Dynamics of Malaria Drug Resistance Patterns in the Amazon Basin Region following Changes in Peruvian National Treatment Policy for Uncomplicated Malaria

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Abstract
Monitoring changes in the frequencies of drug-resistant and -sensitive genotypes can facilitate in vivo clinical trials to assess the efficacy of drugs before complete failure occurs. Peru changed its national treatment policy for uncomplicated malaria to artesunate (ART)-plus-mefloquine (MQ) combination therapy in the Amazon basin in 2001. We genotyped isolates collected in 1999 and isolates collected in 2006 to 2007 for mutations in the Plasmodium falciparum dihydrofolate reductase (Pf dhfr ) and dihydropteroate synthase (Pf dhps ) genes, multidrug resistance gene 1 (Pf mdr-1 ), the chloroquine (CQ) resistance transporter gene (Pf crt ), and the Ca 2+ ATPase gene (Pf ATP6 ); these have been shown to be involved in resistance to sulfadoxine-pyrimethamine (SP), MQ, CQ, and possibly ART, respectively. Microsatellite haplotypes around the Pf dhfr , Pf dhps , Pf crt , and Pf mdr-1 loci were also determined. There was a significant decline in the highly SP resistant Pf dhfr and Pf dhps genotypes from 1999 to 2006. In contrast, a CQ-resistant Pf crt genotype increased in frequency during the same period. Among five different Pf mdr-1 allelic forms noted in 1999, two genotypes increased in frequency while one genotype decreased by 2006. We also noted previously undescribed polymorphisms in the Pf ATP6 gene as well as an increase in the frequency of a deletion mutant during this period. In addition, microsatellite analysis revealed that the resistant Pf dhfr , Pf dhps , and Pf crt genotypes have each evolved from a single founder haplotype, while Pf mdr-1 genotypes have evolved from at least two independent haplotypes. Importantly, this study demonstrates that the Peruvian triple mutant Pf dhps genotypes are very similar to those found in other parts of South America.

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