Posttreatment HRP2 Clearance in Patients with Uncomplicated Plasmodium falciparum Malaria

Abstract

Background: The response to antimalarial treatment is assessed using serial microscopy. New techniques for accurate measurement of the Plasmodium falciparum histidine-rich protein 2 (HRP2) antigen have allowed for monitoring of the antigen concentration over time, offering a potential alternative for assessing treatment response.

Methods: Posttreatment HRP2 concentrations were measured in samples obtained longitudinally from 537 individuals with P. falciparum malaria who were participating in efficacy trials in Angola, Tanzania, and Senegal. The HRP2 half-life was estimated using a first-order kinetics clearance model. The association between the HRP2 concentration 3 days after treatment and recrudescence of infection was assessed.

Results: Despite substantial variation in HRP2 concentrations among participants at baseline, concentrations consistently showed a first-order exponential decline. The median half-life of HRP2 was estimated to be 4.5 days (interquartile range [IQR], 3.3-6.6 days) in Angola, 4.7 days (IQR, 4.0-5.9 days) in Tanzania, and 3.0 days (IQR, 2.1-4.5 days) in Senegal. The day 3 HRP2 concentration was predictive of eventual recrudescence, with an area under the receiver operating characteristic curve of 0.86 (95% confidence interval, .73-.99).

Conclusions: Consistent HRP2 clearance dynamics following successful antimalarial treatment imply a common underlying mechanism of biological clearance. Patients who ultimately did not respond to treatment did not exhibit this same pattern of clearance, even in the absence of other indications of inadequate response to treatment.

Keywords: Antimalarial resistance; antigen concentration; efficacy monitoring.

Figure 1.

Histidine-rich protein 2 (HRP2) concentrations over time following initiation of antimalarial treatment at day 0 in patients with malaria who were followed longitudinally in Angola, Tanzania, and Senegal. Boxes show median values and interquartile ranges. Whiskers show extreme values and points represent outliers.

Figure 2.

Probability density function of estimated histidine-rich protein 2 (HRP2) half-lives in Plasmodium falciparum–infected patients who were followed longitudinally after antimalarial therapy in Angola, Tanzania, and Senegal.

Figure 3.

Modeled posttreatment duration of test positivity as a function of the limit of detection of a histidine-rich protein 2 (HRP2) detection test, estimated from HRP2 concentrations measured in patients who were followed longitudinally in Angola, Tanzania, and Senegal. IQR, interquartile range.

Figure 4.

A, Median normalized histidine-rich protein 2 (HRP2) concentrations over time since initiation of antimalarial treatment at day 0, stratified by treatment outcome in patients from Angola, showing a spike in the HRP2 concentration on the day of treatment failure. B, After exclusion of day of treatment failure data, cases of adequate clinical and parasitological response (ACPR) and reinfection followed a similar linear decline, but cases of recrudescence showed a different clearance behavior.

Figure 5.

Areas under the receiver operating characteristic curve (AUCs) for predicting recrudescent infections on the basis of normalized histidine-rich protein 2 (HRP2) concentrations on day 3 (left; n = 177) and day 7 (right; n = 293) after initiation of antimalarial treatment among patients in Angola. CI, confidence interval.