Quantification of parasite clearance in Plasmodium knowlesi infections

Abstract

Background The incidence of zoonotic Plasmodium knowlesi infections in humans is rising in Southeast Asia, leading to clinical studies to monitor the efficacy of anti-malarial treatments for knowlesi malaria. One of the key outcomes of anti-malarial drug efficacy is parasite clearance. For Plasmodium falciparum, parasite clearance is typically estimated using a two-stage method, that involves estimating parasite clearance for individual patients followed by pooling of individual estimates to derive population estimates. An alternative approach is Bayesian hierarchical modelling which simultaneously analyses all parasite-time patient profiles to determine parasite clearance. This study compared these methods for estimating parasite clearance in P. knowlesi treatment efficacy studies, with typically fewer parasite measurements per patient due to high susceptibility to anti-malarials. Methods Using parasite clearance data from 714 patients with knowlesi malaria and enrolled in three trials, the Worldwide Antimalarial Resistance Network (WWARN) Parasite Clearance Estimator (PCE) standard two-stage approach and Bayesian hierarchical modelling were compared. Both methods estimate the parasite clearance rate from a model that incorporates a lag phase, slope, and tail phase for the parasitaemia profiles. Results The standard two-stage approach successfully estimated the parasite clearance rate for 678 patients, with 36 (5%) patients excluded due to an insufficient number of available parasitaemia measurements. The Bayesian hierarchical estimation method was applied to the parasitaemia data of all 714 patients. Overall, the Bayesian method estimated a faster population mean parasite clearance (0.36/h, 95% credible interval [0.18, 0.65]) compared to the standard two-stage method (0.26/h, 95% confidence interval [0.11, 0.46]), with better model fits (compared visually). Artemisinin-based combination therapy (ACT) is more effective in treating P. knowlesi than chloroquine, as confirmed by both methods, with a mean estimated parasite clearance half-life of 2.5 and 3.6 h, respectively using the standard two-stage method, and 1.8 and 2.9 h using the Bayesian method. Conclusion For clinical studies of P. knowlesi with frequent parasite measurements, the standard two-stage approach (WWARN’s PCE) is recommended as this method is straightforward to implement. For studies with fewer parasite measurements per patient, the Bayesian approach should be considered. Regardless of method used, ACT is more efficacious than chloroquine, confirming the findings of the original trials.

Plasmodium sp: Uma análise interespécie dos aspectos terapêuticos, patológicos e epidemiológicos

“…No que diz respeito ao tratamento do Plasmodium knowlesi, o qual é a principal causa de malária em humanos no Sudeste Asiático e uma das espécies menos estudadas no ramo científico, há uma recomendação da Organização Mundial de Saúde (OMS) para terapia combinada à base de artemisinina (TCA) ou de cloroquina para tratamento de infecções não complicadas. Contudo, os autores concordam que devido à maior eficácia e à possibilidade de diagnóstico microscópico equivocado entre as espécies P. falciparum ou P. vivax, recomenda-se o uso apenas de TCA, seja com artemeter-lumefantrina (AL) ou artesunato-mefloquina(ASMQ), uma vez que as duas espécies citadas são resistentes à cloroquina em áreas endêmicas para P. knowlesi, além de incluir um menor risco de anemia (RATHNAM et al, 2023;GRIGG et al, 2018;BARBER et al, 2022).…”

Plasmodium knowlesi (Pk) Malaria: A Review & Proposal of Therapeutically Rational Exchange (T-REX) of Pk-Resistant Red Blood Cells

“…Some articles explicitly state that there is no evidence of Pk drug resistance [145]. For example, one study compared the in vitro drug susceptibility of Pk strain A1-H.1 and Pf strain 3D7 for one life cycle [146].…”