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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

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

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
George K John, Nicholas M Douglas, Lorenz von Seidlein, Francois Nosten, J Kevin Baird, Nicholas J White, Ric N Price
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-280) contains supplementary material, which is available to authorized users.

Competing interest

JKB serves in an unpaid capacity on a board advising GSK on the clinical development of tafenoquine, a therapy aimed at replacing primaquine. He accepts travel support from GSK in connection with that appointment. All other authors: no conflicts. NJW is co-chairman of the WHO anti-malarial treatment guidelines committee. All other authors declare that they have no conflicts of interest.

Authors’ contribution

GKJ and RNP designed the study and searched the relevant literature. GKJ extracted and analyzed the clinical data and wrote the first draft of the manuscript. All authors appraised and revised the manuscript. All authors gave final approval for submission of the manuscript.

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.
Zusatzmaterial
Additional file 1: Search terms used for the literature review.(TIFF 73 KB)
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Additional file 2: Extracted data.(XLSX 47 KB)
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Additional file 3: Complete list of all articles included in the analysis.(PDF 87 KB)
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Additional file 4: Study design of articles included in the analysis.(PDF 69 KB)
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Additional file 5: Recurrence rates reported for all primaquine treatment arms.(PDF 75 KB)
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Additional file 6: Map of studies documenting the effectiveness of very low dose primaquine. Footnote: Adequate Responders (yellow icon): Recurrence rate < 10% in studies with greater than 6 weeks follow up; Poor responders (red icons): recurrence rate >10% at any time during follow up. Studies of returning US soldiers are placed at country of origin. Indeterminate studies and studies of induced malaria have been excluded. (TIFF 2 MB)
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Additional file 7: Map of studies documenting the effectiveness of low dose primaquine. Footnote: Adequate Responders (yellow icon): Recurrence rate < 10% in studies with greater than 6 weeks follow up; Poor responders (red icons): recurrence rate >10% at any time during follow up. Studies of returning US soldiers are placed at country of origin. Indeterminate studies and studies of induced malaria have been excluded. (TIFF 2 MB)
12936_2012_2461_MOESM7_ESM.tiff
Additional file 8: Map of studies documenting the effectiveness of high dose primaquine. Footnote: Adequate Responders (yellow icon): Recurrence rate < 10% in studies with greater than 6 weeks follow up; Poor responders (red icons): recurrence rate >10% at any time during follow up. Studies of returning US soldiers are placed at country of origin. Indeterminate studies and studies of induced malaria have been excluded. (TIFF 2 MB)
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Additional file 9: Severe adverse events reported.(PDF 58 KB)
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Additional file 10: Main findings of the literature review.(PDF 23 KB)
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Additional file 11: Key components in the design of studies of relapse prevention by primaquine in vivax malaria.(PDF 21 KB)
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Additional file 12: Clinical research priorities for optimising the radical cure of P. vivax.(PDF 14 KB)
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Authors’ original file for figure 1
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