Abstract
BackgroundThe decline in efficacy of artesunate (AS) and mefloquine (MQ) is now the major concern in areas along the Thai-Cambodian and Thai-Myanmar borders.MethodsThe correlation between polymorphisms of pfatp6, pfcrt, pfmdr1 and pfmrp1 genes and in vitro sensitivity of Plasmodium falciparum isolates to the artemisinin-based combination therapy (ACT) components AS and MQ, including the previously used first-line anti-malarial drugs chloroquine (CQ) and quinine (QN) were investigated in a total of 119 P. falciparum isolates collected from patients with uncomplicated P. falciparum infection during 2006–2009.ResultsReduced in vitro parasite sensitivity to AS [median (95% CI) IC50 3.4 (3.1-3.7) nM] was found in 42% of the isolates, whereas resistance to MQ [median (95% CI) IC50 54.1 (46.8-61.4) nM] accounted for 58% of the isolates. Amplification of pfmdr1 gene was strongly associated with a decline in susceptibility of P. falciparum isolates to AS, MQ and QN. Significant difference in IC50 values of AS, MQ and QN was observed among isolates carrying one, two, three, and ≥ four gene copies [median (95% CI) AS IC50: 1.6 (1.3-1.9), 1.8 (1.1-2.5), 2.9 (2.1-3.7) and 3.1 (2.5-3.7) nM, respectively; MQ IC50: 19.2 (15.8-22.6), 37.8 (10.7-64.8), 55.3 (47.7-62.9) and 63.6 (49.2-78.0) nM, respectively; and QN IC50: 183.0 (139.9-226.4), 256.4 (83.7-249.1), 329.5 (206.6-425.5) and 420.0 (475.2-475.6) nM, respectively]. The prevalence of isolates which were resistant to QN was reduced from 21.4% during the period 2006–2007 to 6.3% during the period 2008–2009. Pfmdr1 86Y was found to be associated with increased susceptibility of the parasite to MQ and QN. Pfmdr1 1034C was associated with decreased susceptibility to QN. Pfmrp1 191Y and 1390I were associated with increased susceptibility to CQ and QN, respectively.ConclusionHigh prevalence of CQ and MQ-resistant P. falciparum isolates was observed during the four-year observation period (2006–2009). AS sensitivity was declined, while QN sensitivity was improved. Pfmdr1 and pfmrp1 appear to be the key genes that modulate multidrug resistance in P. falciparum.
Highlights
The decline in efficacy of artesunate (AS) and mefloquine (MQ) is the major concern in areas along the Thai-Cambodian and Thai-Myanmar borders
Applying genetic analysis as a tool for detecting the genetic change of malaria parasite genes that have been shown to link with the decline in efficacy of artesunate (AS) and MQ; i.e., pfmdr1 [10], pfatp6 [11] and pfmrp1 [12,13,14], in association with the in vitro sensitivity of the parasite to both combination partners, would help to detect early changes in P. falciparum sensitivity to this combination therapy
Pfmdr1 copy number A marked difference in IC50 values of AS, MQ and QN was observed among isolates carrying one, two, three, and ≥ four gene copies [median AS IC50: 1.6 (1.3-1.9), 1.8 (1.1-2.5), 2.9 (2.1-3.7) and 3.1 (2.5-3.7) nM, p < 0.001; MQ IC50: 19.2 (15.8-22.6), 37.8 (10.7-64.8), 55.3 (47.7-62.9) and 63.6 (49.2-78.0) nM, p < 0.001; and QN IC50: 183.0 (139.9-226.4), 256.4 (83.7-249.1), 329.5 (206.6-425.5) and 420.0 (475.2-475.6) nM, respectively, p < 0.001]
Summary
The decline in efficacy of artesunate (AS) and mefloquine (MQ) is the major concern in areas along the Thai-Cambodian and Thai-Myanmar borders. Southeast Asia, the Thai-Cambodian border, is one of the malaria-endemic region where multidrugresistant Plasmodium falciparum malaria has been reported [1]. In the 1960s and 1970s, chloroquine (CQ) resistance spread throughout the region and subsequently, the incidence of P. falciparum malaria was markedly reduced [4,5]. Studies during 2008– 2009 showed a marked decline in the 42-day cure rate from 99.2 to 72.58% [8,9]. It is unclear whether artemisinin resistance has spread from the eastern to the western border of the country. Applying genetic analysis as a tool for detecting the genetic change of malaria parasite genes that have been shown to link with the decline in efficacy of artesunate (AS) and MQ; i.e., pfmdr1 [10], pfatp6 [11] and pfmrp1 [12,13,14], in association with the in vitro sensitivity of the parasite to both combination partners, would help to detect early changes in P. falciparum sensitivity to this combination therapy
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