Malaria due to Plasmodium vivax parasites is widespread. The World Health Organization (WHO) recommends that people with P. vivax malaria are treated with chloroquine for three days to eliminate the parasites in the blood that cause the symptoms of malaria, followed by 15 mg/day of primaquine for 14 days to treat the liver stage of the infection to prevent the disease recurring. However, many people do not complete the primaquine treatment once they feel better after chloroquine treatment. In addition, primaquine can destroy red blood cells in people with a genetic enzyme deficiency (glucose-6-phosphate-dehydrogenase enzyme (G6PD) deficiency), and clinicians avoid giving primaquine in areas where people commonly have this deficiency. Shorter courses of primaquine could potentially increase treatment completion and reduce adverse events.
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.
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.
Plasmodium vivax infections are an important contributor to the malaria burden worldwide. The World Health Organization recommends a 14-day course of primaquine (0.25 mg/kg/day, giving an adult dose of 15 mg/day) to eradicate the liver stage of the parasite and prevent relapse of the disease. Many people find a 14-day primaquine regimen difficult to complete, and there is a potential risk of haemolytic anaemia in people with glucose-6-phosphate-dehydrogenase enzyme (G6PD) deficiency. This review evaluates primaquine in P. vivax, particularly alternatives to the standard 14-day course.
To compare alternative primaquine regimens to the recommended 14-day regimen for preventing relapses (radical cure) in people with P. vivax malaria treated for blood stage infection with chloroquine. We also summarize trials comparing primaquine to no primaquine that led to the recommendation for the 14-day regimen.
We searched the Cochrane Infectious Diseases Group's Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE and LILACS up to 8 October 2013. We checked conference proceedings, trial registries and reference lists and contacted researchers and pharmaceutical companies for eligible studies.
Randomized controlled trials (RCTs) and quasi-RCTs comparing various primaquine dosing regimens with the standard primaquine regimen (15 mg/day for 14 days), or with no primaquine, in people with vivax malaria treated for blood stage infection with chloroquine.
We independently assessed trial eligibility, trial quality, and extracted data. We calculated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous data, and used the random-effects model in meta-analyses if there was significant heterogeneity. We assessed the overall quality of the evidence using the GRADE approach.
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.