Primaquine at alternative dosing schedules for preventing relapse in people with Plasmodium vivax malaria

Malaria caused by Plasmodium vivax requires treatment of the blood-stage infection and treatment of the hypnozoites that develop in the liver. This is a challenge to effective case management of P vivax malaria, as well as being a more general substantial impediment to malaria control. The World Health Organization (WHO) recommends a 14-day drug course with primaquine, an 8-aminoquinoline, at 0.25 mg/kg/day in most of the world (standard course), or 0.5 mg/kg/day in East Asia and Oceania (high-standard course). This long treatment course can be difficult to complete, and primaquine can cause dangerous haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, meaning that physicians may be reluctant to prescribe in areas where G6PD testing is not available. This Cochrane Review evaluated whether more patient-friendly alternative regimens are as efficacious as the standard regimen for radical cure ofP vivax malaria.

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 days of primaquine (0.25 or 0.5 mg/kg/day), as well as comparison of these two WHO-recommended regimens.

We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); and LILACS (BIREME) up to 17 December 2018. We also searched the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov, and checked the reference lists of all studies identified by the above methods.

Randomized controlled trials (RCTs) of adults and children with P vivax malaria using any regimen of either chloroquine or an artemisinin-based combination therapy (ACT) plus primaquine with either higher daily doses for 14 days, shorter regimens with the same total dose, or using weekly dosing regimens; compared with the usual standard regimens recommended by the WHO (0.25 or 0.5 mg/kg/day for 14 days), or a comparison of these two WHO-recommended regimens.

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. We analysed safety data where this information was included.

High-standard 14-day course versus standard 14-day courseTwo 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 courseFive 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.