What is this publication about?

The publication outlines the study protocol for a systematic review and analysis of individual patient-level data, aiming to better understand the influence of mutations in the Kelch13 (K13) gene region of the Plasmodium falciparum malaria parasite and the growing resistance to artemisinin-based combination therapy (ACT). The strength of this protocol lies in its ability to continuously investigate antimalarial resistance, as this threat to malaria control continues to evolve and develop in Africa and further abroad.

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 K13 mutations in P. falciparum populations worldwide. The protocol is ideal for evidence synthesis, as it allows for the exploration of different risk factors that would be 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 and are also the most widely used treatment plan deployed throughout malaria-endemic regions. However, the emergence and spread of artemisinin resistance (ART-R) threatens the efficacy of this treatment plan. ART-R is observed as delayed parasite clearance following treatment, which can further facilitate ACT partner drug resistance emergence, which would represent a devastating loss of available medications to treat the disease.

This protocol addresses the urgent need for antimalarial drug resistance investigations to incorporate African-specific data. Before ART-R emergence, minimal data were 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 K13 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.