Abstract

Artemisinin resistance in Plasmodium falciparum posed a critical threat to global malaria control, with delayed 
parasite clearance and treatment failures increasingly reported across endemic regions. This review evaluated the 
biochemical rationale and clinical evidence supporting artemisinin-based combination therapies (ACTs) over 
monotherapy for preventing resistance emergence. A systematic literature review was conducted using PubMed, 
Cochrane Library, and WHO databases from 2015-2025, focusing on clinical trials, molecular surveillance studies, 
and mechanistic research. ACTs demonstrated superior efficacy in preventing resistance through complementary 
pharmacokinetic profiles that reduced selection pressure on artemisinin derivatives. PfKelch13 mutations remained 
the primary molecular marker for artemisinin resistance, with C580Y and other validated mutations showing strong 
correlation with delayed clearance phenotypes. Clinical evidence from Southeast Asia and sub-Saharan Africa 
confirmed that ACT deployment significantly reduced treatment failure rates compared to artemisinin monotherapy, 
with combination therapy providing protection factors ranging from 10-100 fold against resistance selection. 
Molecular surveillance demonstrated that regions with high ACT coverage maintain lower frequencies of kelch13 
mutations. ACTs represented the most effective strategy for preserving artemisinin efficacy, though emerging 
partner drug resistance and suboptimal implementation threaten long-term sustainability. Enhanced surveillance, 
improved diagnostics, and next-generation combination regimens are essential for maintaining therapeutic 
effectiveness.