PLASMODIUM FALCIPARUM DRUG RESISTANCE: MOLECULAR MECHANISMS, GLOBAL DISTRIBUTION, SURVEILLANCE PRIORITIES, AND EMERGING THERAPEUTIC STRATEGIES

A new era in drug resistance of Plasmodium falciparum has begun. Partial resistance to chloroquine and sulfadoxine-pyrimethamine is widespread, and susceptibility to the partner drugs is becoming more complex in Africa, with partial resistance to artemisinin derivatives, as seen with CQ and SDP, now established in multiple countries. This narrative review brings parasite biology, molecular mechanisms, geographical patterns, clinical implications, surveillance tools, as well as the therapeutic pipeline together. Resistance is described as a multilevel phenotype, depending on the combination of mutations and copy-number variants in the genes of pfcrt, pfmdr1, pfdhfr, pfdhps, pfkelch13, plasmepsin II/III, pfcytb and other genes, the genetic background of the parasites, exposure to drugs, immunity, transmission intensity and health-system performance. There are broad differences between molecular evidence of reduced susceptibility, delayed parasite clearance, partner-drug resistance, and proven treatment failure. The review suggests a decision-oriented surveillance model that connects therapeutic-efficacy studies with day-3 phenotypes of parasitaemia and clearance, validated molecular markers, ex vivo or in vitro susceptibility testing, drug-quality surveillance, and pharmacokinetic studies. New strategies being developed include optimized and triple artemisinin combinations, rotation or diversification of partner drugs, and other compounds including non-artemisinin drugs like ganaplacide-lumefantrine, cipargamin, M5717-pyronaridine, and ZY19489-containing combinations. But novelty of mechanism does not imply durability – new combinations must be made durable, by performing resistance-risk assessment, deployability studies, equitable access planning and prospective genomic monitoring. Successful containment will require regional evidence, quick policy adaptation, medicines of good quality, support for adherence, and molecular and clinical surveillance that is coordinated.

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