Investigating the relationship between mutations and response to artemisinin-based treatment for uncomplicated falciparum malaria: a protocol for a systematic review and individual patient data meta-analysis.

INTRODUCTION

Artemisinin-based combination therapies (ACTs) remain the WHO-recommended treatment for uncomplicated 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 specific mutations in the gene.

METHODS AND ANALYSIS

The systematic review and associated meta-analysis aim to determine the correlation between (alleles present in the gene region of the parasite) genotypes and clinical and parasitological response to ACTs from a globally representative data set pooling individual patient data (IPD) from eligible published and unpublished studies. The eligibility criteria include genotyping results at baseline complemented by individually linked parasitological and clinical assessments following artemisinin-based treatment. The data will be curated, standardised and analysed using this proposed statistical analysis plan (SAP), adhering to PRISMA-IPD (PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Our SAP will apply hierarchical modelling to assess the effect of the parasite mutations on parasite clearance half-life and therapeutic efficacy across different regions. This will include study sites as random effects in the model and potential predictors such as age, sex, baseline parasite load and other potential effect modifiers as fixed effects. This analysis will enhance the understanding of the influence of mutations on malaria treatment outcomes.

ETHICS AND DISSEMINATION

Data were obtained with informed consent and ethical approvals from the relevant countries and were pseudonymised before curation in the Infectious Diseases Data Observatory (IDDO)/WorldWide Antimalarial Resistance Network (WWARN) repository. Data ownership remains with contributors. This IPD meta-analysis met the Oxford Tropical Research Ethics Committee criteria for waiving ethical review, as it is a secondary analysis of existing pseudonymised data. The resulting peer-reviewed publication and conference proceedings will help strengthen and enhance the efficiency of ART-R surveillance and response and support policy decisions.

PROSPERO REGISTRATION NUMBER

CRD42019133366.