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

Henry Ntuku; Brooke Whittemore; Lucille Dausab; Ihn Kyung Jang; Allison Golden; William Sheahan; Xue Wu; Hannah Slater; Gonzalo J Domingo; Smita Das; Elias Duarte; Lydia Eloff; Teun Bousema; Kjerstin Lanke; Cara Smith Gueye; Lisa M Prach; Jaishree Raman; Petrina Uusiku; Stark Katokele; Roly Gosling; Bryan Greenhouse; Davis Mumbengegwi; Michelle S Hsiang

doi:10.1016/j.ebiom.2024.105489

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

EBioMedicine. 2024 Dec 9:111:105489. doi: 10.1016/j.ebiom.2024.105489. Online ahead of print.

Authors

Henry Ntuku¹, Brooke Whittemore², Lucille Dausab³, Ihn Kyung Jang⁴, Allison Golden⁴, William Sheahan⁴, Xue Wu¹, Hannah Slater⁴, Gonzalo J Domingo⁴, Smita Das⁴, Elias Duarte⁵, Lydia Eloff³, Teun Bousema⁶, Kjerstin Lanke⁶, Cara Smith Gueye¹, Lisa M Prach¹, Jaishree Raman⁷, Petrina Uusiku⁸, Stark Katokele⁸, Roly Gosling¹, Bryan Greenhouse⁵, Davis Mumbengegwi³, Michelle S Hsiang⁹

Affiliations

¹ Malaria Elimination Initiative, Global Health Group, University of California, San Francisco (UCSF), San Francisco 94158, USA.
² Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75390, USA.
³ Multidisciplinary Research Centre, University of Namibia, Windhoek 13301, Namibia.
⁴ Diagnostics Program, PATH, Seattle 98121, USA.
⁵ Division of HIV, Infectious Diseases, and Global Medicine, Department of Medicine, UCSF, San Francisco 94158, USA.
⁶ Radboud University Medical Centre, Nijmegen 6500HB, the Netherlands.
⁷ Centre for Emerging Zoonotic and Parasitic Diseases, National Institute for Communicable Diseases, A Division of the National Health Laboratory Service, Sandringham, Johannesburg, Gauteng, South Africa.
⁸ Namibia Ministry of Health and Social Services, Windhoek 13198, Namibia.
⁹ Malaria Elimination Initiative, Global Health Group, University of California, San Francisco (UCSF), San Francisco 94158, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75390, USA; Department of Pediatrics, UCSF Benioff Children's Hospital, San Francisco 94158, USA; Department of Epidemiology and Biostatistics, UCSF, San Francisco 94158, USA. Electronic address: michelle.hsiang@ucsf.edu.

PMID: 39657364
DOI: 10.1016/j.ebiom.2024.105489

Abstract

Background: The standard malaria rapid diagnostic test (RDT) and newer ultra-sensitive RDT (uRDT) target Plasmodium falciparum histidine rich protein-2 (HRP2), which persists post-treatment. The duration of test positivity has not previously been studied in a low transmission setting.

Methods: We conducted a longitudinal cohort study in a low transmission setting in Namibia. RDT-positive individuals identified through passive and active case detection were treated and followed weekly for testing by RDT and uRDT, HRP2 quantification, quantitative PCR (qPCR) of parasitemia, and quantitative reverse transcriptase PCR (RT-PCR) of gametocytemia, until RDT and uRDT were negative for two consecutive weeks. Determinants of persistent positivity were identified using Cox proportional hazards models.

Findings: Among 137 participants with complete follow-up and no evidence of resurgence during follow-up, median duration of positivity was 42 days (range: 3-98 range) for RDT, compared to 67 days (range 12-105) for uRDT. In a sub-analysis of those with laboratory data before treatment (n = 60), drug resistance did not explain persistent positivity. Younger age (<15 years versus ≥15 years: aHR: 1.85, 95% CI 1.04-3.30, and 1.67, 95% CI 0.96-2.89, for RDT and uRDT, respectively), higher initial parasite density (highest versus lowest tertile: aHR 0.11, 95% CI 0.04-0.32 and 0.19, 95% CI 0.07-0.48 for RDT and uRDT, respectively), and persistent parasitemia (≥7 days versus reference of <7 days, aHR 0.39, 95% CI 0.20-0.76, and 0.40, 95% CI 0.21-0.76 for RDT and uRDT, respectively) were associated with longer duration of positivity.

Interpretation: Duration of RDT/uRDT positivity was more than double compared to reports from higher endemic settings, potentially due to lower population immunity to clear parasite DNA and antigen. Prolonged duration of positivity compromises their use to detect current infection, but increased detection of recent infection can facilitate surveillance and inform elimination efforts.

Funding: The project was funded by the Bill and Melinda Gates Foundation (A128488 and INV1135840), Horchow Family Fund (5300375400), and Chan Zuckerberg Biohub.

Keywords: Histidine-rich protein; Low transmission; Low-endemic; Malaria; Malaria elimination; Persistence.