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Primaquine radical cure of Plasmodium vivax: a critical review of the literature

George K John1, Nicholas M Douglas12, Lorenz von Seidlein23, Francois Nosten145, J Kevin Baird16, Nicholas J White15 and Ric N Price127*

Author Affiliations

1 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

2 Global Health Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, NT 0811, Australia

3 Vivax Working Group, Asia-Pacific Malaria Elimination Network, Menzies School of Health Research, Darwin, NT, 0811, Australia

4 Shoklo Malaria Research Unit, Mae Sot, Tak, 63110, Thailand

5 Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, 10400, Thailand

6 Eijkman-Oxford Clinical Research Unit, Jalan Diponegoro No. 69, Jakarta, 10430, Indonesia

7 WorldWide Anti-malarial Resistance Network (WWARN), Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Old Road, Oxford, UK

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Malaria Journal 2012, 11:280  doi:10.1186/1475-2875-11-280

Published: 17 August 2012

Abstract

Background

Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax.

Methods

Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up.

Results

Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4–6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001).

Conclusions

Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.