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

被引:0
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作者
Fadilah, Ihsan [1 ,2 ]
Commons, Robert J. [3 ,4 ,5 ]
Chau, Nguyen Hoang [6 ]
Chu, Cindy S. [2 ,7 ]
Day, Nicholas P. J. [2 ,8 ]
Koh, Gavin C. K. W. [9 ]
Green, Justin A. [10 ]
Lacerda, Marcus V. G. [11 ,12 ,13 ]
Llanos-Cuentas, Alejandro [14 ]
Nelwan, Erni J. [15 ,16 ]
Nosten, Francois [2 ,7 ]
Pasaribu, Ayodhia Pitaloka [17 ,18 ]
Sutanto, Inge [19 ]
Taylor, Walter R. J. [2 ,8 ]
Thriemer, Kamala [3 ]
Price, Ric N. [2 ,3 ,4 ,8 ]
White, Nicholas J. [2 ,8 ]
Baird, J. Kevin [1 ,2 ]
Watson, James A. [2 ,6 ,20 ]
机构
[1] Univ Indonesia, Fac Med, Oxford Univ, Clin Res Unit Indonesia, Jakarta, Indonesia
[2] Univ Oxford, Ctr Trop Med & Global Hlth, Nuffield Dept Med, Oxford, England
[3] Charles Darwin Univ, Menzies Sch Hlth Res, Darwin, Australia
[4] Asia Pacific Reg Hub Australia, WorldWide Antimalarial Resistance Network, Melbourne, Australia
[5] Grampians Hlth, Gen & Subspecialty Med, Ballarat, Australia
[6] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam
[7] Mahidol Univ, Fac Trop Med, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Mae Sot, Thailand
[8] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand
[9] GlaxoSmithKline, Global Hlth, Brentford, England
[10] Northwick Pk Hosp & Clin Res Ctr, Dept Infect Dis, Harrow, England
[11] Fundacao Med Trop Dr Heitor Vieira Dourado, Manaus, Brazil
[12] Fiocruz MS, Inst Leonidas & Maria Deane, Manaus, Brazil
[13] Univ Texas Med Branch, Galveston, TX USA
[14] Univ Peruana Cayetano Heredia, Inst Med Trop Alexander von Humboldt, Unit Leishmaniasis & Malaria, Lima, Peru
[15] Univ Indonesia, Fac Med, Jakarta, Indonesia
[16] Cipto Mangunkusumo Hosp, Dept Internal Med, Div Trop & Infect Dis, Jakarta, Indonesia
[17] Univ Sumatera Utara, Med Fac, Dept Pediat, Medan, Indonesia
[18] Tridarma Healthcare Empowerment Fdn, Medan, Indonesia
[19] Univ Indonesia, Fac Med, Dept Parasitol, Jakarta, Indonesia
[20] Infect Dis Data Observ, Oxford, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
PREVENT RELAPSE; TAFENOQUINE; RECURRENCES;
D O I
10.1371/journal.pmed.1004411
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页数:20
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