Molecular Evidence of Increased Resistance to Anti-Folate Drugs in Plasmodium falciparum in North-East India: A Signal for Potential Failure of Artemisinin Plus Sulphadoxine-Pyrimethamine Combination Therapy

• Published in: PloS one Vol. 9; no. 9; p. e105562
• Main Authors: Mohapatra, Pradyumna Kishore, Sarma, Devojit Kumar, Prakash, Anil, Bora, Khukumoni, Ahmed, Md. Atique, Sarma, Bibhas, Goswami, Basanta Kumar, Bhattacharyya, Dibya Ranjan, Mahanta, Jagadish
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.09.2014; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Amino acids; Antimalarials - therapeutic use; Artemisinin; Artemisinins - therapeutic use; Child; Child, Preschool; Chloroquine; Chloroquine - therapeutic use; Codon; Codons; Combination therapy; Dihydrofolate reductase; Disease control; Drug Combinations; Drug resistance; Drug Resistance - genetics; Drug Therapy, Combination; Drugs; Enzymes; Erythrocytes; Failure; Female; Folic acid; Genes; Genotyping; Haplotypes; Humans; In vivo methods and tests; India - epidemiology; Loci; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - epidemiology; Malaria, Falciparum - parasitology; Male; Medical research; Medicine and Health Sciences; Membrane Transport Proteins - genetics; Middle Aged; Multidrug Resistance-Associated Proteins - genetics; Mutants; Mutation; Parasites; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - growth & development; Protozoan Proteins - genetics; Pyrimethamine; Pyrimethamine - therapeutic use; Sulfadoxine - therapeutic use; Therapy; Vector-borne diseases; Vectors (Biology); India
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0105562

North-east India, being a corridor to South-east Asia, is believed to play an important role in transmitting drug resistant Plasmodium falciparum malaria to India and South Asia. North-east India was the first place in India to record the emergence of drug resistance to chloroquine as well as sulphadoxine/pyrimethamine. Presently chloroquine resistance is widespread all over the North-east India and resistance to other anti-malarials is increasing. In this study both in vivo therapeutic efficacy and molecular assays were used to screen the spectrum of drug resistance to chloroquine and sulphadoxine/pyrimethamine in the circulating P. falciparum strains. A total of 220 P. falciparum positives subjects were enrolled in the study for therapeutic assessment of chloroquine and sulphadoxine/pyrimethamine and assessment of point mutations conferring resistances to these drugs were carried out by genotyping the isolates following standard methods. Overall clinical failures in sulphadoxine/pyrimethamine and chloroquine were found 12.6 and 69.5% respectively, while overall treatment failures recorded were 13.7 and 81.5% in the two arms. Nearly all (99.0%) the isolates had mutant pfcrt genotype (76 T), while 68% had mutant pfmdr-1 genotype (86 Y). Mutation in dhps 437 codon was the most prevalent one while dhfr codon 108 showed 100% mutation. A total of 23 unique haplotypes at the dhps locus and 7 at dhfr locus were found while dhps-dhfr combined loci revealed 49 unique haplotypes. Prevalence of double, triple and quadruple mutations were common while 1 haplotype was found with all five mutated codons (F/AGEGS/T) at dhps locus. Detection of quadruple mutants (51 I/59 R/108 N/164 L) in the present study, earlier recorded from Car Nicobar Island, India only, indicates the presence of high levels of resistance to sulphadoxine/pyrimethamine in north-east India. Associations between resistant haplotypes and the clinical outcomes and emerging resistance in sulphadoxine/pyrimethamine in relation to the efficacy of the currently used artemisinin combination therapy are discussed.