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Background   Plasmodium falciparum  infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein ( pfk13 ;  Pf3D7_1343700 ). Global searches have identified almost 200 different non-synonymous mutant  pfk13  genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different  pfk13  mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC 1/2 ) and  pfk13  genotype based on a large set of individual patient records from Asia and Africa.    Methods  A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and  pfk13  genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC 1/2  values and  pfk13  genotype were assessed using multivariable regression models with random effects for study site.    Results  Both the  pfk13  genotypes and the PC 1/2  were available from 3250 (95%) patients ( n  = 3012 from Asia (93%),  n  = 238 from Africa (7%)). Among Asian isolates, all  pfk13  propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC 1/2  compared to the PC 1/2  of wild type isolates (all  p  ≤ 0.002). In addition, mutant allele E252Q located in the  P. falciparum  region of  pfk13  was associated with 1.5-fold (95%CI 1.4–1.6) longer PC 1/2 . None of the isolates from four countries in Africa showed a significant difference between the PC 1/2  of parasites with or without  pfk13  propeller region mutations.  Previously, the association of six  pfk13  propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional  pfk13  alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.    Conclusion  Pooled analysis associated 20  pfk13  propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.    Electronic supplementary material  The online version of this article (10.1186/s12916-018-1207-3) contains supplementary material, which is available to authorized users.

bmc medicine

Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis