Parasite Viability as a Superior Measure of Antimalarial Drug Activity in Humans

• Published in: The Journal of infectious diseases Vol. 223; no. 12; pp. 2154 - 2163
• Main Authors: Rebelo, Maria, Pawliw, Rebecca, Gower, Jeremy, Webb, Lachlan, Mitchell, Hayley, Pava, Zuleima, Watts, Rebecca E, Davenport, Miles P, McCarthy, James S, Khoury, David S
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 15.06.2021
• Subjects: Antimalarial activity; Antimalarial agents; Antimalarials - therapeutic use; Artemisinin; Artemisinins - therapeutic use; Artesunate; Artesunate - therapeutic use; Drug Resistance; Drug therapy; Humans; Malaria; Malaria, Falciparum - drug therapy; Mathematical models; Models, Theoretical; Parasites; Pathophysiology; Plasmodium falciparum; Plasmodium falciparum - drug effects; Polymerase chain reaction; drug development; Malaria; antimalarial; efficacy; parasite clearance; viability
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiaa678

Abstract Background Artemisinin derivatives are the leading class of antimalarial drugs due to their rapid onset of action and rapid clearance of circulating parasites. The parasite clearance half-life measures the rate of loss of parasites from blood after treatment, and this is currently used to assess antimalarial activity of novel agents and to monitor resistance. However, a number of recent studies have challenged the use of parasite clearance to measure drug activity, arguing that many circulating parasites may be nonviable. Methods Plasmodium falciparum–infected subjects (n = 10) in a malaria volunteer infection study were administered a single dose of artesunate (2 mg/kg). Circulating parasite concentration was assessed by means of quantitative polymerase chain reaction (qPCR). Parasite viability after artesunate administration was estimated by mathematical modeling of the ex vivo growth of parasites collected from subjects. Results We showed that in artemisinin-sensitive infection, viable parasites declined to <0.1% of baseline within 8 hours after artesunate administration, while the total number of circulating parasites measured with quantitative polymerase chain reaction remained unchanged. In artemisinin-resistant infections over the same interval, viable parasites declined to 51.4% (standard error of the mean, 4.6%) of baseline. Conclusions These results demonstrate that in vivo drug activity of artesunate is faster than is indicated by the parasite clearance half-life. The study estimated parasite viability after artesunate administration in a volunteer malaria infection study. Findings revealed that parasite viability declines rapidly compared with total parasite numbers in infected subjects, and they indicate that artesunate activity is faster than previously reported.