Abstract: We included 15 trials (two cluster-RCTs) of 4377 adult and child participants. Most trials excluded people with G6PD deficiency. Trials compared various regimens of primaquine with the standard primaquine regimen, or with placebo or no treatment. All trials treated blood stage infection with chloroquine. Alternative primaquine regimens compared to 14-day primaquine Relapse rates were higher over six months with the five-day primaquine regimen than the standard 14-day regimen (RR 10.05, 95% CI 2.82 to 35.86; two trials, 186 participants, moderate quality evidence). Similarly, relapse over six months was higher with three days of primaquine than the standard 14-day regimen (RR 3.18, 95% CI 2.1 to 4.81; two trials, 262 participants, moderate quality evidence; six months follow-up); and with primaquine for seven days followed up over two months, compared to 14-day primaquine (RR 2.24, 95% CI 1.24 to 4.03; one trial, 126 participants, low quality evidence). Relapse with once-weekly supervised primaquine for eight weeks was little different over nine months follow-up compared to 14-day self-administered primaquine in one small study (RR 2.97, 95% CI 0.34 to 25.87; one trial, 129 participants, very low quality evidence). Primaquine regimens compared to no primaquine The number of people that relapsed was similar between people given five days of primaquine or given placebo or no primaquine (four trials, 2213 participants, high quality evidence; follow-up six to 15 months); but lower with 14 days of primaquine (RR 0.6; 95% CI 0.48 to 0.75; ten trials, 1740 participants, high quality evidence; follow-up seven weeks to 15 months). No serious adverse events were reported. Treatment-limiting adverse events were rare and non-serious adverse events were mild and transient. Trial authors reported that people tolerated the drugs. We did not find trials comparing higher dose primaquine regimens (0.5 mg/kg/day or more) for five days or more with the 14-day regimen. The analysis confirms the current World Health Organization recommendation for 14-day primaquine (15 mg/day) to prevent relapse of vivax malaria. Shorter primaquine regimens at the same daily dose are associated with higher relapse rates. The comparative effects with weekly primaquine are promising, but require further trials to establish equivalence or non-inferiority compared to the 14-day regimen in high malaria transmission settings.

Plain-language summary: The review authors included 15 trials of 4377 adults and children older than one year with vivax malaria. All were treated with chloroquine for the blood stage infection, and then randomized to the 14-day primaquine course, or to shorter primaquine courses (three, five, or seven days); or to higher doses of primaquine given once a week for eight weeks; or to a placebo or no treatment. In twelve studies, treatments were supervised. The evidence is current to 8 October 2013. Relapse over six months to one year is probably higher with shorter regimens when compared to the standard 14-day primaquine regimen (moderate quality evidence). We do not know from the available evidence whether the number of relapses with weekly primaquine differs from 14 days of primaquine treatment based on one study of 126 people followed up for nine months (very low quality evidence). Better conducted studies on more people are needed to be sure that they are equally effective against relapse. Five days of primaquine was as ineffective against relapse as placebo or no treatment over six months to 15 months based on four studies (high quality evidence). The 14-day primaquine course prevented many more people relapsing with vivax malaria over 12 months than placebo (high quality evidence). No serious adverse reactions to primaquine were reported. This review update confirms that the 14-day primaquine course recommended by the WHO is more effective against relapse of vivax malaria than treatment with shorter courses of primaquine.