The in-vivo dynamics of Plasmodium falciparum HRP2: implications for the use of rapid diagnostic tests in malaria elimination

Background Rapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 ( Pf HRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by Pf HRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent Pf HRP2 using newer ultra-sensitive Pf HRP2 based RDTs can serve as a surveillance tool to identify recent exposure. Better understanding of the dynamics of Pf HRP2 over the course of a malaria infection can inform optimal use of RDTs. Methods A previously published mathematical model was refined to mimic the production and decay of Pf HRP2 during a malaria infection. Data from 15 individuals from volunteer infection studies were used to update the original model and estimate key model parameters. The refined model was applied to a cohort of patients from Namibia who received treatment for clinical malaria infection for whom longitudinal Pf HRP2 concentrations were measured. Results The refinement of the Pf HRP2 dynamic model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 33.6 × 10 −15 g (95% CI 25.0–42.1 × 10 −15 g) of Pf HRP2 in vivo per parasite replication cycle, with an elimination half-life of 1.67 days (95% CI 1.11–3.40 days). The refined model included these updated parameters and incorporated individualized body fluid volume calculations, which improved predictive accuracy when compared to the original model. The performance of the model in predicting clearance of Pf HRP2 post treatment in clinical samples from six adults with P. falciparum infection in Namibia improved when using a longer elimination half-life of 4.5 days, with 14% to 67% of observations for each individual within the predicted range. Conclusions The updated mathematical model can predict the growth and clearance of Pf HRP2 during the production and decay of a mono-infection with P. falciparum , increasing the understanding of Pf HRP2 antigen dynamics. This model can guide the optimal use of Pf HRP2-based RDTs for reliable diagnosis of P. falciparum infection and re-infection in endemic settings, but also for malaria surveillance and elimination programmes in low transmission areas.