONCLUSIONS
For uncomplicated falciparum malaria in Cambodia, artesunate-amodiaquine had inadequate efficacy owing to amodiaquine-resistant P. falciparum. Amodiaquine resistance was not associated with previously identified molecular markers.
Identifiants
pubmed: 32459308
pii: 5847731
doi: 10.1093/cid/ciaa628
pmc: PMC8326543
doi:
Substances chimiques
Antimalarials
0
Artemisinins
0
Amodiaquine
220236ED28
Artesunate
60W3249T9M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
406-413Commentaires et corrections
Type : CommentIn
Type : CommentOn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.
Références
Mol Biochem Parasitol. 2011 Jul-Aug;178(1-2):1-6
pubmed: 21470564
Lancet Infect Dis. 2019 Nov;19(11):1168-1169
pubmed: 31657776
Clin Infect Dis. 2020 May 6;70(10):2187-2195
pubmed: 31251812
Trop Med Int Health. 2006 Dec;11(12):1800-7
pubmed: 17176344
mBio. 2019 Apr 30;10(2):
pubmed: 31040246
BMJ Glob Health. 2018 Oct 19;3(5):e000999
pubmed: 30397515
Antimicrob Agents Chemother. 2013 Feb;57(2):914-23
pubmed: 23208708
Lancet Infect Dis. 2017 Dec;17(12):1233
pubmed: 29173875
Trop Med Int Health. 2009 May;14(5):504-11
pubmed: 19320869
Am J Trop Med Hyg. 2007 Jan;76(1):20-6
pubmed: 17255223
Antimicrob Agents Chemother. 2019 Sep 23;63(10):
pubmed: 31358594
Malar J. 2009 Jan 12;8:10
pubmed: 19138388
Nat Genet. 2013 Jun;45(6):648-55
pubmed: 23624527
Lancet Infect Dis. 2019 Sep;19(9):943-951
pubmed: 31345709
Nat Commun. 2016 May 18;7:11553
pubmed: 27189525
Nat Commun. 2018 Aug 17;9(1):3314
pubmed: 30115924
N Engl J Med. 2008 Dec 11;359(24):2619-20
pubmed: 19064625
Malar J. 2017 Sep 13;16(1):372
pubmed: 28903755
Lancet Infect Dis. 2017 Feb;17(2):174-183
pubmed: 27818097
Antimicrob Agents Chemother. 2010 Sep;54(9):3714-6
pubmed: 20547800
Diagn Pathol. 2015 Apr 28;10:41
pubmed: 25928117
Am J Trop Med Hyg. 2016 Dec 7;95(6):1228-1238
pubmed: 27928074
Nature. 2014 Jan 2;505(7481):50-5
pubmed: 24352242
Science. 2002 Oct 4;298(5591):210-3
pubmed: 12364805
BMC Med. 2015 Dec 22;13:305
pubmed: 26695060
Malar J. 2016 Nov 8;15(1):541
pubmed: 27825353
Malar J. 2012 Jun 28;11:217
pubmed: 22741618
Lancet Infect Dis. 2019 Sep;19(9):952-961
pubmed: 31345710
Am J Trop Med Hyg. 2014 Oct;91(4):833-843
pubmed: 25048375
Antimicrob Agents Chemother. 2007 Mar;51(3):991-7
pubmed: 17194834
Lancet Infect Dis. 2013 Dec;13(12):1043-9
pubmed: 24035558