1. Compared to lower dose primaquine, higher dose primaquine had higher efficacy in preventing relapse of Plasmodium vivax malaria.
2. Higher dose primaquine demonstrated a significantly higher recurrence-free rate compared to lower dose primaquine.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Malaria is commonly caused by Plasmodium vivax and Plasmodium falciparum or mixed infections. Primaquine therapy offers potential for eradication of these parasites and hypnozoites, but its efficacy depends on the total dose given during a round of therapy (either 3.5mg or 7mg per kilogram of body weight), because of variable drug susceptibility worldwide. In most of the Americas, primaquine is given at a total dose of 3.5mg per kilogram. However, there is a gap in knowledge as to understanding the therapeutic efficacy of lower dose and higher dose primaquine. This study found that higher doses of primaquine had significantly higher efficacy in preventing relapse of Plasmodium vivax malaria. This study was limited by factors such as the limitations in the use of genotyping to categorize Plasmodium vivax recurrence since relapse can be caused by both homologous and heterologous hypnozoites. Nevertheless, these study’s findings are significant, as they demonstrate that a higher dose of primaquine had a higher recurrence-free percentage than those who received a lower total dose of primaquine for Plasmodium vivax malaria.
Click to read the study in NEJM
Relevant Reading: Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria
In-Depth [randomized control trial]: This randomized control trial studied eight malaria diagnostic posts in the western Brazilian Amazon, evaluating three primaquine regimens: group 1 received a total primaquine dose of 3.5mg per kilogram over 7 days; group 2 received the same regimen but with observed administration; and group 3 received a total primaquine dose of 7mg per kilogram over 14 days with observed administration. The groups were subsequently monitored for 168 days. Patients who were at least 5 years of age, documented fever, Plasmodium vivax mono-infection, and a parasite density between 100 and 200,000 asexual parasites per cubic millimeter were eligible for the study. Patients with suspected severe malaria or abnormal G6PD activity were excluded since G6PD deficiency can lead to severe hemolysis during primaquine use. The primary outcome measure was the rate of recurrence or treatment failure, defined as clinical deterioration leading to hospitalization with parasitemia. Outcomes in the primary analysis were assessed via Kaplan-Meier survival analysis and an unadjusted Cox proportional-hazards regression model. Based on the analysis, by day 28, 3 Plasmodium vivax recurrences were observed, with 2 in group one and 1 in group two. By day 168, there had been 70 total recurrences, with 24 in group one, 34 in group two, and 12 in group three. On day 168, the recurrence-free percentage was 58% (95% Confidence Interval [CI], 44 to 70) in group 1, 59% (95% CI, 47 to 69) in group 2, and 86% (95% CI, 76 to 92) in group 3. Survival analysis also demonstrated a difference in day 168 recurrence-free percentage of 27% (97.5% CI, 10 to 44) between group 1 and group 2 and a difference of 27% between group 2 and group 3 (96.5% CI, 12 to 42). Overall, this study demonstrated that a higher total dose of primaquine is significantly associated with higher rates of recurrence-free survival in patients with Plasmodium vivax malaria.
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