Baseline in vivo, ex vivo and molecular responses of Plasmodium falciparum to artemether and lumefantrine in three endemic zones for malaria in Colombia

Abstract

This study generated a susceptibility baseline in response to therapy with Coartem (artemether-lumefantrine) with numerical reference values, which will allow data comparison with future studies to systematically monitor changes in the parasite and to provide an early alert to the health authorities.

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

“…Using our new sequencing protocol, which captures the entire K13 propeller region, we found no evidence for the presence of K13 propeller mutations. This finding is similar to that recently reported for 66 samples from Nariño, Guaviare, and Córdoba in 2012 to 2013 (20), and for 162 samples from Brazil in 2010 to 2013 (23), and contrasts sharply with the deep reservoir of K13 propeller polymorphism in Africa (24,25), where parasite diversity and transmission rates are much higher (26). However, we did identify 4/125 (3.2%) patients with D3 positivity, suggesting the possibility that a subset of parasites is becoming less susceptible to ART through mutation in other loci, that some individuals have relatively poor parasite-clearing immune responses, or that some patients were not self-administering their remaining doses of AL.…”

“…These findings are similar to the 100% S1034 and 93.3% 1042D prevalences reported for Colombian isolates (20,32) and to the 84% 1034C and 100% 1042D prevalences reported for Brazilian isolates (38). Although SNPs at positions 1034 and 1042 have not been adequately evaluated, the 1042D mutation has been associated with increased in vitro susceptibility to LF in Thailand in 1999 to 2002, when AS-MQ was being used to treat falciparum malaria (42).…”

“…Overall, our data suggest that a small minority of Colombian parasites survives ART exposure at 72 h and thus could evolve genetic changes that confer decreased susceptibility to LF. We found multicopy (up to 6 copies) mdr1 genotypes in 12.9% (23/178) of samples, which is lower than the 32% prevalence recently reported for P. falciparum isolates from Nariño, Guaviare, and Córdoba in 2011 to 2012 (20). Whether these mdr1 polymorphisms were selected previously by MQ exposure or more recently by LF exposure or both remains to be investigated.…”

“…Elsewhere in South America, no mdr1 amplification was observed in 26 isolates from Brazil in the late 1990s (28) (30). While the lack of recent published studies prevents us from determining whether these mdr1 polymorphisms are becoming more prevalent over time in Colombia or elsewhere in South America, recent mdr1 copy number data from Aponte et al (20) show that, collectively, 32.0% (26/81) of isolates in Córdoba, Nariño, and Guaviare in 2012 to 2013 had multicopy mdr1 genotypes. Specifically, 67%, 17%, 10%, 2.5%, and 2.5% of 81 isolates had 1, 2, 3, 4, and 5 copies, respectively-a copy number distribution like that in our study ( Table 1).…”

“…Since 2006, only 3 studies (18)(19)(20) have used WHO-recommended protocols to measure the antimalarial efficacy of AL in Colombia; however, those studies did not use specific methods to study ART resistance. In addition, therapeutic efficacy studies are logistically complicated and expensive to perform in Colombia and their findings may not fully reflect the reality of field conditions (21).…”