| Autor: |
Fadilah, Ihsan, Commons, Robert J., Chau, Nguyen Hoang, Chu, Cindy S., Day, Nicholas P. J., Koh, Gavin C. K. W., Green, Justin A., Lacerda, Marcus VG, Llanos-Cuentas, Alejandro, Nelwan, Erni J., Nosten, Francois, Pasaribu, Ayodhia Pitaloka, Sutanto, Inge, Taylor, Walter R. J., Thriemer, Kamala, Price, Ric N., White, Nicholas J., Baird, J. Kevin, Watson, James A. |
| Předmět: |
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| Zdroj: |
PLoS Medicine; 9/27/2024, Vol. 21 Issue 9, p1-20, 20p |
| Abstrakt: |
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. 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. Author summary: Why was this study done?: Plasmodium vivax causes recurrent malaria due to dormant liver stage parasites. The pro-drugs primaquine and tafenoquine are the only available treatments to prevent relapsing malaria, but their optimal dosing remains unclear. The active metabolites of primaquine and tafenoquine cause predictable increases in blood methaemoglobin; these same metabolites also kill liver parasites. This suggests that increases in blood methaemoglobin could be used as a population-level surrogate endpoint for liver stage parasite killing. What did the researchers do and find?: We conducted an individual patient data meta-analysis examining the utility and validity of blood methaemoglobin as a surrogate endpoint for recurrent vivax malaria. We systematically reviewed and pooled the available methaemoglobin and clinical data from patients with P. vivax malaria treated with primaquine over the last 20 years. We fit statistical models to these data to quantify the relationship between day 7 methaemoglobin levels and the risk of recurrent P. vivax malaria. We observed an increasing dose-response relationship between weight-adjusted primaquine dose and methaemoglobin levels measured on day 7. We found that for a fixed primaquine dose regimen, a doubling in day 7 methaemoglobin was associated with an estimated 30% reduction in the risk of vivax recurrence. Using day 7 methaemoglobin levels as a surrogate endpoint for recurrent malaria could reduce sample sizes needed in future studies by about 40% and reduce follow-up duration by 94%. What do these findings mean?: Patients with higher methaemoglobin levels a week after starting primaquine treatment appear to have a lower risk of recurrence. Day 7 methaemoglobin levels can potentially be used as a proxy for later vivax recurrence in exploratory trials, making it more efficient (e.g., fewer volunteers and resources required) to determine whether new drugs or regimens are effective. Study limitations include the inability to determine whether P. vivax recurrences are due to treatment failure, reinfection, or relapse. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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