Persistence of Plasmodium falciparum HRP-2 antigenaemia after artemisinin combination therapy is not associated with gametocytes

Oulton, Tate; Mahamar, Almahamoudou; Sanogo, Koualy; Diallo, Makonon; Youssouf, Ahamadou; Niambele, Sidi Mohamed; Samake, Siaka; Kéita, S.; Sinaba, Youssouf; Sacko, Adama; Traorè, Sékou F.; Lanke, Kjerstin; Collins, Katharine A.; Bradley, John; Drakeley, Chris; Dicko, Alassane

doi:10.1186/s12936-022-04387-0

Cited by 6 publications

(2 citation statements)

References 30 publications

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“…In this study, three RDT-positive samples were negative with qPCR. These samples are from patients who remain RDT-positive for several weeks after parasite treatment, due to the detection of residual HRP2 [23].…”

Section: Discussionmentioning

confidence: 99%

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Comparison of SD Bioline Malaria Ag Pf/Pan and Acro Malaria P.f./P.v./Pan with Microscopy and Real Time PCR for the Diagnosis of Human Plasmodium Species

Madamet,

Fonta,

Mosnier

et al. 2024

Diagnostics

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The early diagnosis of malaria is crucial to controlling morbidity and mortality. The World Health Organization (WHO) recommends diagnosing malaria either using light microscopy or a malaria rapid diagnostic test (RDT). Most RDTs use antibodies to detect two P. falciparum histidine-rich proteins named PfHRP2 and PfHRP3. However, false-negative results are known to occur due to the poor performance of RDTs depending on the species and the deletion of the Pfhrp2 and Pfhrp3 genes. This study evaluated new malaria RDTs for the detection of the human Plasmodium species. The Acro Malaria P.f./P.v./Pan Rapid Test Cassette allows the qualitative detection of parasite antigens, such as PfHRP2 specific to Plasmodium falciparum, PvLDH specific to Plasmodium vivax, and/or panLDH Plasmodium genus lactate dehydrogenase, in the blood of infected individuals. This RDT was assessed against 229 samples collected from imported malaria cases, mainly from Africa. The samples were previously diagnosed using light microscopy and RDT (SD Malaria Ag P.f./Pan, SD Bioline Alere Abbott), then confirmed using real time PCR. The two RDTs were evaluated using a comparison with real time PCR as the reference method, and their performances were compared with each other. Compared to SD RDT, the Acro RDT showed a better sensitivity to P. falciparum (96.8% vs. 89.8%), P. vivax (78.6% vs. 64.3%), P. ovale (73.7% vs. 5.3%), and P. malariae (20.0% vs. 0%). The respective specificities of the Acro RDT and SD RDT are 90.7% vs. 95.3% to P. falciparum, 100% to P. vivax, and 100% vs. 100% to Plasmodium genus. Therefore, Acro RDT showed better performance in the identification of P. ovale and low parasitaemia of P. falciparum. In addition, Acro RDT has the advantage of detecting PvLDH-specific antigens. The Acro Malaria RDT presents the benefits of detecting a P. falciparum antigen (PfHRP2) and a P. vivax antigen (PvLDH) with high sensitivity (96.8% and 73.7%, respectively) and specificity (90.7% and 100%, respectively). Acro Malaria P.f./P.v./Pan rapid diagnostic tests could be effectively used in endemic areas, especially when microscopic examination cannot be performed.

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Section: Discussionmentioning

confidence: 99%

“…The prevalence of Pfhrp2 gene deletion has been well documented in P. falciparum isolates [23][24][25][26][27][28][29][30]. The Pfhrp2-deleted parasites are capable of inducing malaria, and may significantly reduce the effectiveness of RDTs.…”

Section: Discussionmentioning

confidence: 99%

Comparison of SD Bioline Malaria Ag Pf/Pan and Acro Malaria P.f./P.v./Pan with Microscopy and Real Time PCR for the Diagnosis of Human Plasmodium Species

Madamet,

Fonta,

Mosnier

et al. 2024

Diagnostics

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Post-treatment duration of positivity for standard and ultra-sensitive Plasmodium falciparum antigen-based rapid diagnostic tests, a cohort study from a low-endemic setting in Namibia

Ntuku,

Whittemore,

Dausab

et al. 2025

eBioMedicine

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Slow clearance of histidine-rich protein-2 in Gabonese with uncomplicated malaria

Lamsfus Calle,

Schaumburg,

Rieck

et al. 2024

Microbiol Spectr

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Malaria rapid diagnostic tests (RDTs), which detect Plasmodium falciparum (Pf)-specific histidine-rich protein-2 (HRP2), have increasing importance for the diagnosis and control of malaria, especially also in regions where routine diagnosis by microscopy is not available. HRP2-based RDTs have a similar sensitivity to expert microscopy, but their reported low specificity can lead to high false positivity rates, particularly in high-endemic areas. Despite the widespread use of RDTs, models investigating the dynamics of HRP2 clearance following Pf treatment focus rather on short-term clearance of the protein. The goal of this observational cohort study was to determine the long-term kinetic of HRP2-levels in peripheral blood after treatment of uncomplicated malaria cases with Pf mono-infection using a 3-day course of artesunate/amodiaquine. HRP2 levels were quantified at enrollment and on days 1, 2, 3, 5, 7, 12, 17, 22, and 28 post-treatment initiation. The findings reveal an unexpectedly prolonged clearance of HRP2 after parasite clearance from capillary blood. Terminal HRP2 half-life was estimated to be 9 days after parasite clearance using a pharmacokinetic two-compartmental elimination model. These results provide evidence that HRP2 clearance has generally been underestimated, as the antigen remains detectable in capillary blood for up to 28 days following successful treatment, influencing RDT-based assessment following a malaria treatment for weeks. A better understanding of the HRP2 clearance dynamics is critical for guiding the diagnosis of malaria when relying on RDTs. IMPORTANCE Detecting Plasmodium falciparum , the parasite responsible for the severest form of malaria, typically involves microscopy, polymerase chain reaction (PCR), or rapid diagnostic tests (RDTs) targeting the histidine-rich protein 2 or 3 (HRP2/3). While microscopy and PCR quickly turn negative after the infection is cleared, HRP2 remains detectable for a prolonged period. The exact duration of HRP2 persistence had not been well defined. Our study in Gabon tracked HRP2 levels over 4 weeks, resulting in a new model for antigen clearance. We discovered that a two-compartment model accurately predicts HRP2 levels, revealing an initial rapid reduction followed by a much slower elimination phase that can take several weeks. These findings are crucial for interpreting RDT results, as lingering HRP2 can lead to false positives, impacting malaria diagnosis and treatment decisions.

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Persistence of Plasmodium falciparum HRP-2 antigenaemia after artemisinin combination therapy is not associated with gametocytes

Cited by 6 publications

References 30 publications

Comparison of SD Bioline Malaria Ag Pf/Pan and Acro Malaria P.f./P.v./Pan with Microscopy and Real Time PCR for the Diagnosis of Human Plasmodium Species

Comparison of SD Bioline Malaria Ag Pf/Pan and Acro Malaria P.f./P.v./Pan with Microscopy and Real Time PCR for the Diagnosis of Human Plasmodium Species

Post-treatment duration of positivity for standard and ultra-sensitive Plasmodium falciparum antigen-based rapid diagnostic tests, a cohort study from a low-endemic setting in Namibia

Slow clearance of histidine-rich protein-2 in Gabonese with uncomplicated malaria

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