Abstract: High-standard 14-day course versus standard 14-day course Two RCTs compared the high-standard 14-day regimen with the standard 14-day regimen. People with G6PD deficiency and pregnant or lactating women were excluded. We do not know if there is any difference in P vivax recurrences at 6 months with 0.5 mg/kg/day primaquine therapy for 14 days compared to 0.25 mg/kg/day primaquine therapy for 14 days (with chloroquine: RR 0.82, 95% CI 0.47 to 1.43, 639 participants, very low-certainty evidence; with chloroquine or an ACT: RR 1.11, 95% CI 0.17 to 7.09, 38 participants, very low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events with the higher dosage (very low-certainty evidence). 0.5 mg/kg/day primaquine for 7 days versus standard 14-day course Five RCTs compared 0.5 mg/kg/day primaquine for 7 days with the standard 14-day course. There may be little or no difference in P vivax recurrences at 6 to 7 months when using the same total dose (0.5 mg/kg/day to 210 mg) over 7 days as compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 1211 participants; low-certainty evidence). No serious adverse events were reported. There may be little or no difference in the number of adverse events known to occur with primaquine between the primaquine shorter regimen as compared to the longer regimen (RR 1.06, 95% CI 0.64 to 1.76; 1154 participants; low-certainty evidence). We do not know whether there is any difference in the frequency of anaemia or discontinuation of treatment between groups (very low-certainty evidence). Three trials excluded people with G6PD deficiency, and two did not provide this information. Pregnant and lactating women were either excluded or no details were provided regarding their inclusion or exclusion. 0.75 mg/kg primaquine/week for 8 weeks versus high-standard course One RCT compared weekly primaquine with the high-standard 14-day course. G6PD-deficient patients were not randomized but were included in the weekly primaquine group. Only one G6PD-deficient participant was detected during the trial. We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to the 14-day regimen at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.6; 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. Three other RCTs evaluated different alternative regimens and doses of primaquine, but one of these RCTs did not have results available, and two used regimens that have not been widely used and the evidence was of very low certainty. Although limited data were available, the analysis did not detect a difference in recurrence between the 7-day regimen and the standard 14-day regimen of 0.5 mg/kg/day primaquine, and no serious adverse events were reported in G6PD-normal participants taking 0.5 mg/kg/day of primaquine. This shorter regimen may be useful in G6PD-normal patients if there are treatment adherence concerns. Further large high-quality RCTs are needed, such as the IMPROV trial, with more standardised comparison regimens and longer follow-up to help resolve uncertainties.

Plain-language summary: We summarized trials that compared the World Health Organization (WHO)-recommended primaquine regimen of 15 to 30 mg per day for 14 days with the same or higher 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 17 December 2018, and included nine randomized controlled trials (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 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 6 months (very low-certainty evidence). No serious side effects were reported, but it is unclear whether or not there is a difference in other side effects between doses (very low-certainty evidence). When using 30 mg primaquine per day for 7 days compared to 15 mg per day for 14 days, there may be no difference in P vivax recurrences at 6 to 7 months (low-certainty evidence). No serious adverse events were reported. There may be no difference in the number of side effects known to occur with primaquine between the two treatment regimens (low-certainty evidence). We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to the 14-day regimen at 11 months' follow-up (very low-certainty evidence). Further large high-quality RCTs are needed, such as the IMPROV trial, to 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 17 December 2018.