Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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 primaquineRelapse 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 primaquineThe 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.

Authors' conclusions: 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.

Figure 1

Study flow diagram: 2013 review update

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 4

Forest plot of comparison: 1 Primaquine: 5 days versus 14 days, outcome: 1.1 P. vivax parasitaemia > 30 days after starting primaquine.

Figure 5

Primaquine (5 days) plus chloroquine versus chloroquine: P. vivax parasitaemia detected > 30 days after starting primaquine.

Figure 6

Forest plot of comparison: 6 Chloroquine plus primaquine (14 days) versus chloroquine, outcome: 6.1 P. vivax parasitaemia detected > 30 days after starting primaquine.

Analysis 1.1

Comparison 1 Primaquine: 5 days versus 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.

Analysis 2.1

Comparison 2 Primaquine: 3 days versus 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.

Analysis 3.1

Comparison 3 Primaquine: 7 days versus 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.

Analysis 4.1

Comparison 4 Primaquine: weekly for 8 weeks versus daily for 14 days, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.

Analysis 5.1

Comparison 5 Primaquine 5 days versus no primaquine, Outcome 1 P. vivax parasitaemia > 30 days after starting primaquine.

Analysis 6.1

Comparison 6 Primaquine 14 days versus no primaquine, Outcome 1 P. vivax parasitaemia detected > 30 days after starting primaquine.