Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia.
Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia.
复制标题
DOI：
10.1128/aac.00759-17
复制
发表时间：
2017-12
影响因子：
4.9
通讯作者：
D'Alessandro U
中科院分区：
文献类型：
--
作者：
Amambua-Ngwa A;Okebe J;Mbye H;Ceesay S;El-Fatouri F;Joof F;Nyang H;Janha R;Affara M;Ahmad A;Kolly O;Nwakanma D;D'Alessandro U
抗疟干预措施已使冈比亚的疟疾患病率显着下降，十年来，蒿甲醚-本芴醇 (AL) 一直被用作一线抗疟药。对 2012 年至 2015 年收集的临床恶性疟原虫分离株进行离体抗疟药敏感性分析，并对耐药标记（pfcrt K76T、pfmdr1 密码子 86、184 和 1246 以及 pfk13）和微卫星变异进行基因分型。此外，还根据 2008 年 (n = 79) 和 2014 年 (n = 168) 的基因组序列数据集比较了其他耐药相关基因的单核苷酸多态性 (SNP) 等位基因频率。没有发现与青蒿素耐药相关的 pfk13 突变，2015 年测试的分离株中只有 4% 在接触双氢青蒿素后表现出显着生长。相反，阿莫地喹和苯芴醇的 50% 抑制浓度 (IC50) 在此期间有所增加。 pfcrt 76T 和 pfmdr1 184F 突变体的流行率仍高于 80%。 pfcrt 76T 与氯喹较高的 IC50 呈正相关。由于本芴醇的选择，pfmdr1 NYD 的频率在 2012 年至 2015 年期间有所增加。在 2008 年实施 AL 后，TNYD（pfcrt 76T 和 pfmdr1 NYD 野生型单倍型）的频率也有所增加。这些结果表明选择能够耐受本芴醇的 pfcrt 和 pfmdr1 基因型。由于对苯芴醇的耐受性增加，冈比亚需要持续进行化疗监测，以尽量减少未来青蒿素联合治疗 (ACT) 的完全失败。
Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical Plasmodium falciparum isolates collected from 2012 to 2015 were analyzed ex vivo for antimalarial susceptibility and genotyped for drug resistance markers (pfcrt K76T, pfmdr1 codons 86, 184, and 1246, and pfk13) and microsatellite variation. Additionally, allele frequencies of single nucleotide polymorphisms (SNPs) from other drug resistance-associated genes were compared from genomic sequence data sets from 2008 (n = 79) and 2014 (n = 168). No artemisinin resistance-associated pfk13 mutation was found, and only 4% of the isolates tested in 2015 showed significant growth after exposure to dihydroartemisinin. Conversely, the 50% inhibitory concentrations (IC50s) of amodiaquine and lumefantrine increased within this period. pfcrt 76T and pfmdr1 184F mutants remained at a prevalence above 80%. pfcrt 76T was positively associated with higher IC50s to chloroquine. pfmdr1 NYD increased in frequency between 2012 and 2015 due to lumefantrine selection. The TNYD (pfcrt 76T and pfmdr1 NYD wild-type haplotype) also increased in frequency following AL implementation in 2008. These results suggest selection for pfcrt and pfmdr1 genotypes that enable tolerance to lumefantrine. Increased tolerance to lumefantrine calls for sustained chemotherapeutic monitoring in The Gambia to minimize complete artemisinin combination therapy (ACT) failure in the future.