title: Efficacy of artemisinin-based combination therapies for the treatment of falciparum malaria in Pakistan (2007-2015): In vivo response and dhfr and dhps mutations.
abstract: Artesunate+sulfadoxine-pyrimethamine (AS+SP) and artemether+lumefantrine (AL) are the first- and second line treatments, respectively, for the treatment of falciparum infections and dihydroartemsinin+piperaquine (DHA+PPQ) is a potential candidate in case AS+SP or AL fails in Pakistan. The therapeutic efficacies of AS+SP (5 sites in 2007, 2 sites in 2011 and 2 sites in 2012), AL (2 sites in 2012) and DHA+PPQ (2 sites in 2015) were evaluated in seven sentinel sites. Clinical and parasitological outcomes were evaluated among eligible patients. Mutations of the P. falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes were investigated. After PCR correction, a 98.5-100% adequate clinical and parasitological response (ACPR) for AS+SP and a 98.8-100% ACPR for AL were observed by day 28, as well as a 100% ACPR by day 42 for DHA+PPQ. The prevalences of mutants dhfr S108N (100%) and C59R (98%-100%) reached or were near fixation. The double dhfr (C59R/S108N) mutant was dominant (96%-100%) at all sites. The triple dhfr (N51I/C59R/S108N) mutant was rare (1.1%-2.3%). The prevalence of dhps A437G varied between 38% and 70%. A combination of triple dhfr/dhps (C59R/S108N+A437G or N51I/S108N+A437G) mutants was observed (38%-69%). A quadruple dhfr/dhps (N51I/C59R/S108N+A437G) mutation was very rare and no quintuple (N51I/C59R/S108N+A437G/K540E) mutations were detected. AS+SP remains highly effective in Pakistan. However, molecular data indicate that SP resistance is being established, although mutations that confer a high risk of SP treatment failure are rare or non-existent. This underscores the need for close monitoring of both in vivo AS+SP efficacy and dhfr and dhps mutations to inform national treatment policy. Trial registration numbers: ISRCTN21926128 (2007), ACTRN12611001244998 (2011), ACTRN12612001090808 (2012), ACTRN12615001248550 (2015).
authors: World Health Organization, WHO Country Office, Islamabad, Pakistan.
authors: Qutbuddin
authors: Q
authors: Kakar
authors: Liaqat University of Health Sciences Jamshoro, Sindh, Pakistan.
authors: Salma
authors: S
authors: Sheikh
authors: Liaqat University of Health Sciences Jamshoro, Sindh, Pakistan.
authors: Imran
authors: I
authors: Ahmed
authors: Institute of Public Health, Quetta, Provincial Reference Laboratory, Balochistan, Pakistan.
authors: Munir Ahmed
authors: MA
authors: Khan
authors: Malaria Control Programme, Provincial Reference Laboratory, Directorate Health Services, Federally Administered Tribal Areas, Pakistan.
authors: Muhammad
authors: M
authors: Jamil
authors: US Naval Medical Research Unit-3, Cairo, Egypt.
authors: Hanan
authors: H
authors: ElMohammady
authors: World Health Organization, Global Malaria Programme, Geneva, Switzerland. Electronic address: warsamem@who.int.
authors: Marian
authors: M
authors: Warsame
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004983:Ethanolamines / Q000627:therapeutic use; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D009154:Mutation; D010154:Pakistan; D010963:Plasmodium falciparum / Q000235:genetics*; D011446:Prospective Studies; D011739:Pyrimethamine / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; C578917:sulfadoxine-pyrimethamine-artesunate; D013413:Sulfadoxine; D000077549:Artemether; D000078102:Lumefantrine; D011739:Pyrimethamine
keywords: Artemisinin-based combinations; Efficacy; Pakistan; Plasmodium falciparum; dhfr and dhps