Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis

Ihsan Fadilah, Robert J Commons, Nguyen Hoang Chau, Cindy S Chu, Nicholas P J Day, Gavin C K W Koh, Justin A Green, Marcus VG Lacerda, Alejandro Llanos-Cuentas, Erni J Nelwan, Francois Nosten, Ayodhia Pitaloka Pasaribu, Inge Sutanto, Walter R J Taylor, Kamala Thriemer, Ric N Price, Nicholas J White, J Kevin Baird and James A Watson

PLOS Medicine, 2024, vol. 21, issue 9, 1-20

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). 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. Ihsan Fadilah and colleagues conduct an individual patient data meta-analysis examining the utility and validity of blood methaemoglobin as a surrogate endpoint for recurrent vivax malaria.Why was this study done?: What did the researchers do and find?: What do these findings mean?:

Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pmed00:1004411

DOI: 10.1371/journal.pmed.1004411

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