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Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> 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 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> recurrence.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>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 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> 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 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> 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).<\/jats:p>\n<jats:p>We identified 219 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> 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 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; <jats:italic>p<\/jats:italic> = 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 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> recurrences.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> 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 <jats:italic>P<\/jats:italic>. <jats:italic>vivax<\/jats:italic> malaria who have normal G6PD activity.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1004411","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T17:38:46Z","timestamp":1727458726000},"page":"e1004411","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9507-6427","authenticated-orcid":true,"given":"Ihsan","family":"Fadilah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3359-5632","authenticated-orcid":true,"given":"Robert J.","family":"Commons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7826-3850","authenticated-orcid":true,"given":"Nguyen Hoang","family":"Chau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy S.","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P. J.","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7336-1566","authenticated-orcid":true,"given":"Gavin C. K. 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