Local variability in Pfhrp2 and Pfhrp3 gene deletions prevalence: Approaches, estimation methods, and reporting - A systematic review and meta-analysis

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Abstract
Background. Currently, the widely used antigen-based malaria rapid diagnostic tests (RDTs) in sub-Saharan Africa primarily detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2). However, their diagnostic accuracy is being compromised by the increasing report of evolving parasite strains with deletion of pfhrp2 and pfhrp3 genes in malaria endemic regions. Therefore, elucidating local heterogeneity and addressing methodological variability are critical for guiding diagnostic strategies. Materials and Methods. We systematically searched PubMed and Google Scholar for studies published between 2015 to 2024 reporting the prevalence of pfhrp2 and/or pfhrp3 gene deletions. Eligible studies utilised molecular confirmation methods and provided regional or national prevalence estimates. A random-effects meta-analysis was conducted to estimate pooled prevalence and evaluate heterogeneity. Additionally, study methodologies and compliance with World Health Organization (WHO) guidelines were evaluated. Results. Forty-three studies from 60 sampling sites across Africa, the Americas, and Asia were included. The highest pooled prevalence of pfhrp2 deletion was observed in the Americas (35%, 95% CI: 17–55%), followed by Africa (9%, 95% CI: 4–17%) and Asia (3%, 95% CI: 2–4%). Markedly elevated high local deletion rates (>80%) were reported in specific areas of Ethiopia, Eritrea, Peru, and Colombia. Notably, substantial intra-national variability was evident, particularly within Central Africa and South America. Most studies (81%) complied with WHO-recommended protocols for deletion surveillance. Delays of 5-10 yrs between sample collection and publication were common, raising concerns about data timeliness although methodological heterogeneity in sampling strategies, molecular detection methods, and study design contributed to variability in reported estimates. Conclusions. High prevalence of pfhrp2/3 gene deletions compromises the effectiveness of PfHRP2-based RDTs in several regions. Countries with a prevalence rate of 5% and above are strongly encouraged to transition to alternative antigen-based RDTs, such as pLDH-based or combination tests. Standardising molecular surveillance methods, expediting data reporting and ensuring alignment with WHO protocols are critical to inform and sustain an evidence-based diagnostic framework tailored to region-specific malaria control policies.

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