Persistence of P. falciparum diagnostic antigens after treatment with artemisinins: association with parasite stage and mechanism of clearance

Abstract

The most sensitive rapid diagnostic tests of P. falciparum are based on detection of histidine-rich protein 2 (HRP2), but HRP2 persists in the blood after treatment and cannot be used to assess treatment response. We measured antigen levels over a 4-week period in ACT-treated hyperparasitaemic patients with P. falciparum in Uganda and Thailand (prior to the emergence of artemisinin resistance). Antigen clearance was quantified by calculation of area-undercurve (AUC) after normalization to baseline antigen level. Whole blood HRP2 levels showed a wide range of AUCs: Uganda median 415 d·% (range 48–2588); Thailand 590 d·% (33–1534). The primary determinant of AUC was admission stage; in patients presenting with >75% tiny/small rings (32/40 in Uganda, 24/38 in Thailand), median HRP2 AUCs were respectively 6.4 and 10.7-fold higher than cases with later stages (p=0.0005, <0.0001). Stage was also a key determinant of the time for the Paracheckä RDT to become negative during follow-up. These data support the hypothesis that the mechanism for HRP2 persistence is pitting in the spleen since once-infected erythrocytes returning to the circulation can provide a source for persistently high levels of HRP2 and ongoing positivity of HRP2-based RDTs.