Berzosa Pedro, Esteban-Cantos Andrés, García Luz, González Vicenta, Navarro Marisa, Fernández Taiomara, Romay-Barja María, Herrador Zaida, Rubio José Miguel, Ncogo Policarpo, Santana-Morales María, Valladares Basilio, Riloha Matilde, Benito Agustín
Malaria Laboratory, National Centre of Tropical Medicine, Institute of Health Carlos III, C/Monforte de Lemos 5, 28029, Madrid, Spain.
Network Collaborative Research in Tropical Diseases, RICET, Madrid, Spain.
Malar J. 2017 Jan 13;16(1):28. doi: 10.1186/s12936-016-1672-0.
The emergence of drug resistance in Plasmodium falciparum has been a major contributor to the global burden of malaria. Drug resistance complicates treatment, and it is one of the most important problems in malaria control. This study assessed the level of mutations in P. falciparum genes, pfdhfr, pfdhps, pfmdr1, and pfcrt, related to resistance to different anti-malarial drugs, in the Continental Region of Equatorial Guinea, after 8 years of implementing artesunate combination therapies as the first-line treatment.
A triple mutant of pfdhfr (51I/59R/108N), which conferred resistance to sulfadoxine/pyrimethamine (SP), was found in 78% of samples from rural settings; its frequency was significantly different between urban and rural settings (p = 0.007). The 164L mutation was detected for the first time in this area, in rural settings (1.4%). We also identified three classes of previously described mutants and their frequencies: the partially resistant (pfdhfr 51I/59R/108N + pfdhps 437G), found at 54% (95% CI 47.75-60.25); the fully resistant (pfdhfr 51I/59R/108N + pfdhps 437G/540E), found at 28% (95% CI 7.07-14.93); and the super resistant (pfdhfr 51I/59R/108N + pfdhps 437G/540E/581G), found at 6% (95% CI 0.48-4.32). A double mutation in pfmdr1 (86Y + 1246Y) was detected at 2% (95% CI 0.24-3.76) frequency, distributed in both urban and rural samples. A combination of single mutations in the pfmdr1 and pfcrt genes (86Y + 76T), which was related to resistance to chloroquine and amodiaquine, was detected in 22% (95% CI 16.8-27.2) of samples from the area.
The high level of mutations detected in P. falciparum genes related to SP resistance could be linked to the unsuccessful withdrawal of SP treatment in this area. Drug resistance can reduce the efficacy of intermittent prophylactic treatment with SP for children under 5 years old and for pregnant women. Although a high number of mutations was detected, the efficacy of the first-line treatment, artemisinin/amodiaquine, was not affected. To avoid increases in the numbers, occurrence, and spread of mutations, and to protect the population, the Ministry of Health should ensure that health centres and hospitals are supplied with appropriate first-line treatments for malaria.
恶性疟原虫耐药性的出现是全球疟疾负担的主要促成因素。耐药性使治疗变得复杂，是疟疾控制中最重要的问题之一。本研究评估了赤道几内亚大陆地区在将青蒿琥酯联合疗法作为一线治疗实施8年后，与不同抗疟药物耐药性相关的恶性疟原虫基因pfdhfr、pfdhps、pfmdr1和pfcrt的突变水平。
在农村地区78%的样本中发现了对磺胺多辛/乙胺嘧啶（SP）耐药的pfdhfr三重突变体（51I/59R/108N）；其频率在城市和农村地区之间存在显著差异（p = 0.007）。在该地区农村地区首次检测到164L突变（1.4%）。我们还鉴定出三类先前描述的突变体及其频率：部分耐药（pfdhfr 51I/59R/108N + pfdhps 437G），占54%（95%置信区间47.75 - 60.25）；完全耐药（pfdhfr 51I/59R/108N + pfdhps 437G/540E），占28%（95%置信区间7.07 - 14.93）；超级耐药（pfdhfr 51I/59R/108N + pfdhps 437G/540E/581G），占6%（95%置信区间0.48 - 4.32）。在pfmdr1中检测到双突变（86Y + 1246Y），频率为2%（95%置信区间0.24 - 3.76），分布在城市和农村样本中。在该地区22%（95%置信区间16.8 - 27.2）的样本中检测到与氯喹和阿莫地喹耐药相关的pfmdr1和pfcrt基因单突变组合（86Y + 76T）。
在与SP耐药相关的恶性疟原虫基因中检测到的高水平突变可能与该地区SP治疗的不成功停用有关。耐药性会降低5岁以下儿童和孕妇使用SP进行间歇性预防性治疗的疗效。尽管检测到大量突变，但一线治疗青蒿素/阿莫地喹未受影响。为避免突变数量增加、发生和传播，并保护人群，卫生部应确保卫生中心和医院配备适当的疟疾一线治疗药物。
