What is this publication about?

The publication outlines a study protocol that can be used by researchers that analyse patient data with the aim to better understand the correlation between mutations in a gene region of the Plasmodium falciparum malaria parasite, called Kelch13 (K13), and the growing resistance to the artemisinin-based combination therapy (ACT).

The protocol includes a pragmatic search strategy and a robust statistical analysis plan (SAP), specifically curated to explore the prevalence, distribution, and functional and clinical significance of Pfkelch13 markers in P. falciparum populations globally. The protocol is ideal for evidence synthesis as it allows exploration of different risk factors, otherwise impossible through an aggregate data meta-analysis alone.

Why is this important?

Artemisinin-based combination therapies (ACTs) remain the WHO-recommended treatment for uncomplicated P. falciparum malaria. However, the emergence and spread of artemisinin resistance (ART-R) threatens ACT efficacy. ART-R is phenotypically expressed as delayed parasite clearance, which can facilitate ACT partner drug resistance. ART-R has been causally linked to defined mutations in the Pfkelch13 gene of the parasite.

This protocol responds to the dire need for antimalarial drug resistance investigations to include African-specific data. Before ART-R emergence, minimal data was available and thus not included in previous meta-analyses of individual participant data (IPD). Given that ART-R has recently emerged in Africa, and the region accounts for 95% of the global malaria burden, an improved understanding of the genetic determinants driving ART-R and its clinical consequences is of paramount importance. Insight into the association between specific Pfkelch13 mutations is crucial, as when ART-R emerged previously in the Southeast Asia region, it soon became coupled with resistance to ACT partner drugs, resulting in ACT treatment failures. This protocol will support researchers in promptly detecting up-to-date ART-R markers and coordinating efforts to mitigate their impact.

How can this make a difference?

As the global ART-R landscape continues to evolve, this protocol aims to serve as a model for further standardised statistical methodologies and definitions of subsequent IPD meta-analyses. Its widespread use would contribute to its reproducibility in future studies and potentially regular updates as the resistance landscape continues to evolve.