Determinants of recurrent parasitemia following artemisinin based combination therapy in a high transmission setting in Zambia

Recurrent parasitemia following artemisinin-based combination therapy (ACT) remains a major challenge in high-transmission settings, where distinguishing true drug failure from reinfection is difficult. While ACTs demonstrate high efficacy under controlled conditions, real-world effectiveness is influenced by adherence, ongoing transmission, and socio-environmental factors. This study aimed to identify behavioral, environmental, and treatment-related determinants of recurrent parasitemia following ACT in a rural high-transmission setting in Zambia. A prospective cohort study was conducted among 272 patients aged 6 months and above with microscopy-confirmed uncomplicated Plasmodium falciparum malaria at Chavuma Mission Hospital, Zambia. All participants received standard artemether–lumefantrine therapy. The primary outcome was recurrent parasitemia within 28 days, defined as the presence of parasitemia with or without symptoms after treatment initiation. Molecular genotyping was not performed; therefore, recrudescence and reinfection were not distinguished. Data on adherence, preventive practices, and household characteristics were collected using structured interviews and direct observation. Multivariable logistic regression was used to identify factors associated with recurrent parasitemia. Recurrent occurred in 25.7% (70/272) of participants. Adherence to the recommended 8-h interval between the first and second doses was significantly associated with lower odds of recurrent parasitemia (adjusted odds ratio [AOR]: 0.12; 95% CI 0.05–0.27; p<0.001). Use of insecticide-treated nets (ITNs) was also associated with reduced odds of recurrence (AOR: 0.32; 95% CI 0.13–0.75; p=0.009). Participants living in houses with metal roofing had substantially lower odds of recurrent parasitemia compared to those in thatched-roof dwellings (AOR: 0.07; 95% CI 0.03–0.17; p<0.001), although this likely reflects underlying socioeconomic and structural factors. Missed doses were not associated with recurrent parasitemia after adjustment. Recurrent parasitemia following ACT is common in this high-transmission setting but is likely driven primarily by reinfection and modifiable factors affecting drug exposure rather than intrinsic drug resistance. Improving adherence to dosing schedules, strengthening vector control measures such as ITN use, and addressing structural determinants of malaria exposure may substantially enhance the real-world effectiveness of ACT. Future studies incorporating molecular genotyping are needed to more accurately distinguish recrudescence from reinfection.