Comparative Efficacies of Artemisinin Combination Therapies in Plasmodium falciparum Malaria and Polymorphism of pfATPase6 , pfcrt , pfdhfr , and pfdhps Genes in Tea Gardens of Jalpaiguri District, India

Abstract

In India, chloroquine has been replaced by a combination of artesunate and sulfadoxine-pyrimethamine (AS-SP) for uncomplicated P. falciparum malaria. Other available combinations, artemether-lumefantrine (AM-LF) and artesunate-mefloquine (AS-MQ), not included in the national program, are widely used by private practitioners. Little is known about the therapeutic efficacy of these artemisinin combinations and the prevalence of molecular markers associated with antimalarial drug resistance. A total of 157 patients with P. falciparum monoinfection were recruited and randomized into three study groups (AS-SP, AM-LF, and AS-MQ). All patients were followed up for 42 days to study the clinical and parasitological responses according to the WHO protocol (2009). We assessed the polymorphism of the pfATPase6, pfcrt, pfdhfr, and pfdhps genes by the DNA-sequencing method. The PCR-corrected therapeutic efficacies of AS-SP, AM-LF, and AS-MQ were 90.6% (95% confidence interval [CI], 0.793 to 0.969), 95.9% (95% CI, 0.860 to 0.995), and 100% (95% CI, 0.927 to 1.00), respectively. No specific mutational pattern was observed in the pfATPase6 gene. All isolates had a K76T mutation in the pfcrt gene. In the pfdhfr-pfdhps genotype, quadruple mutation was frequent, and quintuple mutation was documented in 6.3% of P. falciparum isolates. The significant failure rate of AS-SP (9.5%), although within the limit (10%) for drug policy change, was due to SP failure because of prevailing mutations in pfdhfr, I 51 R 59 N 108 , with pfdhps, G 437 and/or E 540 . The efficacy of this ACT needs periodic monitoring. Artemether-lumefantrine and artesunate-mefloquine are effective alternatives to the artesunate-sulfadoxine-pyrimethamine combination.

High prevalence of pfdhfr–pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine–pyrimethamine in combination with artesunate as first-line treatment in Iran

“…In a previous work (Kublin et al, 2002), it has been demonstrated that quadruple mutations in pfdhfr-pfdhps loci are required for the parasites to show clinical failure. Such mutant was not detected among Iranian (Zakeri et al, 2010;Afsharpad et al, 2012, the present study) and Pakistan (Khattak et al, 2013) P. falciparum isolates but reported in very low and high frequencies from Afghanistan (Awab et al, 2013) and India (Saha et al, 2012), respectively. Concerning combined mutations in pfdhfr-pfdhps, quintuple-mutant haplotypes have remained absent in Iran.…”

Prevalence of Polymorphisms in Antifolate Drug Resistance Molecular Marker Genes pvdhfr and pvdhps in Clinical Isolates of Plasmodium vivax from Kolkata, India

“…Reports on polymorphisms in pvdhfr and pvdhps are not available from the present study area before the introduction of ASϩSP, so the data could not be compared. We reported a high prevalence of quadruple and quintuple mutations in the pfdhfr-pfdhps genes in field isolates of P. falciparum from the same state (34) where SP was introduced for the treatment of chloroquine-resistant falciparum malaria in 2002, but no such data are available from urban Kolkata. The types and rates of multiple mutations of the pvdhfrpvdhps genotypes are lower than those found in other parts of the country (21,22).…”

High Prevalence of Asymptomatic Malaria in a Tribal Population in Eastern India

“…In the present study, we used an ACT, a combination of AS and SP, to treat all positive cases, and we observed that this combination was highly effective in the study population against the P. falciparum strain (efficacy, 97%). As a higher level of resistance to this combination has been reported from the Jalpaiguri district of the state (25), the efficacy of this combination should be monitored periodically.…”