Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of failure. We investigated the effect of chloroquine dose and adding primaquine on the risk of recurrence, in a range of vivax-endemic settings.
A systematic review identified prospective P. vivax clinical trials published between January 2000 and March 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methodology. Multivariable Cox regression analyses with random effects for study site investigated the role of chloroquine dose and primaquine use on rate of recurrence between day 7 and 42.
In total, 37 studies and 5,240 patients were included. 2,990 patients were treated with chloroquine alone, of whom 1,041 (34·8%) received a dose below the recommended 25 mg/kg. The risk of recurrence was 10·4% (95%CI 9·3-11·6) by day 28 and 32·4% (29·8-35·1) by day 42. After controlling for age, parasitaemia, relapse periodicity and gender, a 5mg/kg higher chloroquine dose reduced the rate of recurrence by 18% (Adjusted Hazard Ratio (AHR) 0·82, 0·69-0·97; p=0·0210). The greatest reduction was in children aged <5 years (AHR 0·59, 0·41-0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 1·4% (0·9-2·1) at day 28 and 4·9% (3·1-7·7) at day 42, a rate of recurrence 90% lower than those treated with chloroquine alone (AHR 0·10, 0·05-0·17; p<0·0001).
Chloroquine is commonly underdosed in the treatment of vivax malaria. Increasing the recommended dose of chloroquine to 30 mg/kg in children <5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine resistant P. vivax.