Okell Lucy C, Reiter Lisa Malene, Ebbe Lene Sandø, Baraka Vito, Bisanzio Donal, Watson Oliver J, Bennett Adam, Verity Robert, Gething Peter, Roper Cally, Alifrangis Michael
MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
Global Health Section, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
BMJ Glob Health. 2018 Oct 19;3(5):e000999. doi: 10.1136/bmjgh-2018-000999. eCollection 2018.
Artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the multidrug resistance 1 () gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient() of -0.083), compared with policies of AS-AQ or both AL and AS-AQ (median =-0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7-10 years after AL introduction. Observed rates of selection have implications for planning strategies to cycle drugs or use multiple first-line therapies to maintain drug efficacy.
蒿甲醚-本芴醇(AL)和青蒿琥酯-阿莫地喹(AS-AQ)是非洲治疗疟疾最常用的青蒿素联合疗法(ACT)。这两种疗法仍然有效,但多药耐药1()基因中的单核苷酸多态性(SNP)可能会损害敏感性。AL和AS-AQ施加相反的选择压力:基因型为86Y、Y184和1246Y的寄生虫对AS-AQ治疗部分耐药,而N86、184F和D1246则受AL治疗青睐。通过系统评价,我们在非洲30个国家确定了397项测量86、184或1246位点多态性流行率的调查。在32个地点分析了引入AL或AS-AQ作为一线治疗后SNP频率的时间趋势,并估计了选择系数。我们研究了抗疟政策、药物使用量、传播强度和SNP选择率之间的关联。与推荐AS-AQ或同时推荐AL和AS-AQ的政策相比(中位数分别为-0.035和0.021,p<0.001),在国家政策推荐AL的地区,1246Y频率平均下降得更快(中位数选择系数()为-0.083)。ACT政策实施后,86Y频率显著下降,在采用AL政策的国家下降更快的趋势接近显著水平(p=0.055)。然而,这些趋势也可以用ACT引入时初始SNP频率的差异来解释。在AL使用量较高的地区,N86和D1246的选择趋势不显著,与传播强度无关。在收集数据的地点和时间,AS-AQ的记录使用量较低。采用AL政策的国家的SNP趋势表明,在引入AL后7至10年,寄生虫对AS-AQ的敏感性普遍增加。观察到的选择率对规划循环用药策略或使用多种一线疗法以维持药物疗效具有启示意义。