Phytochemical synergy in artemisia annua herbal tea against malaria: a systematic review of its efficacy and safety in the context of emerging Pfkelch13 resistance

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BACKGROUND: Emerging Plasmodium falciparum resistance to artemisinin derivatives, mediated principally by mutations in the Pfkelch13 propeller domain, is reshaping the antimalarial therapeutic landscape across sub-Saharan Africa and the Greater Mekong subregion. Concurrently, whole-plant Artemisia annua herbal tea has re-emerged in malaria-endemic settings, prompting renewed scrutiny of its phytochemical matrix and its clinical performance relative to artemisinin-based combination therapy. The present systematic review synthesises the contemporary evidence on the efficacy and safety of Artemisia annua herbal tea against P. falciparum malaria in the context of emerging Pfkelch13 resistance, and delineates the priorities for future clinical, phytochemical, and resistance-monitoring research on the basis of that synthesis. METHODS: A PRISMA-2020-compliant systematic review was conducted across six databases for the period January 2000 to December 2025. Randomised controlled trials, quasi-experimental studies, in vitro phytochemical synergy assays, and rodent Plasmodium infection models were eligible. Two reviewers screened, extracted, and quality-rated the studies independently (Cohen's κ =0.83) using RoB 2.0, Newcastle-Ottawa, and the RITAM stacking criteria. A qualitative narrative synthesis with GRADE-style confidence rating across twelve outcomes was performed. RESULTS: values were 3-5 × lower than those of equivalent-concentration purified artemisinin on 3D7, chloroquine-resistant, and multidrug-resistant strains. In Pfkelch13-mutant rodent P. falciparum lines, stable resistance to whole-plant therapy emerged three times more slowly than to equivalent-dose purified dihydroartemisinin. Clinically, retained randomised trials demonstrated rapid initial parasite clearance within 72 h-Mueller day-7 cure 74% vs 91% (quinine); Blanke day-7 cure 7/10 vs 7/9 and day-28 cure 1/9 (11.1%); Magalhães first-day parasitaemia-negative at ~ 175 mg cumulative artemisinin- but day-28 parasitological cure rates of A. annua monotherapy fell consistently below the 95.5-98.6% artemisinin-based combination therapy (ACT) benchmark band wherever directly reported [Blanke 1/9 (11.1%) vs sulfadoxine-pyrimethamine 3/8 (37.5%); Magalhães 0/7 sustained cure]. The Mueller 2004 trial did not directly report day-28 parasitological cure as a primary endpoint; an end-of-follow-up recrudescence of approximately 26% overall precludes direct day-28 numerical benchmarking but is consistent with a sustained-cure extrapolation of ~ 74% at that horizon-a derived figure numerically coincident with the Mueller day-7 cure rate that should not be conflated with a directly measured day-28 endpoint. Adverse events were predominantly mild (bitter taste, transient GI discomfort), with no serious events recorded in any retained study; safety data for children under five, pregnant or lactating women, and patients with hepatic or renal co-morbidity remain critically insufficient. CONCLUSIONS: Whole-plant A. annua herbal tea achieves reproducible early parasitological clearance and preserves the multi-target pharmacological substrate whose pre-clinical resistance-modulation profile (three-fold slower resistance emergence in Pfkelch13-mutant murine lines) is biologically coherent with a Pfkelch13-modulating effect, although this effect has not yet been clinically reproduced in Pfkelch13-endemic African settings. The ≥ 84-percentage-point day-28 cure-rate gap between directly-reported A. annua monotherapy and the African ACT benchmark band frames the present-day clinical use of A. annua infusion as a complementary or adjourning intervention rather than a replacement for ACT. This positioning is preserved while Pfkelch13-stratified randomised trials, vulnerable-population safety studies, and population-scale molecular resistance surveillance are designed and executed.

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