New: Study Group to correlate K13 mutations and clinical outcomes

Artemisinin derivatives are the recommended antimalarial treatments worldwide. Unfortunately resistance to these drugs is now firmly established in many parts of Southeast Asia.

Antimalarial drug resistance to chloroquine and sulfadoxine/ pyrimethamine was monitored by tracking the prevalence of simple validated markers of resistance to those drugs. When the Kelch13 propeller gene was first defined as a marker of artemisinin resistance, researchers hoped to use it in the same way. Unfortunately, resistance to artemisinins is more complex; as groups have examined parasites in locations worldwide, more than 100 different alleles of K13 have been identified. In Southeast Asia, many of these alleles are associated with the slow clearance of parasites after artemisinin treatment, but in other areas, the simple presence of a parasite with a K13 mutant allele does not guarantee that the parasites are slow clearing. 

The WWARN Clinical & Molecular Scientific Groups have established a new study group to investigate the correlation between these different K13 mutations and parasites that show a slow clearing clinical response in patients, the phenotype. The goal is to collate data from both published and unpublished studies to assess statistically the association of particular K13 alleles with the clinical phenotype that identifies truly resistant parasites.

It is especially confusing that many K13 mutations have been identified at low prevalence in sub-Saharan Africa but, as yet, there seems to be little or no evidence to link them to antimalarial drug resistance on the continent – so what is the clinical significance of these mutations? The Study Group is using pooled analysis to increase the statistical power of the quality-assured individual patient data to try to answer these crucial questions.

“Tracking K13 mutations is key to tackling the emergence of resistance to artemisinin derivatives but there are still many unanswered questions about the role these mutations play,” says Dr Aurélia Vessière, Scientific Coordinator of the Clinical Group. “By increasing statistical power, we anticipate that our Study Group will be able to clarify some of these important questions and get a better picture of the genotype/ phenotype relationship for particular K13 alleles.”

As part of the data standardisation and analysis process, all information on parasite clearance rates will be analysed with the WWARN Parasite Clearance Estimator, an innovative tool that provides a consistent and reliable way of estimating the rate of parasite clearance after treatment. This tool is freely available to all researchers to use.

“With this study group, we expect to define the association of particular K13 mutants with the resistant phenotype, and use this information to understand the differences between that group and the K13 mutants that lack that phenotype association. As our understanding of these mutations grows and expands, we hope to validate these resistance-associated K13 alleles, and perhaps identify other genes in addition to K13 that are also required for resistance to artemisinins,” says Professor Carol Sibley, WWARN Scientific Director.

The team has also developed a K13 Molecular Surveyor. This interactive visualisation tool collates and summarises the prevalence of K13 baseline mutations by geographical location and year. Researchers and policy makers can use this tool to view the temporal trends and prevalence of K13 mutations associated with resistance, and use this evidence to better inform key regional, national and international malaria monitoring strategies.