Tafenoquine for travelers' malaria: evidence, rationale and recommendations

J Kevin Baird, J Kevin Baird

Abstract

Background: Endemic malaria occurring across much of the globe threatens millions of exposed travelers. While unknown numbers of them suffer acute attacks while traveling, each year thousands return from travel and become stricken in the weeks and months following exposure. This represents perhaps the most serious, prevalent and complex problem faced by providers of travel medicine services. Since before World War II, travel medicine practice has relied on synthetic suppressive blood schizontocidal drugs to prevent malaria during exposure, and has applied primaquine for presumptive anti-relapse therapy (post-travel or post-diagnosis of Plasmodium vivax) since 1952. In 2018, the US Food and Drug Administration approved the uses of a new hepatic schizontocidal and hypnozoitocidal 8-aminoquinoline called tafenoquine for the respective prevention of all malarias and for the treatment of those that relapse (P. vivax and Plasmodium ovale).

Methods: The evidence and rationale for tafenoquine for the prevention and treatment of malaria was gathered by means of a standard search of the medical literature along with the package inserts for the tafenoquine products Arakoda™ and Krintafel™ for the prevention of all malarias and the treatment of relapsing malarias, respectively.

Results: The development of tafenoquine-an endeavor of 40 years-at last brings two powerful advantages to travel medicine practice against the malaria threat: (i) a weekly regimen of causal prophylaxis; and (ii) a single-dose radical cure for patients infected by vivax or ovale malarias.

Conclusions: Although broad clinical experience remains to be gathered, tafenoquine appears to promise more practical and effective prevention and treatment of malaria. Tafenoquine thus applied includes important biological and clinical complexities explained in this review, with particular regard to the problem of hemolytic toxicity in G6PD-deficient patients.

Figures

Figure 1.
Figure 1.
Evolution of the 8-aminoquinoline hypnozoitocides, including the winnowing out of irreversible severe neurotoxicity of plasmocid and related compounds distinguished by fewer than four methylene groups separating the amino groups of the alkyl chain at the defining 8-amino position. Plasmochin and others (including primaquine) having at least four methylene groups exhibited no such neurotoxicity but instead reversible toxicity at sub-lethal doses involving principally hepatic, hematological and gastrointestinal systems
Figure 2.
Figure 2.
Antimalarial classes as guided by life cycle of the plasmodia
Figure 3.
Figure 3.
Schematic illustrating pitfalls and protections of suppressive (yellow dose indicators) or causal (orange dose indicators) chemoprevention of non-relapsing malaria like P. falciparum (top panel; red triangles and squares for inoculation and attack, respectively) or relapsing species like P. vivax (bottom panel; green triangles and squares)
Figure 4.
Figure 4.
Geographic distribution and prevalence of P. vivax (A) and P. falciparum (B) in 2010, reproduced here under Creative Commons license
Figure 5.
Figure 5.
Hypothesized relative attack rates in the months following radical cure illustrate possible impacts of variable risks of relapse or reinfection on the estimation hypnozoitocidal efficacy of tafenoquine (TQ) fixed at a presumed ‘actual’ 95% rate compared to a chloroquine (CQ) arm without hypnozoitocidal therapy (relapse and reinfection attacks)

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