Monitoring for multidrug-resistant Plasmodium falciparum isolates and analysis of pyrimethamine resistance evolution in Uige province, Angola

• Published in: Tropical medicine & international health 2009-10, Vol.14 (10), p.1251-1257
• Main Authors: Menegon, Michela, Pearce, Richard J, Inojosa, Walter O, Pisani, Vincenzo, Abel, Paulo M, Matondo, Alexandre, Bisoffi, Zeno, Majori, Giancarlo, Ord, Rosalynn, Warhurst, David C, Roper, Cally, Severini, Carlo
• Format: Article
• Language: English
• Subjects: Angola; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - therapeutic use; Antiparasitic agents; Biological and medical sciences; Child; Drug resistance; drug resistance molecular markers; Drug Resistance, Multiple - genetics; evolución resistencia pirimetamina; Evolutionary biology; General aspects; Genetics; Genotype; Humans; Malaria, Falciparum - drug therapy; Malaria, Falciparum - genetics; marcadores molecular de resistencia a fármacos; Medical sciences; Membrane Transport Proteins - genetics; microsatellite repeats; Microsatellite Repeats - genetics; microsatellites; microsatélites; Multidrug Resistance-Associated Proteins - genetics; Mutation; Mutation - genetics; Parasites; Pharmacology. Drug treatments; Plasmodium falciparum; Protozoan Proteins - genetics; Pyrimethamine - therapeutic use; pyrimethamine resistance evolution
• ISSN: 1360-2276; 1365-3156
• DOI: 10.1111/j.1365-3156.2009.02369.x

To assess the extent of drug resistance in Uige through molecular genetic analysis and to test whether the dhfr triple mutant alleles present in Angola are of southeast Asian origin. Seventy-one samples of blood from children admitted to the Pediatric Emergency Unit of Uige Provincial Hospital in 2004 were screened for resistance mutations at pfcrt, pfmdr1, pfdhfr, pfdhps and pfATPase6. Mutations in pfcrt (codon76), pfmdr1 (codon86), pfdhfr (codons 51, 59, 108) and pfdhps (codons 436, 437) were common. Among the 66 isolates for which we were able to determine complete genetic information 13.7% carried all seven of these mutations. Flanking microsatellite analysis revealed the triple mutant pfdhfr was derived from the southeast Asian lineage, while the N51I+S108N double mutant pfdhfr alleles are a local origin. pfATPase6 mutations were rare and S769N was not found. The parasite population of Uige Angola has high frequency mutations in pfcrt, dhfr and dhps associated with resistance to chloroquine and sulphadoxine pyrimethamine, reflecting past reliance on these two drugs which were the mainstay of treatment until recently. Our findings show that drug resistance in Uige has occurred through a combination of local drug pressure and the regional and international dispersal of resistance mutant alleles.