Plasmodium falciparum and Plasmodium vivax Genotypes and Efficacy of Intermittent Preventive Treatment in Papua New Guinea

Abstract

Intermittent preventive treatment of infants (IPTi) reduces early childhood malaria-related morbidity. While genotypic drug resistance markers have proven useful in predicting the efficacy of antimalarial drugs in case management, there are few equivalent data relating to their protective efficacy when used as IPTi. The present data from an IPTi trial in Papua New Guinea demonstrate how these markers can predict protective efficacy of IPTi for both Plasmodium falciparum and Plasmodium vivax. Intermittent preventive treatment of infants (IPTi) has reduced early childhood malaria-related morbidity in many settings (1,2). Although its precise mechanism of action has been debated, it is now generally agreed that the intermittent short courses of slowly eliminated antimalarial drugs provide protection due to prolonged prophylactic activity (2). Therefore, the pharmacokinetic and pharmacodynamic properties that determine a drug's suitability for IPTi may differ from those important for therapeutic efficacy in case management.Genotypic drug resistance markers correlate well with in vivo therapeutic response in the case management of acute infections. Mutations of Plasmodium falciparum and Plasmodium vivax dihydrofolate reductase (pfdhfr and pvdhfr) and dihydropteroate synthase (pfdhps and pvdhps) genes are associated with resistance to pyrimethamine and sulfadoxine, respectively (3-6). Parasite resistance to 4-aminoquinolines is associated with mutations in the chloroquine resistance transporter gene (pfcrt) (7) and multidrug resistance gene 1 (pfmdr1) in P. falciparum infections and with P. vivax multidrug resistance gene 1 (pvmdr1) mutations in some studies of vivax malaria (8, 9) but not others (10).IPTi effectiveness is likely to be highly dependent on drug resistance patterns in local parasite populations. Current IPTi regimens utilize either 4-aminoquinoline or antifolate drugs (2), and so existing genotypic resistance markers should predict protective efficacy in a given setting without the need for large expensive field-based efficacy studies. However, data directly relating drug resistance genotypes to IPTi efficacy is limited to African IPTi trials of sulfadoxine-pyrimethamine (SP) dual therapy, which have demonstrated that the pfdhfr triple mutant genotype predicts reduced efficacy (11,12). No studies have examined the relationship between IPTi efficacy and genotypic markers in P. vivax infections nor between 4-aminoquinoline resistance markers and IPTi efficacy in falciparum malaria. In addition, there are concerns that the high burden of antimalarial drug use through IPTi will drive the selection and spread of parasite drug resistance, with a consequent reduction in public health benefit (13). Serial monitoring of validated genotypic markers could help identify this phenomenon at an early stage (12).In Papua New Guinea (PNG), an IPTi study of 1,121 infants conducted from 2006 to 2010 showed that amodiaquine plus SP (AQ-SP) reduced P. falciparum and P. vivax incidence by 35% and 23%, respectively, compared ...

Rapid selection of sulphadoxine-resistant Plasmodium falciparum and its effect on within-population genetic diversity in Papua New Guinea

“…The sulphadoxine-resistant S GE AA allele emerged between 2003 and 2010 in the present study area. This finding coincides with previous observations in Madang Province, where this allele appeared between 2006 and 2010 40 – 42 . However, frequencies of the S GE AA allele in our study (84% in 2011) were much higher than those in the previous studies (~25%) 40 – 42 .…”

Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial

“…One concern with use of SP is emergence of drug resistance that limits efficacy or could even exacerbate infection [ 39 ]. Parasites from this study have not been typed for drug resistance markers, but contemporaneous parasites from children and adults in the same locale have recently been analysed [ 18 ]. ‘Highly resistant’ patterns of molecular markers (quintuple mutations in the dhfr and dhps genes) and ‘super resistant’ parasites (also featuring dhfr 164 or dhps 581 mutations) [ 21 ] have not been detected, and the prevalence of dhps 540 mutations associated with drug failure in young children [ 21 ] was <20%.…”

“…Because there is currently insufficient evidence to support a general recommendation for the use of IPTp-SP outside Africa [ 7 ], and because SP alone is often ineffective against P.v. [ 18 ], which causes around 40% of malaria infections in PNG, we compared SPAZ-IPTp to a single course of SP and chloroquine (CQ) to eliminate infection. The study was conducted in accordance with Good Clinical Practice guidelines (ICH GCP E6).…”

“…A previous survey of molecular markers of SP resistance in children from the study area demonstrated absence of ‘high’ and ‘super’ resistant P.f. and a low prevalence of the dhps K540E mutation (20%) [ 18 , 21 ]. The dose and regimen for AZ was selected based on previous pharmacokinetic and tolerability studies [ 10 ], and to give adequate drug levels at 96 hours to clear P.f.…”

Temporal changes in Plasmodium falciparum anti-malarial drug sensitivity in vitro and resistance-associated genetic mutations in isolates from Papua New Guinea

“…Parasite isolates where tested for genetic markers associated with drug resistance using a multiplex polymerase chain reaction ligase detection reaction fluorescent microsphere assay (PCR-LDR-FMA) assay as previously described [ 14 , 19 ]. In brief, PCR-LDR-FMA was performed using established primer sequences to detect single nucleotide polymorphisms in the known resistance loci of pfdhfr (codons 51, 58, 108, 164) , pfdhps (codons 436–437, 540, 581, 613) , pfcrt (codons 72–76) and pfmdr1 (codons 86, 184, 1034, 1042, 1246) .…”