Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072, Kampala, Uganda.
Africa Centre for Systematic Reviews and Knowledge Translation, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda.
Malar J. 2019 Mar 7;18(1):60. doi: 10.1186/s12936-019-2701-6.
Efficacy of artemisinin (ART) agents, a critical element of current malaria control efforts is threatened by emergence and spread of resistance. Mutations in pfkelch13 gene associated with ART-resistance evolved in Southeast Asia (SEA). k13 mutations whose role in ART-resistance remains unknown, have subsequently emerged independently across all malaria-affected regions. The aim of this systematic review was to determine the prevalence and identify risk factors of Plasmodium falciparum k13 mutations in malaria-endemic countries.
An electronic search of studies from 2014 to date was done in MEDLINE via PubMED, SCOPUS, EMBASE and LILACS/VHL databases. Mesh terms and Boolean operators (AND, OR) were used. Two librarians independently conducted this search (RS and AK). The articles were screened for inclusion using a priori criteria set following PRISMA-P and STREGA guidelines. Three independent reviewers (NL, BB, and OM) extracted the data. Data analysis was performed in Open Meta Analyst software. Random effects analysis (DL) was used and heterogeneity established using I-statistic.
A total of 482 articles were retrieved from Pubmed = 302, Lilacs/Vhl = 50, Embase = 80, and Scopus = 37; Bibliography/other searches = 13, of which 374 did not meet the inclusion criteria. The aggregate prevalence of single nucleotide polymorphisms (SNPs) in pfkelch13 gene was 27.6% (3694/14,827) (95% CI 22.9%, 32.3%). Sub-group analysis showed that aggregate prevalence of non-synonymous SNPs in pfkelch13 gene was higher, 45.4% (95% CI 35.4%, 55.3%) in Southeast Asia as opposed to 7.6% (95% CI 5.6%, 9.5%) in the African region. A total of 165 independent k13 mutations were identified across malaria-affected regions globally. A total of 16 non-validated k13 mutations were associated with increased ART parasite clearance half-life (t > 5 h). The majority, 45.5% (75/165), of the mutations were reported in single P. falciparum parasite infections. Of the 165 k13-mutations, over half were reported as new alleles. Twenty (20) non-propeller mutations in the pfkelch13 gene were identified.
This review identified emergence of potential ART-resistance mediating k13 mutations in the African region. Diversity of mutations in pfkelch13 gene is highest in African region compared to SEA. Mutations outside the pfkelch13 propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions.
青蒿素（ART）药物的疗效是当前疟疾控制工作的关键要素，但该药物的疗效正受到抗药性的出现和传播的威胁。与抗药性相关的 pfkelch13 基因突变首先出现在东南亚（SEA），随后在所有疟疾流行地区独立出现。本系统评价的目的是确定疟疾流行国家恶性疟原虫 k13 基因突变的流行率，并确定其危险因素。
通过 MEDLINE 下的 Pubmed、SCOPUS、EMBASE 和 LILACS/VHL 数据库，对 2014 年以来的研究进行电子检索。使用了主题词和布尔运算符（AND、OR）。两名图书管理员（RS 和 AK）独立进行了这项搜索。根据 PRISMA-P 和 STREGA 指南设定的事先标准，对文章进行了纳入筛选。三名独立的审稿人（NL、BB 和 OM）提取了数据。使用 Open Meta Analyst 软件进行数据分析。使用随机效应分析（DL），并使用 I 统计量确定异质性。
从 Pubmed 检索到 302 篇文章，从 Lilacs/Vhl 检索到 50 篇文章，从 Embase 检索到 80 篇文章，从 Scopus 检索到 37 篇文章；从 Bibliography/other searches 检索到 13 篇文章，其中 374 篇文章不符合纳入标准。 pfkelch13 基因中单个核苷酸多态性（SNP）的总流行率为 27.6%（3694/14827）（95%CI 22.9%，32.3%）。亚组分析显示，pfkelch13 基因中非同义 SNP 的总流行率更高，东南亚为 45.4%（95%CI 35.4%，55.3%），而非洲为 7.6%（95%CI 5.6%，9.5%）。全球疟疾流行地区共发现 165 个独立的 k13 突变。共有 16 个未经证实的 k13 突变与 ART 寄生虫清除半衰期延长（t>5 h）有关。大多数（45.5%，75/165）突变发生在单一恶性疟原虫寄生虫感染中。在 165 个 k13 突变中，超过一半被报告为新等位基因。在 pfkelch13 基因中发现了 20 个非螺旋桨突变。
本研究在非洲地区发现了潜在的 ART 耐药性介导的 k13 突变。与 SEA 相比，pfkelch13 基因突变的多样性在非洲地区最高。与 ART 寄生虫清除半衰期延长相关的 pfkelch13 基因螺旋桨区以外的突变发生在疟疾流行地区。
