Primaquine for preventing relapses in people with Plasmodium vivax malaria

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Plasmodium vivax infections contribute to a significant proportion of the malaria infections in many countries. Primaquine is the most widely used drug for treating the dormant liver stage. Different primaquine dosing regimens are in use. To compare primaquine regimens for preventing relapses in people with P. vivax malaria. In 2006, we searched the Cochrane Infectious Diseases Group's Specialized Register (January), CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE (October), EMBASE (January), LILACS (January). We also checked conference proceedings and reference lists, and contacted researchers, the World Health Organization (WHO), malaria mailing lists, and pharmaceutical companies. Randomized and quasi-randomized controlled trials comparing primaquine plus chloroquine with chloroquine alone, and the standard primaquine regimen (15 mg/day for 14 days) with other primaquine-containing regimens in people with vivax malaria. All authors independently assessed trial eligibility and quality, and extracted data. We calculated odds ratios (OR) with 95% confidence intervals (CI) for dichotomous data, and used the random-effects model if there was significant heterogeneity. Nine trials (3423 participants) met the inclusion criteria. Compared with chloroquine alone, five-day primaquine plus chloroquine was no better at preventing relapses (OR 1.04, 95% CI 0.64 to 1.69, random-effects model; 2104 participants; 3 trials), while 14-day primaquine plus chloroquine was significantly better (OR 0.24, 95% CI 0.12 to 0.45, random-effects model; 1071 participants, 6 trials). Limited data suggest the advantage for the 14-day primaquine regimen persisted for over six months (OR 0.41, 95% CI 0.29 to 0.60; 585 participants, 2 trials). Direct comparisons of the 14-day and five-day primaquine plus chloroquine regimens also confirm the superiority of the longer course (OR 13.33, 95% CI 3.45 to 51.44; 186 participants, 2 trials). Adverse effects were poorly reported, with three trials reporting skin rash, vertigo, headache, abdominal pain and/or nausea, and two trials reporting that primaquine was well tolerated. Primaquine (15 mg/kg/day for 14 days) plus chloroquine is more effective than chloroquine alone or primaquine (15 mg/kg for 5 days) plus chloroquine in preventing relapses of vivax malaria. Primaquine (five days) plus chloroquine appears no better than chloroquine. Countries should follow the WHO's recommendation for 14-day primaquine plus chloroquine regimen. Alternative regimens need to be evaluated in randomized controlled trials, which should also consider variations in regional P. vivax strains and the possibility of primaquine resistance, reinfection, and adherence in those who relapse.