{"doi":"10.1371/journal.pmed.1004411","title":"Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis","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.","journal":"PLoS Medicine","year":2024,"id":429411,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9618,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":316969,"name":"Robert J. Commons","orcid":"0000-0002-3359-5632","position":1,"is_corresponding":false},{"id":236307,"name":"Nguyễn Hoàng Châu","orcid":"0000-0002-7826-3850","position":2,"is_corresponding":false},{"id":339933,"name":"Cindy S. Chu","orcid":"0000-0001-9465-8214","position":3,"is_corresponding":false},{"id":236338,"name":"Nicholas Day","orcid":"0000-0003-2309-1171","position":4,"is_corresponding":false},{"id":1035776,"name":"Gavin Koh","orcid":"0000-0002-7336-1566","position":5,"is_corresponding":false},{"id":616883,"name":"Justin A. Green","orcid":null,"position":6,"is_corresponding":false},{"id":3855,"name":"Marcus V. G. de Lacerda","orcid":"0000-0003-3374-9985","position":7,"is_corresponding":false},{"id":378657,"name":"Alejandro Llanos‐Cuentas","orcid":"0000-0002-7567-5534","position":8,"is_corresponding":false},{"id":881034,"name":"Erni Juwita Nelwan","orcid":"0000-0003-4064-5412","position":9,"is_corresponding":false},{"id":295838,"name":"François Nosten","orcid":"0000-0002-7951-0745","position":10,"is_corresponding":false},{"id":1035777,"name":"Ayodhia Pitaloka Pasaribu","orcid":"0000-0002-3830-8073","position":11,"is_corresponding":false},{"id":881033,"name":"Inge Sutanto","orcid":"0000-0003-2488-5133","position":12,"is_corresponding":false},{"id":1035772,"name":"Walter Taylor","orcid":"0000-0001-6236-0464","position":13,"is_corresponding":false},{"id":316971,"name":"Kamala Thriemer","orcid":"0000-0001-7536-7497","position":14,"is_corresponding":false},{"id":316986,"name":"Ric N. Price","orcid":"0000-0003-2000-2874","position":15,"is_corresponding":false},{"id":236339,"name":"Nicholas J. White","orcid":"0000-0002-1897-1978","position":16,"is_corresponding":false},{"id":881036,"name":"J. Kevin Baird","orcid":"0000-0002-2170-300X","position":17,"is_corresponding":false},{"id":919679,"name":"James A Watson","orcid":"0000-0001-5524-0325","position":18,"is_corresponding":false},{"id":1231499,"name":"Ihsan Fadilah","orcid":"0000-0001-9507-6427","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T01:59:06.668462Z","pmid":"39331646","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}