Plasmodium vivax malaria can sometimes cause potentially life-threatening illness, and the infection continues to make many people unwell. The infection includes a liver stage, and this requires primaquine to eradicate it and prevent the infection recurring. However, the current dosing schedule requires 14 days of daily treatment.
What are the concerns about primaquine?
Primaquine is the only drug currently recommended to treat the liver parasites in P vivax malaria. It can cause anaemia in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is a relatively common genetic blood disorder. Shorter regimens would help reduce the risk of default with the current two-week regimen.
What does the research say?
We summarized trials that compared the World Health Organization (WHO)-recommended primaquine regimen of 15 mg to 30 mg per day for 14 days with the same (210 mg) or higher total doses of primaquine given over different lengths of time to determine whether alternative regimens were as successful as the recommended courses at preventing future episodes of P vivax malaria. We searched for trials up to 2 September 2019 and included 11 randomized controlled trials (RCTs) (studies in which participants are assigned to one of two or more treatment groups in a random manner) in our analysis.
When using 30 mg primaquine per day for seven days compared to 15 mg per day for 14 days, there may be little or no difference in P vivax recurrences at six to seven months (low-certainty evidence). No serious adverse events were reported. We do not know if there is a difference in the number of adverse events that cause people to stop taking the drug (low-certainty evidence).
When using 30 mg per day compared to 15 mg per day primaquine therapy for 14 days, we do not know if there is any difference in P vivax recurrences at six months (very low-certainty evidence). No serious adverse events were reported, but it is unclear whether or not there is a difference between doses in other adverse events that cause people to stop taking the drug (very low-certainty evidence).
We do not know whether primaquine at 45 mg once per week for eight weeks increases or decreases recurrences of P vivax compared to the high standard 30 mg per day for 14-days, at 11 months' follow-up (very low-certainty evidence).
There is probably little or no difference for recurrence using high dose 60 mg per day for seven days compared to the high standard 30 mg per day for 14 days, but there may be an increase in serious adverse events in the high-dose shorter course regimen group.
Further RCTs will help improve the certainty of the evidence around alternative regimens,
How up-to-date is this review?
The review authors searched for studies up to 2 September 2019.
Trials available to date do not detect a difference in recurrence between the following regimens: 1) 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days; 2) high-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days; 3) 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days; 4) 1 mg/kg/day for seven days versus high-standard 0.5 mg/kg/day for 14 days. There were no differences detected in adverse events for Comparisons 1, 2 or 3, but there may be more serious adverse events with the high seven-day course in Comparison 4.
The shorter regimen of 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days may suit G6PD-normal patients. Further research will help increase the certainty of the findings and applicability in different settings.
Plasmodium vivax liver stages (hypnozoites) may cause relapses, prolonging morbidity, and impeding malaria control and elimination. The World Health Organization (WHO) recommends three schedules for primaquine: 0.25 mg/kg/day (standard), or 0.5 mg/kg/day (high standard) for 14 days, or 0.75 mg/kg once weekly for eight weeks, all of which can be difficult to complete. Since primaquine can cause haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, clinicians may be reluctant to prescribe primaquine without G6PD testing, and recommendations when G6PD status is unknown must be based on an assessment of the risks and benefits of prescribing primaquine. Alternative safe and efficacious regimens are needed.
To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high-standard 14-day courses.
We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); LILACS (BIREME); WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 2 September 2019, and checked the reference lists of all identified studies.
Randomized controlled trials (RCTs) of adults and children with P vivax malaria using either chloroquine or artemisinin-based combination therapy plus primaquine at a total adult dose of at least 210 mg, compared with the WHO-recommended regimens of 0.25 or 0.5 mg/kg/day for 14 days.
Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow-up, partner drug, and trial location. We analysed safety data where included.
0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days
There may be little or no difference in P vivax recurrences at six to seven months when using the same total dose (210 mg adult dose) over seven days compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 4 RCTs, 1211 participants; low-certainty evidence). No serious adverse events were reported. We do not know if there is any difference in the number of adverse events resulting in discontinuation of primaquine (RR 1.04, 95% CI 0.15 to 7.38; 5 RCTs, 1427 participants) or in the frequency of anaemia (RR 3.00, 95% CI 0.12 to 72.91, 1 RCT, 240 participants) between the shorter and longer regimens (very low-certainty evidence). Three trials excluded people with G6PD deficiency; two did not provide this information. Pregnant and lactating women were either excluded or no details were provided.
High-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days
There may be little or no difference in P vivax recurrences at six months with 0.5 mg/kg/day primaquine for 14 days compared to 0.25 mg/kg/day for 14 days (RR 0.84 (95% CI 0.49 to 1.43; 2 RCTs, 677 participants, low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events resulting in discontinuation of treatment with the high-standard dosage (RR 4.19, 95% CI 0.90 to 19.60; 1 RCT, 778 participants, very low-certainty evidence). People with G6PD deficiency and pregnant or lactating women were excluded.
0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days
We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to high-standard 0.5 mg/kg/day for 14 days, at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.60; 1 RCT, 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. G6PD-deficient patients were not randomized but included in the weekly primaquine group (only one patient detected).
1 mg/kg/day for seven days versus high standard 0.5 mg/kg/day for 14 days
There is probably little or no difference in P vivax recurrences at 12 months between 1.0 mg/kg/day primaquine for seven days and the high-standard 0.5 mg/kg/day for 14 days (RR 1.03, 95% CI 0.82 to 1.30; 2 RCTs, 2526 participants; moderate-certainty evidence). There may be moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for seven days compared with the high-standard 0.5 mg/kg/day for 14 days, during 42 days follow-up (RR 12.03, 95% CI 1.57 to 92.30; 1 RCT, 1872 participants, low-certainty evidence). We do not know if there is a difference between 1.0 mg/kg/day primaquine for seven days and high-standard 0.5 mg/kg/day for 14 days in adverse events that resulted in discontinuation of treatment (RR 2.50, 95% CI 0.49 to 12.87; 1 RCT, 2526 participants, very low-certainty evidence), nor if there is difference in frequency of anaemia by 42 days (RR 0.93, 95% CI 0.62 to 1.41; 2 RCTs, 2440 participants, very low-certainty evidence). People with G6PD deficiency were excluded.
Other regimens
Two RCTs evaluated other rarely-used doses of primaquine, one of which had very high loss to follow-up. Adverse events were not reported. People with G6PD deficiency and pregnant or lactating women were excluded.