Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis
Issued Date
2024-09-01
Resource Type
ISSN
15491277
eISSN
15491676
Scopus ID
2-s2.0-85205141359
Journal Title
PLoS Medicine
Volume
21
Issue
9
Rights Holder(s)
SCOPUS
Bibliographic Citation
PLoS Medicine Vol.21 No.9 (2024)
Suggested Citation
Fadilah I., Commons R.J., Chau N.H., Chu C.S., Day N.P.J., Koh G.C.K.W., Green J.A., Lacerda M.V.G., Llanos-Cuentas A., Nelwan E.J., Nosten F., Pasaribu A.P., Sutanto I., Taylor W.R.J., Thriemer K., Price R.N., White N.J., Baird J.K., Watson J.A. Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis. PLoS Medicine Vol.21 No.9 (2024). doi:10.1371/journal.pmed.1004411 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/101487
Title
Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis
Author's Affiliation
Infectious Diseases Data Observatory
Mahidol Oxford Tropical Medicine Research Unit
Oxford University Clinical Research Unit
Universidad Peruana Cayetano Heredia, Instituto de Medicina Tropical Alexander von Humboldt
Universitas Sumatera Utara
Universitas Indonesia, RSUPN Dr. Cipto Mangunkusumo
Universitas Indonesia
Northwick Park Hospital
Menzies School of Health Research
GlaxoSmithKline plc.
Fiocruz Amazônia
The University of Texas Medical Branch at Galveston
Nuffield Department of Medicine
Tridarma Healthcare Empowerment Foundation
WorldWide Antimalarial Resistance Network
Grampians Health
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Mahidol Oxford Tropical Medicine Research Unit
Oxford University Clinical Research Unit
Universidad Peruana Cayetano Heredia, Instituto de Medicina Tropical Alexander von Humboldt
Universitas Sumatera Utara
Universitas Indonesia, RSUPN Dr. Cipto Mangunkusumo
Universitas Indonesia
Northwick Park Hospital
Menzies School of Health Research
GlaxoSmithKline plc.
Fiocruz Amazônia
The University of Texas Medical Branch at Galveston
Nuffield Department of Medicine
Tridarma Healthcare Empowerment Foundation
WorldWide Antimalarial Resistance Network
Grampians Health
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Corresponding Author(s)
Other Contributor(s)
Abstract
Background The:8-aminoquinolines, primaquine and tafenoquine, are the: only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. Methods and findings We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. Conclusions For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity.