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Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of  falciparum  malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the  Plasmodium falciparum  chloroquine resistance transporter ( pfcrt ) are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the  pfcrt  exon 2 from 771  P. falciparum -infected individuals to explore the spatial and temporal variation in  falciparum  malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of  P. falciparum  varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of  P. falciparum  in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique  pfcrt  haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two  pfcrt  mutations (N75D and K76T) implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu) eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in  pfcrt  exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in  P. falciparum .

Diversity of Plasmodium falciparum Chloroquine Resistance Transporter (pfcrt) Exon 2 Haplotypes in the Pacific from 1959 to 1979