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Review
, 2015 (4), CD010458

Tafenoquine for Preventing Relapse in People With Plasmodium Vivax Malaria

Affiliations
Review

Tafenoquine for Preventing Relapse in People With Plasmodium Vivax Malaria

Senaka Rajapakse et al. Cochrane Database Syst Rev.

Abstract

Background: Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission. Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, there is some evidence of parasite resistance to the drug. Tafenoquine is a new alternative with a longer half-life.

Objectives: To assess the effects of tafenoquine in people with P. vivax infection.

Search methods: We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS. We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015.

Selection criteria: Randomized controlled trials (RCTs) in people with P. vivax malaria. Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency.

Data collection and analysis: All review authors independently extracted data and assessed trial quality. Meta-analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals. We assessed the quality of the evidence using the GRADE approach.

Main results: Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded. Tafenoquine dose comparisonsThree of the included trials compared eight different dosing regimens. Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow-up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence). Tafenoquine versus primaquine Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days. A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow-up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence)In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine.

Authors' conclusions: Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria. The drug is untested in pregnancy, children and in G6PD-deficient people. The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half-life may have more substantive consequences if given inadvertently to people with G6PD deficiency.

Conflict of interest statement

SR: none declared. CR: none declared. SDF: none declared.

Figures

Figure 1
Figure 1
PRISMA flow diagram indicating the process of inclusion and exclusion of studies.
Figure 2
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Figure 3
Figure 3
Forest plot of comparison: 1 TQ and CQ versus CQ alone, outcome: 1.2 Recurrent P. vivax parasitaemia by six months (excluding TQ doses < 300 mg).
Figure 4
Figure 4
Forest plot of comparison: 2 TQ versus PQ (both received CQ), outcome: 2.1 Recurrent P. vivax parasitaemia by six months (excluding TQ doses < 300 mg).
Analysis 1.1
Analysis 1.1
Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 1 Recurrent P. vivax parasitaemia by 6 months.
Analysis 1.2
Analysis 1.2
Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 2 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).
Analysis 1.3
Analysis 1.3
Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 3 Serious adverse events.
Analysis 1.4
Analysis 1.4
Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 4 Any adverse event by tafenoquine dose.
Analysis 1.5
Analysis 1.5
Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 5 Comparison by type of adverse event for tafenoquine 300 mg.
Analysis 1.6
Analysis 1.6
Comparison 1 Tafenoquine versus no hypnozoite treatment, Outcome 6 Comparison by type of adverse event for tafenoquine 600 mg.
Analysis 2.1
Analysis 2.1
Comparison 2 Tafenoquine versus primaquine, Outcome 1 Recurrent P. vivax parasitaemia by 6 months (excluding tafenoquine doses < 300 mg).
Analysis 2.2
Analysis 2.2
Comparison 2 Tafenoquine versus primaquine, Outcome 2 Serious adverse events.
Analysis 2.3
Analysis 2.3
Comparison 2 Tafenoquine versus primaquine, Outcome 3 Any adverse event by tafenoquine dose.
Analysis 2.4
Analysis 2.4
Comparison 2 Tafenoquine versus primaquine, Outcome 4 Comparison by type of adverse event for tafenoquine 300 mg.
Analysis 2.5
Analysis 2.5
Comparison 2 Tafenoquine versus primaquine, Outcome 5 Comparison by type of adverse event for tafenoquine 600 mg.
Analysis 2.6
Analysis 2.6
Comparison 2 Tafenoquine versus primaquine, Outcome 6 Comparison by type of adverse event for tafenoquine doses > 600 mg.

Update of

  • Cochrane Database Syst Rev. doi: 10.1002/14651858.CD010458

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References

References to studies included in this review

    1. Llanos‐Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, et al. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double‐blind, randomised, phase 2b dose‐selection study. Lancet 2014;383(9922):1049‐58. - PubMed
    1. Walsh DS, Looareesuwan S, Wilairatana P, Heppner DG Jr, Tang DB, Brewer TG, et al. Randomized dose‐ranging study of the safety and efficacy of WR 238605 (Tafenoquine) in the prevention of relapse of Plasmodium vivax malaria in Thailand. Journal of Infectious Diseases 1999;180(4):1282‐7. - PubMed
    1. Walsh DS, Wilairatana P, Tang DB, Heppner DG Jr, Brewer TG, Krudsood S, et al. Randomized trial of 3‐dose regimens of tafenoquine (WR238605) versus low‐dose primaquine for preventing Plasmodium vivax malaria relapse. Clinical Infectious Diseases 2004;39(8):1095‐103. - PubMed

References to studies excluded from this review

    1. Dow GS, McCarthy WF, Reid M, Smith B, Tang D, Shanks GD. A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic anti‐malarials in non‐immune individuals during deployment to a malaria‐endemic area. Malaria Journal 2014;13:49. - PMC - PubMed
    1. Edstein MD, Kocisko DA, Walsh DS, Eamsila C, Charles BG, Rieckmann KH. Plasma concentrations of tafenoquine, a new long‐acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis. Clinical Infectious Diseases 2003;37(12):1654‐8. - PubMed
    1. Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD. The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post‐exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific. Transactions of Royal Society of Tropical Medicine and Hygiene 2008;102(11):1095‐101. - PubMed
    1. Green JA, Patel AK, Patel BR, Hussaini A, Harrell EJ, McDonald MJ, et al. Tafenoquine at therapeutic concentrations does not prolong Fridericia‐corrected QT interval in healthy subjects. Journal of Clinical Pharmacology 2014;54(9):995‐1005. - PMC - PubMed
    1. Hale BR, Owusu‐Agyei S, Fryauff DJ, Koram KA, Adjuik M, Oduro AR, et al. A randomized, double‐blind, placebo‐controlled, dose‐ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum. Clinical Infectious Diseases 2003;36(5):541‐9. - PubMed

References to ongoing studies

    1. A Phase I Study to Investigate the Hemolytic Potential of tafenoquine in Healthy Subjects With Glucose‐6‐phosphate Dehydrogenase Deficiency and the Safety and Tolerability of tafenoquine in Acute Plasmodium vivax Malaria Patients With Glucose‐6‐phosphate Dehydrogenase Deficiency. Ongoing studyJuly 2009.
    1. A Randomized, Active‐control, Double‐blind, Double‐dummy Study to Evaluate the Efficacy and Safety of Tafenoquine for the Treatment of Plasmodium vivax in Adults. Ongoing studySeptember 2003.
    1. A Randomized, Double‐Blind, Double Dummy, Comparative, Multicenter Study to Assess the Incidence of Hemolysis, Safety, and Efficacy of Tafenoquine (SB‐252263, WR238605) Versus Primaquine in the Treatment of Subjects With Plasmodium Vivax Malaria. Ongoing studySeptember 2014.

Additional references

    1. Baird JK, Hoffman SL. Primaquine therapy for malaria. Clinical Infectious Diseases 2004;39(9):1336‐45. - PubMed
    1. Brueckner RP, Coster T, Wesche DL, Shmuklarsky M, Schuster BG. Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8‐aminoquinoline antimalarial. Antimicrobial Agents and Chemotherapy 1998;42(5):1293–4. - PMC - PubMed
    1. Brueckner RP, Lasseter KC, Lin ET, Schuster BG. First‐time‐in‐humans safety and pharmacokinetics of WR 238605, a new antimalarial. American Journal of Tropical Medicine and Hygiene 1998;58(5):645–9. - PubMed
    1. Carmona‐Fonseca J, Alvarez G, Maestre A. Methemoglobinemia and adverse events in Plasmodium vivax malaria patients associated with high doses of primaquine treatment. American Journal of Tropical Medicine and Hygiene 2009;80(2):188‐93. - PubMed
    1. Ehrman FC, Ellis JM, Young MD. Plasmodium vivax Chesson strain. Science 1945;101(2624):377. - PubMed

References to other published versions of this review

    1. Rajapakse S, Rodrigo C, Fernando SD. Tafenoquine for Plasmodium vivax malaria infection. Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/14651858.CD010458] - DOI

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