Journal of Travel Medicine, 2018, 1–13

doi: 10.1093/jtm/tay110
Review

Review

Tafenoquine for travelers’ malaria: evidence, rationale

and recommendations
J. Kevin Baird, PhD*
Eijkman-Oxford Clinical Research Unit, Eijkman Institute of Molecular Biology, Jakarta 10430, Indonesia; and Nuffield
Department of Medicine, the Centre for Tropical Medicine and Global Health, University of Oxford, OX3 7FZ, UK
*To whom correspondence should be addressed. Email: kevin.baird@ndm.ox.ac.uk

Submitted 25 September 2018; Revised 17 October 2018; Editorial decision 21 October 2018; Accepted 30 October 2018

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 prac-
tice 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 hypno-
zoitocidal 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 tra-
vel 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.

Key words: Malaria, prevention, treatment, travelers, primaquine, tafenoquine, G6PD deficiency

Introduction illness posing a potentially mortal threat in non-immune

Each of the five species of malaria-causing plasmodial parasites patients.6 The notion of intrinsically benign or malignant species
naturally infecting humans often progress to threatening clinical of the plasmodia should be acknowledged as dangerous dogma
syndromes in malaria-naïve patients unless prompt diagnosis and the diagnosis of any malaria managed as a clinical emer-
and appropriate therapy first occurs. Death as an outcome of gency.7 Successfully preventing such emergencies in travelers
infection is confirmed in all of these species: Plasmodium falcip- merits the relatively complex and difficult clinical task of doing
arum, Plasmodium vivax, Plasmodium malariae, Plasmodium so practically and effectively.
ovale and Plasmodium knowlesi.1–5 Infections by some species Naturally acquired immunity, community-based measures of
may more rapidly and frequently progress to serious illness than prevention and control, along with local access to competent
others, but malaria in all its forms provokes a debilitating febrile healthcare provided by malaria—aware governments, together

© International Society of Travel Medicine, 2018. Published by Oxford University Press.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com
2 Journal of Travel Medicine

greatly mitigate the harm caused by these parasites in endemic 1978 during an era of historic neglect of antimalarial drug develop-
areas.8–10 In contrast, protection of relatively vulnerable trave- ment25,26 relative to the comparatively vigorous current efforts.27
lers almost wholly depends on the recommendations and prac- Tafenoquine thus lingered through fits and starts of clinical develop-
tices of travel medicine providers—local protections for them ment in the three decades that followed.28 Approximately 10 years
effectively do not exist beyond the passive benefit of reduced ago, dawning realization of the clinical and public health import-
transmission and risk. Among the agencies and experts offering ance of vivax malaria helped spur commitment to making tafeno-
the distinct advice to travelers and residents alike, strategic quine available for use (Bill and Melinda Gates Foundation,
thinking has historically been focused on the species once Medicines for Malaria Venture and GSK).29,30
known as ‘malignant tertian malaria’, P. falciparum. In contrast, Complex biology governs the rationale underpinning safe
‘benign tertian malaria’, P. vivax, was deeply neglected, and the and appropriate use of tafenoquine in travel medicine. The class
tools and advice for its prevention, treatment or control were effect of hemolytic toxicity in patients having the X-linked trait
inadequate.11–14 In 2015, the World Health Organization of glucose-6-phosphate dehydrogenase (G6PD) deficiency sub-
(WHO) acknowledged the mortal risk of vivax malaria and the stantially deepens the complexity of its use. This review aims to
neglect of it in public health and clinical medicine.15 explain these complexities along with the evidence and rationale
A great deal of recent work and progress begins to correct for potential roles of tafenoquine for the prevention or treat-
the problem of neglect of vivax malaria in endemic communi- ment of malaria.
ties,16 but travel medicine strategy and practices remain aimed
principally at falciparum malaria.17–19 Up to the present day,
suppressive chemoprophylaxis applying blood schizontocidal Essential Biology
drugs dominates travel medicine practice.20 A fundamental bio- The life cycles of the plasmodia guide chemotherapeutic and
logical distinction between falciparum and vivax malarias- chemopreventive strategies. The many stages of them are vari-
dormant liver stages called hypnozoites present in the latter and ably susceptible to antimalarial classes of drugs (Figure 2), most
absent in the former—explains the inadequacy of suppressive having class-specific therapeutic effects. Clinically applied blood
chemoprophylaxis alone against the malarias.21–23 Latent mal- schizontocidal drugs, for example, have no hypnozoitocidal
aria and the threat of relapse require additional (post-travel pre- activity. Nonetheless, cross-class effects among antimalarials
sumptive anti-relapse therapy (PART)) or alternative (causal occur, sometimes species-specific in manner; e.g. the blood schi-
prophylaxis) approaches to chemoprevention. zontocide chloroquine also exerts gametocytocidal activity in P.
Two regulatory events in the USA in 2018 offer potentially vivax but not P. falciparum.31 Tafenoquine may be unique
transformative changes in how travel medicine deals with the mal- among registered antimalarial compounds in having demon-
aria threat.24 The Food and Drug Administration (FDA) approved strable activity among all classes of antimalarials.32,33
a new 8-aminoquinoline drug called tafenoquine for uses in the All malarias derive from the bite of infectious anopheline
treatment or prevention of malaria: Krintafel™ (GlaxoSmithKline®, mosquitos (excepting congenital or transfusion/transplant
USA) or Arakoda™ (60 Degrees Pharmaceuticals® LLC, USA), malarias). Injected plasmodial tachysporozoites invade hepatic
respectively (Figure 1). The US Army discovered tafenoquine in cells, multiply as hepatic schizonts and after a week or more

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 pos-
ition. 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
Journal of Travel Medicine 3

Figure 2. Antimalarial classes as guided by life cycle of the plasmodia

Table 1. Characteristics of relapsing and non-relapsing malarias

Relapsing Non-relapsing

Species P. vivax, P. ovale, P. cynomolgia P. falciparum, P. malariae, P. knowlesib

Hypnozoites Present Absent
Clinical attacks/infection Variable, typically >3 1
Curative therapy Blood schizontocidal, Hypnozoitocidal Blood schizontocidal
Gametocytocidalc
Suppressive chemoprophylaxis Ineffective against relapses occurring post- Effective
chemoprophyaxis
Post-travel presumptive anti-relapse therapy Not indicated after causal prophylaxis but Not indicated
necessary after suppressive prophylaxis
Causal chemoprophylaxis Effective Effective

a
A natural zoonosis of Southeast Asian macaques confirmed in only a single patient but perhaps more common than now appreciated.
b
A natural zoonosis of Southeast Asian macaques confirmed in thousands of patients.
c
A single dose of 0.25 mg/kg primaquine to prevent onward transmission. Not recommended in relapsing malarias because hypnozoitocidal therapy also gametocytocidal.

emerge as infectious merozoites into the bloodstream where primaquine not considered here), whereas that of the relapsing
they again multiply asexually (schizogony) in red blood cells. malarias includes a hypnozoitocide. Strategy for the prevention of
Repeated cycles of that reproduction provoke the non-specific the malarias also invokes non-relapsing and relapsing biology and
cyclic symptoms of acute malaria; typically daily bouts of spik- antimalarial drug classes; suppressive chemoprophylaxis employs
ing fever and shaking chills, often accompanied by headache, blood schizontocides against asexual reproduction in blood,
nausea, vomiting and myalgia. Some of those parasites become whereas causal chemoprophylaxis applies hepatic schizontocides
circulating sexual forms called gametocytes that may infect feed- or hypnozoitocides in killing parasites before they mature to either
ing anophelines but provoke no illness. hepatic schizonts or hypnozoites (Figure 2). Widely used suppres-
The infective bite of the relapsing malarias, P. vivax and P. ovale, sive chemoprophylactic drugs do not interfere with hepatic devel-
includes bradysporozoites that become latent hepatic hypnozoites. opment, with the exception of the causal activity of atovaquone
The timing of their activation to hepatic schizogony and subsequent against hepatic schizonts of P. falciparum34,35 but not against hyp-
clinical attacks varies greatly, between a month and several years nozoites of P. vivax36,37 or those of Plasmodium cynomolgi in rhe-
after infection. In general, attacks occurring less than a month after sus macaques.38
infection derive from tachysporozoite-borne active hepatic schizonts, This review specifically considers the role of the new 8-
whereas after 1 month attacks probably derive from the delayed aminoquinoline called tafenoquine in travel medicine practice.
hepatic schizogony of bradysporozoite-borne activated hypnozoites. In terms of chemotherapy, only the relapsing malarias and hyp-
These clinical events are called primary attacks and relapses. nozoitocidal activity are relevant here. On the other hand, che-
The malarias infecting humans may be divided into relapsing moprevention engages all malarias and activity against the
and non-relapsing species, i.e. P. vivax and P. ovale, and P. falcip- hepatic stages of any plasmodial species, be those active schi-
arum, P. malariae, and P. knowlesi, respectively (Table 1). This zonts, latent hypnozoites, or, more probably, their respective
fundamental distinction defines essential features of the treatment earliest (<48 h) post-invasion forms.39 The broad spectrum
of the malarias; therapy of non-relapsing acute malarias involves activity of tafenoquine includes relatively potent blood schizon-
only blood schizontocidal drugs (and gametocytocidal single-dose tocidal effects,40 but its clinical use as such is not recommended.
4 Journal of Travel Medicine

Rationale for prioritized causal prophylaxis appropriate suppressive chemoprophylaxis—tends to obscure

Suppressive chemoprophylaxis of malaria with blood schizonto- the broader geographic dominance of P. vivax. Excepting rela-
cides like quinine, atabrine, chloroquine, doxycycline, mefloquine tively few and minor geographic areas (e.g. Haiti), endemic
and atovaquone–proguanil has successively dominated practice transmission of P. vivax occurs wherever P. falciparum occurs,
in travel medicine for over a century.41,42 This strategy served the including much of malarious Africa.62–64 Endemic transmission
intended purpose of effectively preventing attacks by what had of P. vivax extends well beyond the tropical range of P. falcip-
been considered the only intrinsically dangerous species, P. falcip- arum (e.g. to the Korean Peninsula).65 Once travelers are
arum. The inadequacy of chemoprophylactic suppression alone deemed to be in need of chemoprevention against malaria by
against the delayed attacks of the relapsing malarias has long estimated weight of risk of exposure,66,67 most of them will be
been understood and thoroughly demonstrated.43–46 Though not at risk of infection by the hypnozoites of P. vivax, P. ovale or
always prescribed or even recommended,20 post-travel PART both (Figure 4). There may thus be few travelers not benefiting
using hypnozoitocidal primaquine addressed that inherent inad- from an approach to chemoprophylaxis that prevents the form-
equacy. However, that practice also imposed G6PD-deficiency ation of latent hypnozoites and post-travel attacks.
risk management, along with the inconvenience and adherence The availability of tafenoquine offers the critical strategic
issues of 14 daily doses. Some authorities and experts have advantages of causal prophylaxis, along with practical advan-
recommended daily primaquine (0.5 mg/kg) during exposure tages over primaquine for that indication. Tafenoquine over-
under some circumstances as safe, well-tolerated and effective comes three of the four key disadvantages of primaquine in
causal prophylaxis (in non-pregnant, G6PD-normal travelers),47 comparison to most suppressive prophylaxis options: (i) chemo-
but with the important drawback of off-label use. Further, prima- prophylaxis is an approved indication; (ii) dosing is weekly rather
quine having poor activity against the asexual blood stages of P. than daily; and (iii) blood schizontocidal activity may mitigate
falciparum48 raises the specter of unmitigated prophylaxis break- prophylaxis breakthroughs. The relatively very long plasma half-
throughs. Primaquine as primary causal prophylaxis has thus not life of tafenoquine relative to primaquine (~15 days vs 6 h) con-
been widely adopted in travel medicine. fers many of its advantages. The key disadvantage is the 8-
While chemoprophylaxis of any sort against significant risk of aminoquinoline liability of hemolytic toxicity in G6PD-deficient
malaria imposes some obstacles and pitfalls, it is certainly preferred patients, and that problem is deepened by slow excretion. The
over no protection and may be less problematic than standby emer- safe use of tafenoquine or primaquine is nonetheless manageable
gency self-treatment practices.49–51 Figure 3 illustrates the practical by understanding G6PD deficiency and its diagnosis.
protections and pitfalls of suppressive prophylaxis against non-
relapsing (upper panel) and relapsing malarias (lower panel) relative
to those of causal prophylaxis. The failure to properly load suppres- G6PD deficiency
sive dosing before travel or to continue dosing sufficiently long after The inherited X chromosome-linked G6PD deficiency trait is the
travel results in attacks during and after travel in both types of most common human genetic abnormality and its genotypes and
malarias. Fully compliant loading and post-exposure suppressive frequencies vary tremendously.68 It tends to be absent in Native
dosing successfully prevents non-relapsing but not relapsing malaria Americans, present at low frequencies (<1%) among most
attacks delayed after travel. Causal prophylaxis during exposure Caucasians and prevalent among people residing in malaria-
(loading or post-exposure dosing is minimal), in contrast, effectively endemic nations (averaging 8%).69 The extent of harm caused by
prevents both types of malarias. Causal prophylaxis exceeds sup- daily primaquine as hypnozoitocide depends on dose, the variant
pressive approaches in terms of simplicity of use and thoroughness of G6PD deficiency involved, and whether hemi-, homo- or het-
of protection, but the good efficacy of fully compliant suppressive erozygous.70 Effects range from relatively mild and self-limiting
prophylaxis against P. falciparum has been broadly accepted as the to life-threatening. Caucasian, Middle Eastern and Asian peoples
standard-of-care in travel medicine. tend to have the most severely impaired G6PD deficiency var-
Acute falciparum malaria is unquestionably a dangerous infec- iants.71 In moderately deficient (40–60% of normal activity)
tion that may rapidly progress to complicated and severe disease G6PD-deficient heterozygous females having the moderately
syndromes in malaria-naïve patients. It does so in travelers more impaired Asian Mahidol variant, a single 300-mg dose of tafeno-
often than the other plasmodia,52 with the possible exception of P. quine proved slightly more hemolytic (nadir of ~23% Hb drop)
knowlesi.53 However, the notion of P. falciparum as the only spe- than a 14-day daily regimen of 15-mg primaquine in that trial
cies capable of such harm has been discredited with evidence, (~16% drop)72 or others (~13% Hb drop).73 Prescribing tafeno-
much of it only recently gathered.2–5,54–59 When the malarias are quine for any indication requires ruling out any G6PD deficiency,
allowed to progress to severe and complicated disease in travelers, excepting female heterozygotes having >70% of normal activity.
the frequency of death among them appears essentially equal, ~5– Conventional qualitative screening for G6PD deficiency prior to
10%.52 All of the plasmodia are intrinsically dangerous and poten- tafenoquine use may not suffice and quantitative testing is indicated
tially lethal. Chemoprophylaxis strategy aimed at some species but by standard laboratory spectrophotometric assay. Patients having
not others, unless absolutely necessary, fails reason and many <70% of normal G6PD activity may not receive tafenoquine.74
patients. Broad spectrum chemoprophylaxis against attacks by Qualitative screening, for example by the NADPH fluorescent spot
any plasmodial species, be those primary or relapsing, would test (FST) or newly available point-of-care rapid diagnostic tests for
potentially offer a conspicuously superior option. G6PD deficiency (RDT), lack sensitivity to deficiency above 30% of
The fact that P. falciparum acquired in Africa indeed causes normal activity.75–77 Although qualitative screening offers nearly
most (~70%) malaria in travelers19,60,61—a problem solved by 100% sensitivity and specificity for male hemizygotes, female
Journal of Travel Medicine 5

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)

homozygotes and female heterozygotes having <30% of normal active/inactive normal vs abnormal X-chromosomes and red blood
activity,78,79 the latter having 30–70% of normal G6PD activity cell mosaicism for G6PD deficiency.76 Recent efforts to develop sim-
will often screen as normal.80 The basis of this problem lies in the ple and practical quantitative point-of-care test technologies may
phenomenon of lyonization during embryonic development of soon bear devices that greatly increase access to such testing and
female heterozygotes resulting in apparently random frequencies of safe use of 8-aminoquinolines.81
6 Journal of Travel Medicine

Figure 4. Geographic distribution and prevalence of P. vivax (A) and P. falciparum (B) in 201065,120 reproduced here under Creative Commons
license

Impaired CYP2D6 metabolism body of evidence is as yet far from thorough or conclusive.
Clinical and laboratory evidence suggested that the efficacy of Tafenoquine activity may or may not come with the liability of
primaquine may depend on natural variation in cytochrome P-450 CYP2D6 dependency—decisive studies are needed to inform
2D6 (CYP2D6) isotype activity.82–84 In a trial of 177 Indonesian this important question.
patients with vivax malaria given directly observed high-dose
primaquine (0.5 mg/kg/day for 14 day) as PART in combination Weekly tafenoquine for causal prophylaxis
with artesunate, artesunate–pyronaridine or dihydroartemisinin– Tafenoquine was registered with the US FDA under the trade-
piperaquine, 26 (15%) experienced relapses during 1 year of name Arakoda™ by 60 Degrees Pharmaceuticals® (USA) in
follow-up free of reinfection risk.85 Among the 21 relapsing sub- 2018 with a labeled indication for chemoprevention of malaria
jects evaluated for CYP2D6 genotype and dextromethorphan in adult patients (≥18 year) confirmed to be G6PD-normal
metabolism phenotype, 20 exhibited significantly impaired (>70% of normal activity) and not pregnant, lactating or having
CYP2D6 activity.86 Relatively common impaired CYP2D6 alleles a history of psychoses.74 The drug is available as tablets con-
like *10 (in Asian people) coupled with other less frequent taining 100 mg base. A loading dose of 200 mg tafenoquine dai-
impaired alleles (e.g. *4, *5 or *41) appeared to explain most ly for 3 days during the week before travel is recommended,
therapeutic failures despite otherwise adequate dosing. followed by weekly maintenance doses of 200 mg commencing
Although tafenoquine activity against rodent hepatic schi- 7 days after the last loading dose. Upon return from travel, the
zonts seems to also depend on CYP2D6 activity,87 one rando- final dose should occur 7 days after the last maintenance dose
mized multi-center trial did not detect an association of taken in the malarious area.74
CYP2D6 genotypes with tafenoquine efficacy (but did with the The label for Arakoda™ includes an indication for ‘terminal
primaquine comparator arm).88 The efficacy of tafenoquine in prophylaxis’, an antiquated term for post-travel PART in con-
humans is not known to require metabolism by CYP2D6 or any nection with suppressive prophylaxis during travel.89 The term
other cytochrome P-450 isotype or monoamine oxidase, but this is not particularly apt for tafenoquine as Arakoda™ because it
Journal of Travel Medicine 7

is no more than a final weekly dose after travel rather than the incubation period of P. falciparum (i.e. less than several weeks) if
distinct dosing for PART with tafenoquine (i.e. 300 mg rather hepatic schizontocidal activity (causal) had been inadequate.
than 200 mg). Post-travel PART, i.e. terminal prophylaxis, is Nonetheless, given the proven causal activity of primaquine
not necessary with tafenoquine (or primaquine) causal prophy- against acute P. falciparum and acute or latent P. vivax mal-
laxis. On the other hand, when suppressive chemoprophylaxis aria,39 the structural relatedness of primaquine to tafenoquine
is used and post-travel PART is indicated, tafenoquine as a sin- (Figure 1), and evidence from an experiment in rhesus macaques
gle 300-mg dose may suffice in lieu of 14 days of primaquine challenged with P, cynomolgi sporozoites,38 a causal mechanism
(Table 2). of prophylaxis very likely pre-empts the suppressive activity of
The clinical experience with 200-mg weekly tafenoquine tafenoquine. Nonetheless, some workers argue that tafenoquine
prophylaxis is now limited to trials conducted in 462 non- prophylaxis may include a significant suppressive activity compo-
immune subjects naturally exposed to falciparum and vivax nent.97 A randomized, placebo-controlled trial at Gabon mea-
malaria in Southeast Asia90; 152 semi-immune subjects exposed sured the durability of post-treatment prophylaxis of tafenoquine
to falciparum malaria in holoendemic sub-Saharan Africa91,92 at variable daily doses administered for only 3 days: after 77
and 12 non-immune, malaria-naïve volunteers experimentally days, 14 of 82 placebos experienced P. falciparum, whereas 16/
challenged with blood stages of P. falciparum.74 Comparators 79, 3/86, 1/79 and 0/84 subjects did with daily doses of 31.25,
in these trials included mefloquine (with or without post-travel 62.5, 125 and 250 mg tafenoquine, respectively.98 Such protec-
PART with primaquine) or placebo (Table 3). There was no pla- tion very long after dosing logically hints at suppressive prophy-
cebo control in Trial 1 (Australian soldiers in Timor Leste), but laxis, but this is not relevant with weekly tafenoquine dosing.
a comparator of weekly mefloquine followed by post-travel Efficacious monthly dosing of tafenoquine during long-term tra-
PART with primaquine; four post-exposure attacks occurred vel, perhaps exploiting both causal and suppressive activities,
among subjects taking tafenoquine, and one also occurred in may yet be demonstrated.
that period among mefloquine-treated subjects. Another ana- The label for Arakoda™ warns that adverse reactions may be
lysis of this trial mathematically derived a hypothetical malaria delayed in onset or prolonged in duration due to the relatively
attack rate (8%) and estimated 100% protective efficacies of very long plasma half-life of tafenoquine.99 The listed warnings
tafenoquine or mefloquine against primary attacks.93 The and precautions include hemolytic anemia, G6PD deficiency in
placebo-controlled trial of tafenoquine prophylaxis in Kenyan pregnancy and lactation, methemoglobinemia, psychiatric effects
adults91 showed 86% protective efficacy during 15 weeks of and hypersensitivity reactions. An integrated safety analysis by
heavy exposure to risk of P. falciparum (Trial 2, Table 3). the developers of Arakoda™ reported that diarrhea, nausea,
Another trial in Ghana also included a placebo control but with vomiting, sinusitis, gastroenteritis and back/neck pain occurred at
a mefloquine comparator (Trial 3, Table 3):92 after 12 weeks higher frequencies (≥1%) relative to placebo; only the latter two
the protective efficacy of tafenoquine or mefloquine was 87% occurring at >5%.100 Two trials followed up on the observed
for each for P. falciparum. A separate analysis of these African high rate (93%) of mild reversible vortex keratopathy and retinal
trials estimated 94% and 95% protective efficacies for tafeno- abnormalities (39%) in the subjects of the trial in Southeast Asia
quine and mefloquine, respectively.94 The African studies did and Australia91 and reported no concerns with regard to func-
not assess efficacy against late attacks by relapsing malarias. tional visual impairment.101,102 The 6-month limitation on tafe-
Shanks95 explained the limitations and obstacles to conducting noquine prophylaxis in the Arakoda™ label stems from a lack of
chemoprophylaxis trials. While head-to-head trials of the data rather than any indication of harm beyond that period.
chemoprophylactic options against primary and delayed attacks Necessity in practice with tafenoquine will likely extend that
would be ideal, they are also unlikely to be possible. exposure period, and the reporting of adverse events in practice
No clinical trial of tafenoquine has definitively demonstrated will later inform evidence-based limitations of use (https://www.
a causal vs suppressive prophylaxis mechanism. An early human fda.gov/safety/MedWatch/default.htm).
challenge trial demonstrated a single 600 mg dose of tafenoquine For most G6PD-normal, non-pregnant adult travelers at sub-
successfully prevented P. falciparum in three of four subjects chal- stantial risk of any malaria, weekly tafenoquine as causal prophy-
lenged.96 At such a dose, slowly eliminated tafenoquine would laxis provisionally (pending greater clinical experience with it)
have exerted blood schizontocidal activity over the normal offers a superior option to either causal daily primaquine or any

Table 2. Chemoprophylactic strategies and agents

Chemoprophylaxis strategy

Suppressive Causal

Agent Mefloquine Doxycycline Atovaquone–proguanil Primaquine Tafenoquine

Dosing Weekly Daily Daily Daily Weekly
Post-exposure PART required Yes Yes Yes No No
Pregnancy Yes No No No No
G6PD-deficient safety Yes Yes Yes No No
Children Yes No Yes Yes Insufficient evidence
Parasite resistance Yes Yes Yes No Improbable
CYP-dependent No evidence No evidence No evidence Yes Insufficient evidence
8 Journal of Travel Medicine

Table 3. Human trials of 200 mg weekly tafenoquine for prophylaxis against malaria

Trial 1 Trial 2 Trial 3 Trial 4

Location Timor Leste/Australia Kenya Ghana Australia

Exposure 6mo meso-endemic P. falciparum and P. vivax; 15 weeks exposure to 12 weeks exposure to Experimental P.
6mo post-exposure holoendemic P. holoendemic P. falciparum falciparum blood
falciparum stages
Subjects Australian soldiers Resident adults Resident adults (excluding Malaria-naïve adults
reproductive age females)
Number of TQ = 462 TQ = 61 TQ = 91 TQ = 12
subjects and MQ + PQ = 153 Placebo = 62 MQ = 46 Placebo: 4
armsa Placebo = 94
Protective Not estimable without placebo; 5 attacks 86% TQ = 87% 100%
Efficacy occurred, all post-exposure; 4 in TQ group MQ = 87%
Reference 87 88 89 71

a
TQ, tafenoquine administered weekly 200 mg; MQ, mefloquine administered weekly 250 mg; PQ, primaquine administered daily 30 mg for 14 days immediately following travel.

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)

suppressive malaria prophylactic regimen (weekly or daily with Single-dose tafenoquine for radical cure of relapsing
or without post-travel PART). It is compatible with both short- malaria
notice or short-duration travel and particularly favored where The introduction of tafenoquine into practice as a hypnozoitoci-
endemic vivax or ovale malaria transmission occurs. Mainstream dal 8-aminoquinoline requires examination of the therapeutic
use of tafenoquine for the prevention of malaria in travelers principles at work. The primaquine standard-of-care, problematic
offers a potential solution to the problem of delayed attacks by as it may be, defines those with decades of experience and many
the relapsing malarias. millions of patients.103–106 Primaquine nonethless imposes the

SUMMARY BOX 1. KEY POINTS ON TAFENOQUINE PROPHYLAXIS IN TRAVEL MEDICINE

• Suppressive malaria prophylaxis standard-of-care is not adequate to the threat of delayed attacks after travel by the
relapsing malarias.
• Relapsing malarias occur wherever there is falciparum malaria, with few and minor exceptions.
• Causal prophylaxis is effective against all malarias and prevents delayed attacks after travel.
• Causal prophylaxis is suitable for both short-notice and short-duration travel.
• Tafenoquine is a new drug that offers the advantages of causal prophylaxis with a weekly dosing regimen.
• Tafenoquine is hemolytically toxic to patients having inherited G6PD deficiency, so is prohibited in those patients along
with pregnant and lactating women. Safety in children is not yet established.
Journal of Travel Medicine 9

Table 4. Randomized clinical trials of tafenoquine for PART against vivax malaria

Trial 1 Trial 2 Trial 3

Location Multi-centers in Asia, Africa, and Multi-centers in Asia, Africa and Multi-centers in Asia, Africa and
Americas Americas Americas
Subjects Adult non-pregnant G6PD-normal Adult non-pregnant G6PD-normal Adult non-pregnant G6PD-normal
residents with acute vivax malaria residents with acute vivax malaria residents with acute vivax malaria
Treatment arms, and TQ + CQ = 57 TQ + CQ = 260 TQ + CQ = 166
numbers of subjectsa PQ + CQ = 50 PQ + CQ = 129 PQ + CQ = 85
Placebo + CQ = 54 Placebo + CQ = 133
% Recurrence-free after TQ + CQ = 89 TQ + CQ = 62 TQ + CQ = 73
6 months PQ + CQ = 77 PQ + CQ = 70 PQ + CQ = 75
Placebo + CQ = 38 Placebo + CQ = 28
Reference 105 106 106

a
TQ, 300 mg single dose tafenoquine; CQ, 1500 mg chloroquine in three daily doses; PQ, 15 mg primaquine daily for 14 days.

difficulties of unknown mechanism of therapeutic activity against Ethiopia, Thailand, Cambodia and the Philippines (Trials 1 and
a cryptic and highly nuanced stage of some plasmodia—the hyp- 2, Table 4).110,111 A total of 187 subjects in those trials received
nozoite—coupled with a vitally important hemolytic toxicity chloroquine and a placebo of tafenoquine. Subjects were fol-
problem also of unknown mechanism in patients having a highly lowed for recurrent infections for six months. A total of 226 of
prevalent and diverse genetic abnormality, G6PD deficiency. 317 (71%) subjects did not experience recurrence within 6
Estimates of primaquine efficacy as impacted by parasite biology, months of tafenoquine and chloroquine therapy, whereas 79 of
epidemiology and partner blood schizontocides imposes great 187 (42%) subjects treated with chloroquine and placebo did so.
complexity of interpretation.107 These issues all also bear on tafe- In a third trial lacking a placebo control, tafenoquine (n = 166)
noquine and its use in radical cure of the relapsing malarias. or primaquine (n = 85) combined with chloroquine resulted in
Estimates of the efficacy of hypnozoitocides like tafenoquine 73% and 75% remaining free of recurrence for 6 months (Trial
are subject to important confounding factors. The natural acti- 3, Table 4), consistent with non-inferiority of single-dose tafeno-
vation of hypnozoites typically occurs over months following quine relative to daily 15 mg primaquine for 14 days.110
infection.108 When relapse occurs in the presence of risk of An important factor regarding hypnozoitocidal therapy bear-
reinfection, these two sources of acute malaria temporally min- ing upon both efficacy and safety is co-administration with var-
gle and no molecular laboratory technology differentiates them. ied blood schizontocidal therapies. Indeed, the discovery effort
Post-hypnozoitocidal recurrences in endemic areas may thus be leading to primaquine stemmed from an unexpected drug–drug
represented by both therapeutic failures (relapse) and the pri- interaction (DDI) between atabrine (mepacrine) and plasmochin
mary attacks of mosquito-borne reinfection—recrudescence (pamaquine) disqualifying co-administration for radical cure.112
with blood schizontocidal failure may also occur but is not con- The developers of plasmochin and primaquine each reported
sidered here. The rates of both relapse and reinfection naturally DDI phenomena with varied partner blood schizontocides
vary widely across endemic zones and each may impact inher- impacting efficacy, safety or both. Tafenoquine has thus far
ently variable estimates of hypnozoitocidal efficacy. Figure 5 been examined only in combination with chloroquine in vivax
presents hypothetical rates of each in high and low transmission malaria patients. However, it was evaluated with several distinct
settings in order to illustrate these potential impacts. High trans- partner blood schizontocides against P. cynomolgi relapses in
mission with low relapse risk (e.g. <30%) may greatly under- rhesus macaques.113 Those investigators reported a 10-fold
estimate efficacy (left panels), an effect mitigated by high relapse increase in tafenoquine efficacy when administered with chloro-
risk (e.g. >70%), especially where there is low risk of reinfection quine, mefloquine or artemether–lumefantrine compared to tafe-
(right panels). Reported estimates of efficacy from endemic noquine alone. Over 60 years ago, Alving et al. reported
areas are thus not absolute but reported as the fraction of essentially similar findings with primaquine given concurrent vs
patients not experiencing a recurrent parasitemia during months consecutive quinine or chloroquine.114 How these purely blood
of follow-up, often relative to a hypnozoitocidal comparator or schizontocidal drugs so dramatically impact the hypnozoitocidal
placebo control group (also called a relapse control). efficacy of 8-aminoquinolines remains unknown.
Conducting treatment and follow-up where reinfection does not While chloroquine or artemether–lumefantrine did not sig-
occur and with a relapse control arm largely resolves these nificantly impact tafenoquine pharmacokinetics in healthy sub-
ambiguities.85,109 Such a trial for tafenoquine has yet to be com- jects, dihydroartemisinin–piperaquine increased the Cmax of
pleted, though one is in progress in Indonesia in 2018. tafenoquine by 38%, the area under the concentration (AUC)
The two multi-center, double-blind and placebo-controlled curve by 12%, and the plasma half-life by 29%.115,116
randomized clinical trials estimating efficacy of tafenoquine at a Tafenoquine did not appear to impact the pharmacokinetics or
single dose of 300 mg combined with standard chloroquine ther- dynamics of chloroquine, artemether–lumefantrine, or dihy-
apy (1500 mg base over 3 days) included 317 subjects thus dosed droartemisinin–piperaquine. The FDA label for Krintafel™ cites
against naturally acquired P. vivax infections in Brazil, Peru, chloroquine as an example of appropriate companion therapy,
10 Journal of Travel Medicine

implicitly allowing for other partner blood schizontocides for Conclusions

radical cure.110 The data from P. cynomolgi in macaques seem
The availability of tafenoquine for the prevention and treatment
to affirm that view so far as mefloquine and artemether–lume-
of malaria appears to offer potentially transformative new
fantrine are concerned.112
options in the practice of travel medicine. These applications
The package insert for Krintafel™ expresses an indicated use
strictly require reliable screening for G6PD deficiency, like the
in radical cure of P. vivax malaria in patients at least 16 years
current standard of responsible care involving primaquine for
of age who are also receiving companion blood schizontocidal
causal prophylaxis or for post-travel or post-diagnosis PART in
therapy.111 The warnings and precautions expressed therein are
travelers. Excepting travel to the very few malarious areas
essentially similar to those for Arakoda™ (see above). Both
where infection by hypnozoites is highly improbable, G6PD
labels warn of serious psychotic adverse reactions having
screening should be acknowledged as indicated in any traveler
occurred at the indicated dose (for Krintafel™) or higher dosing
taking any chemoprophylactic option. Avoidance of G6PD
(for Arakoda™) in patients with a history of psychoses, along
screening with non-hemolytic suppressive chemoprophylactics
with serious hypersensitivity events (e.g. angioedema).74,111
(without post-travel PART) invites risk of post-travel attacks.
Tafenoquine (as Arakoda™ or Krintafel™) may or may not be
No species of plasmodia is intrinsically benign. They all merit
suited to patients with psychiatric histories; the evidence needed
the diligence and relative difficulty of preventing them.
to definitively inform that question is lacking. In the instance of
Tafenoquine offers G6PD-normal and non-pregnant adults a
primaquine, there have been no significant clinical neurotoxicity
convenient, safe, well-tolerated and efficacious means of pre-
signals after decades of use.117,118 Indeed, in the defining neuro-
venting all malarias during travel or treating those that relapse
toxicological studies of 8-aminoquinolines in rhesus macaques,
after travel. The important work needed to assure the safety of
severe irreversible brainstem neuronal injury occurred only
tafenoquine in children is in progress, along with appropriate
among compounds of the plasmocid (or Rhodoquine) subclass
formulation for them. Far broader clinical experience with tafe-
(Figure 1).119 Among the plasmochin (or pamaquine) subclass
noquine will have to accrue before fully understanding both its
of 8-aminoquinolines (all 8-aminoquinolines that advanced to
advantages and limitations, but its promise certainly merits such
human clinical trials, including primaquine and, later, tafeno-
accrual.
quine), no such neurotoxicity occurred.
In summary, adult G6PD-normal non-pregnant or lactating Conflict of interest: None declared.
patients diagnosed with acute P. vivax malaria, or those return-
ing from travel of risk without causal prophylaxis, a single
300 mg dose of tafenoquine provides safe, well-tolerated, and Disclaimer
efficacious PART. Post-diagnosis PART may be confidently
combined with chloroquine, mefloquine, or artemether–lume- The author served as a paid consultant to GlaxoSmithKline®
fantrine. Post-travel PART should consider the apparently con- (GSK, UK) in support of the application of Krintafel™ for regis-
spicuous dependency of tafenoquine efficacy on the presence of tration with the US FDA. His laboratory in Jakarta, Indonesia,
select blood schizontocides as convincingly demonstrated in the today conducts a pivotal clinical trial of Krintafel™ for radical
P. cynomolgi animal model. Tafenoquine without a companion cure of vivax malaria for which GSK is the sponsor. He receives
blood schizontocide possibly not killing hypnozoites at pre- no personal financial incentive or award for that work from
scribed dose merits clinical caution and scientific attention. GSK or any other organization. The author holds no financial
More details are available in the FDA Advisory Committee interest in GSK or any of its products. At the invitation of 60
Briefing Document for Krintafel™: https://www.fda.gov/ Degrees Pharmaceuticals® (USA), the author provided testimony
downloads/advisorycommittees/committeesmeetingmaterials/ to the US FDA favorable to the registration of Arakoda™ for
drugs/anti-infectivedrugsadvisorycommittee/ucm612875.pdf chemoprevention of malaria, for which he received no financial

SUMMARY BOX 2. KEY POINTS ON TAFENOQUINE RADICAL CURE IN TRAVEL MEDICINE

• Suppressive malaria prophylaxis standard-of-care requires post-travel presumptive anti-relapse therapy (PART) to des-
troy latent hypnozoites and prevent delayed attacks in the months following travel.
• A diagnosis of acute relapsing malaria (P. vivax or P. ovale) in any patient requires PART to destroy latent hypnozoites
and prevent subsequent attacks by them.
• Primaquine has been the standard-of-care for PART as 14 daily doses of 0.5 mg/kg for the past 66 years.
• Tafenoquine is a new drug with an indication for post-travel or post-diagnosis PART against relapsing malarias as a sin-
gle adult dose of 300 mg.
• Tafenoquine is, like primaquine, hemolytically toxic to patients having inherited G6PD deficiency, so is prohibited in
those patients along with pregnant and lactating women. Safety in children is not yet established.
Journal of Travel Medicine 11

compensation or award. He holds no financial interest in that 20. Baird JK. Management of Plasmodium vivax risk and illness in tra-
drug, its manufacturer or any of its products. velers. Trop Dis Travel Med Vaccines 2017; 3:7.
21. Mühlberger N, Jelinek T, Gascon J et al. Epidemiology and clinical
features of vivax malaria imported to Europe: sentinel surveillance
data from TropNetEurop. Malar J 2004; 3:5.
References 22. Steinhardt LC, Magill AJ, Arguin PM. Review: malaria chemo-
1. Newton CR, Taylor TE, Whitten RO. Pathophysiology of fatal fal- prophylaxis for travellers to Latin America. Am J Trop Med Hyg
ciparum malaria in African children. Am J Trop Med Hyg 1998; 2011; 85:1015–24.
58:673–83. 23. Schwartz E, Parise M, Kozarsky P, Cetron M. Delayed onset of
2. Park SW, Kim DW, Park JW et al. A case of fatal Plasmodium malaria – implications for chemoprophylaxis in travellers. N Engl
vivax malaria with multiple-organ failure. Infect Chemother 2005; J Med 2003; 349:1510–16.
37:111–5. 24. Tan KR, Hwang J. Tafenoquine receives regulatory approval in U.
3. Groger M, Fischer HS, Veletzky L, Lalremruata A, Ramharter M. S. for prophylaxis of malaria and radical cure of Plasmodium
A systematic review of the clinical presentation, treatment, and vivax. J Travel Med 2018. doi:10.1093/jtm/tay071.
relapse characteristics of human Plasmodium ovale malaria. Malar 25. Gutteridge WE. Antimalarial drugs currently in development. J R
J 2017; 16:112. Soc Med 1989; 17:63–6.
4. Collins WE, Jeffery GM. Plasmodium malariae: parasite and dis- 26. Davidson DE Jr, Ager AL, Brown JL, Chapple FE, Whitmire RE,
ease. Clin Microbiol Rev 2007; 20:579–92. Rossan RN. New tissue schizontocidal antimalarial drugs. Bull
5. Rajahram G, Barber BE, William T, Menon J, Anstey NM, Yeo World Health Organ 1981; 59:463–79.
TW. Deaths due to Plasmodium knowlesi malaria in Sabah, 27. Ashley EA, Phyo AP. Drugs in development for malaria. Drugs
Malaysia: association with reporting as P. malariae and delayed 2018; 78:861–79.
parenteral artesunate. Malar J 2012; 11:284. 28. Peters W. The evolution of tafenoquine – antimalarial for a new
6. Kain KC, Harrington MA, Tennyson S, Keystone JS. Imported millennium? J R Soc Med 1999; 92:345–52.
malaria: prospective analysis of problems in diagnosis and manage- 29. Kitchener S, Nasveld P, Edstein MD. Tafenoquine for the treat-
ment. Clin Infect Dis 1998; 27:142–9. ment of current Plasmodium vivax malaria. Am J Trop Med Hyg
7. Baird JK, Nelwan J, Taylor WR. Approach to the patient with 2007; 76:494–6.
malaria. In: Keystone JS, Kozarsky PE, Connor BA, Nothdurft 30. Crockett M, Kain KC. Tafenoquine: a promising new antimalarial
HD, Leder K, Mendelson M (eds). Travel Medicine, 4th edn. agent. Expert Opin Investig Drugs 2007; 16:705–15.
Elsevier, 2019 Chapter 17. 31. Jeffery GM. Infectivity of mosquitoes of Plasmodium vivax follow-
8. Tediosi F, Lengeler C, Castro M et al. Chapter 13: Malaria con- ing treatment with chloroquine and other antimalarials. Am J Trop
trol. In: Holmes KK, Bertozzi S, Bloom BR, and Jha P (eds). Major Med Hyg 1958; 7:207–11.
Infectious Diseases. Disease Control Priorities, 3rd edn, Vol. 6. 32. Peters W, Robinson BL, Milhous WK. The chemotherapy of rodent
Washington: DC: World Bank, 2017, pp. 347–364. malaria. LI. Studies on a new 8-aminoquinoline, WR 238,605.
9. Bhatt S, Weiss DJ, Cameron E et al. The effect of malaria control Ann Trop Med Parasitol 1993; 87:547–52.
on Plasmodium falciparum in Africa between 2000 and 2015. 33. Coleman RE. Sporontocidal activity of the antimalarial WR-
Nature 2015; 526:207–11. 238605 against Plasmodium berghei ANKA in Anopheles stephen-
10. Cibulskis RE, Alonso PE, Aponte J et al. Malaria: global progress si. Am J Trop Med Hyg 1990; 42:196–2015.
2000–2015 and future challenges. Infect Dis Poverty 2016; 9:61. 34. Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P.
11. Mendis K, Sina BJ, Marchesini P, Carter R. The neglected burden Prophylactic activity of atovaquone against Plasmodium falcip-
of Plasmodium vivax malaria. Am J Trop Med Hyg 2001; 64: arum in humans. Am J Trop Med Hyg 1999; 60:831–6.
97–106. 35. Berman JD, Nielsen R, Chulay JD et al. Causal prophylactic activ-
12. Baird JK. Neglect of Plasmodium vivax malaria. Trends Parasitol ity of atovaquone-proguanil (Malarone) in a human challenge
2007; 23(11). PMID: 17933585. model. Trans R Soc Trop Med Hyg 2001; 95:429–32.
13. Price RN, Tjitra E, Guerra CA, Yeung S, White NJ, Anstey NM. 36. Maguire JD, Llewellyn DM. Relapsing malaria after 6 months of
Vivax malaria: neglected and not benign. Am J Trop Med Hyg daily atovaquone-proguanil in Afghanistan: the case for expanded
2007; 77:79–87. use of primaquine as a causal prophylactic. J Travel Med 2007;
14. Bassat Q, Velarde M, Mueller I et al. Key knowledge gaps for 14:411–14.
Plasmodium vivax control and elimination. Am J Trop Med Hyg 37. Metlzer E, Rahav G, Schwartz E. Vivax malaria chemoprophy-
2016; 95:62–71. laxis: the role of atovaquone-proguanil compared to other options.
15. Carlton JM, Sina BJ, Adams JH. Why is Plasmodium vivax a Clin Infect Dis 2018; 66:1751–5.
neglected tropical disease? PLoS Negl Trop Dis 2011; 5:e1160. 38. DiTusa C, Kozar MP, Pybus B et al. Causal prophylactic efficacy
16. World Health Organization. World Malaria Report 2017. Geneva; of primaquine, tafenoquine, and atovaquone-proguanil against
2018. Geneva: World Health Organization. ISBN: 978 92 4 Plasmodium cynomolgi in a rhesus monkey model. J Parasitol
156552 3. 2014; 100:671–3.
17. Freedman DO, Chen LH, Kozarsky PE. Medical considerations 39. Baird JK, Fryauff DJ, Hoffman SL. Primaquine for the prevention
before international travel. N Engl J Med 2016; 375:247–60. of malaria in travelers. Clin Infect Dis 2003; 37:1659–67.
18. Boggild A, Brophy J, Charlebois P et al. Summary of recommenda- 40. Nasveld P, Kitchener S. Treatment of acute vivax malaria with
tions for the prevention of malaria by the Committee to Advise on tafenoquine. Trans R Soc Trop Med Hyg 2005; 99:2–5.
Tropical Medicine and Travel (CATMAT). Can Commun Dis Rep 41. Shanks GD. Historical review: problematic malaria prophylaxis
2014; 40:118–32. with quinine. Am J Trop Med Hyg 2016; 95:269–72.
19. PHE Advisory Committee for Malaria Prevention for UK 42. Arguin PM, Magill AJ. For the record: a history of malaria chemo-
Travelers. Guidelines for malaria prevention in travelers from the prophylaxis. https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-
UK: 2017; 2017. London: Public Health England; 146pp. diseases-related-to-travel/emfor-the-record-a-history-of-malaria-
chemoprophylaxisem. Visited 13 September 2018.
12 Journal of Travel Medicine

43. Sinton JA, Smith S, Pottinger D. Studies on malaria with special 64. Brazeau NF, Whitesell A, Doctor SM et al. Plasmodium vivax infec-
reference to treatment. XII. Further researches into the treatment tions in Duffy-negative individuals in the Democratic Republic of
of chronic benign tertian malaria with plasmoquine and quinine. the Congo. Am J Trop Med Hyg 2018. doi:10.4269/ajtmh.18-0277.
Indian J Med Res 1929; 20:793–814. 65. Gething PW, Elyazar IR, Moyes CL et al. A long neglected world
44. Shannon JA. Chemotherapy in malaria. Bull N Y Acad Med 1946; map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis
22:345–57. 2012; 6:e1814.
45. Centers for Disease Control. Malaria among US military personnel 66. Schlagenhauf P, Petersen E. Malaria chemoprophylaxis: strategies
returning from Somalia, 1993. MMWR Morb Mortal Wkly Rep for risk group. Clin Microbiol Rev 2008; 21:466–72.
1993; 42:524–6. 67. Davlantes EA, Tan KR, Arguin PM. Quantifying malaria risk in
46. Krafts K, Hempelmann E, Skorska-Stania A. From methylene blue travelers: a quixotic pursuit. J Travel Med 2017; 24(6). doi10.
to chloroquine: a brief review of the development of antimalarial 1093/jtm/tax066.
therapy. Parasitol Res 2012; 111:1–6. 68. Luzzatto L, Seneca E. G6PD deficiency: a classic example of
47. Kolifarhood G, Raeisi A, Ranjbar M et al. Prophylactic efficacy of pharmacogenetics with on-going clinical implications. Br J
primaquine for preventing Plasmodium falciparum and Haematol 2014; 164:469–80.
Plasmodium vivax parasitemaemia in travelers: a meta-analysis 69. Howes RE, Piel FB, Patil AP et al. G6PD deficiency prevalence esti-
and systematic review. Travel Med Infect Dis 2017; 17:5–18. mates of affected populations in malaria endemic countries: a geos-
48. Arnold J, Alving AS, Hockwald RS et al. The antimalarial action tatistical model-based map. PLoS Med 2012; 9:e1001339.
of primaquine against the blood and tissue stages of falciparum 70. World Health Organization Evidence Review Group. Point-of-care
malaria (Panama P-F-6 strain). J Lab Clin Med 1955; 46:391–7. testing to support safe use of primaquine for the treatment of vivax
49. Flaherty GT, Walden LJ, Townend M. Travel medicine physician malaria. Malaria Policy Advisory Committee Meeting, 5-7 March,
adherence to guidelines for the emergency self-treatment of mal- 2015, Geneva, Switzerland. WHO/HTM/GMP/MPAC/2015.6.
aria. J Travel Med 2016; 23(5). doi:10.1093/jtm/taw036. http://www.who.int/malaria/mpac/mpac-march2015-erg-g6pd.pdf
50. Behrens R. Standy emergency treatment of malaria for travelers to accessed on 15 September 2018.
low transmission destinations: does it make sense or save lives? 71. Howes RE, Dewi M, PIel FB et al. Spatial distribution of G6PD
J Travel Med 2017; 24(5). doi:10.1093/jtm/tax034. deficiency variants across malaria-endemic regions. Malar J 2013;
51. Boubaker R, Harard Fossati A, Meige P et al. Malaria preven- 12:418.
tion strategies and recommendations from chemoprophylaxis to 72. Rueangweerayut R, Bancone G, Harrell EJ et al. Hemolytic poten-
stand-by emergency treatment: a 10-year prospective study in a tial of tafenoquine in female volunteers heterozygous for glucose-6-
Swiss travel clinic. J Travel Med 2017; 24(5). doi:10.1093/jtm/ phosophate dehydrogenase (G6PD) deficiency (G6PD Mahidol
tax043. variant) versus G6PD-normal volunteers. Am J Trop Med Hyg
52. Hwang J, Cullen CA, Kachur SP, Arguin PM, Baird JK. Severe 2017; 97:702–11.
morbidity and mortality risk from malaria in the United States, 73. Chu CS, Bancone G, Moore KA et al. Haemolysis in G6PD hetero-
1985-2011. Open Forum Infect Dis 2014; 1:ofu034. zygous females treated with primaquine for Plasmodium vivax
53. Barber BE, Grigg MJ, Piera KA et al. Intravascular haemolysis in malaria: a nested cohort in a trial of radical curative regimens.
severe Plasmodium knowlesi malaria: association with endothelial PLoS Med 2017; 14:e1002224.
activation, microvascular dysfunction, and acute kidney injury. 74. Arakoda™ package insert. 60 Degrees Pharmaceuticals LLC,
Emerg Microbes Infect 2018; 7:106. Washington, DC; 2018. https://www.accessdata.fda.gov/drugsatfda_
54. Anstey NM, Douglas NM, Poespoprodjo JR, Price RN. docs/label/2018/210607lbl.pdf
Plasmodium vivax: clinical spectrum, risk factors and pathogen- 75. Baird JK, Dewi M, Subekti D, Elyazar I, Satyagraha AW.
esis. Adv Parasitol 2012; 80:151–202. Noninferiority of glucose-6-phosphate dehydrogenase deficiency
55. Baird JK. Evidence and implications of mortality in acute diagnosis by a point-of-care rapid test vs the laboratory fluorescent
Plasmodium vivax malaria. Clin Microbiol Rev 2013; 26:36–57. spot test demonstrated by copper inhibition in normal human red
56. Naing C, Whittaker MA, Wai VN, Mak JW. Is Plasmodium vivax blood cells. Transl Res 2015; 165:677–88.
malaria a severe malaria? A systematic review and meta-analysis. 76. Chu CS, Bancone G, Nosten F, White NJ, Luzzatto L. Primaquine-
PLoS Negl Trop Dis 2014; 8:e3071. induced haemolysis in females heterozygous for G6PD deficiency.
57. Quispe AM, Pozo E, Guerrero E et al. Plasmodium vivax hospitali- Malar J 2018; 17:101.
zations in a monoendemic malaria region: severe vivax malaria? 77. Recht J, Ashley EA, White NJ. Use of primaquine and glucose-6-
Am J Trop Med Hyg 2014; 91:11–7. phosphate dehydrogenase deficiency testing: divergent policies and
58. Douglas NM, Pontororing GJ, Lampah DA et al. Mortality attrib- practices in endemic countries. PLoS Negl Trop Dis 2018; 12:
utable to Plasmodium vivax malaria: a clinical audit from Papua, e0006230.
Indonesia. BMC Med 2014; 12:217. 78. Roca-Feltrer A, Khim N, Kim S et al. Field trial evaluation of the
59. Siqueira AM, Lacerda MVG, Magalhaes BML et al. performance of point-of-care tests for screening G6PD deficiency
Characterization of Plasmodium vivax-associated admissions to in Cambodia. PLoS One 2014; 9:e116143.
reference hospitals in Brazil and India. BMC Med 2015; 13:57. 79. Bancone G, Chu CS, Chowwiwat N et al. Suitability of capillary
60. Mace KE, Arguin PM, Tan KR. Malaria surveillance – United blood for quantitative assessment of G6PD activity and performances
States, 2015. MMWR Surveill Summ 2018; 67:1–28. of G6PD point-of-care tests. Am J Trop Med Hyg 2015; 92:818–24.
61. Tatem AJ, Jia P, Ordanovich D et al. The geography of imported 80. Oo NN, Bancone G, Maw LZ et al. Validation of G6PD point-of-
malaria to non-endemic countries: a meta-analysis of nationally care tests among healthy volunteers in Yangon, Myanmar. PLoS
reported statistics. Lancet Infect Dis 2017; 17:98–107. One 2016; 11:e0152304.
62. Ryan JR, Stoute JA, Amon J et al. Evidence for transmission of 81. Ley B, Bancone G, von Seidlein L et al. Methods for the field evaluation
Plasmodium vivax among a duffy antigen negative population in of quantitative G6PD diagnostics: a review. Malar J 2017; 16:361.
Western Kenya. Am J Trop Med Hyg 2006; 75:575–81. 82. Marcsisin SR, Reichard G, Pybus BS. Primaquine pharmacology in
63. Howes RE, Reiner RC Jr, Battle KE et al. Plasmodium vivax trans- the context of CYP 2D6 pharmacogenomics: current state of the
mission in Africa. PLoS Negl Trop Dis 2015; 9:e0004222. art. Pharmacol Ther 2016; 16:1–10.
Journal of Travel Medicine 13

83. Bennett JW, Pybus BS, Yadava A et al. Primaquine failure and 100. Novitt-Moreno A, Ransom J, Dow G, Smith B, Read LT, Toovey
cytochrome P-450 2D6 in Plasmodium vivax malaria. N Engl J S. Tafenoquine for malaria prophylaxis in adults: an integrated
Med 2013; 369:1381–2. safety analysis. Travel Med Infect Dis 2017; 17:19–27.
84. Ingram RJ, Crenna-Darusallam C, Soebianto S, Noviyanti R, Baird 101. Leary KJ, Riel MA, Roy MJ et al. A randomized, double-blind,
JK. The clinical and public health problem of relapse despite safety and tolerability study to assess the ophthalmic and renal
primaquine therapy: case review of repeated relapses of effects of tafenoquine 200mg weekly versus placebo for 6 months
Plasmodium vivax acquired in Papua New Guinea. Malar J 2014; in healthy volunteers. Am J Trop Med Hyg 2009; 81:356–62.
13:488. 102. Fukuda M, Krudsood S, Mohamed K et al. A randomized, double-
85. Nelwan EJ, Ekawati LL, Tjahjono B et al. Randomized trial of blind, active-control trial to evaluate the efficacy and safety of a
primaquine hypnozoitocidal efficacy when administered with three day course of tafenoquine monotherapy for the treatment of
artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax malaria. PLoS One 2017; 12:e0187376.
Plasmodium vivax in Indonesia. BMC Med 2015; 13:294. 103. Baird JK, Hoffman SL. Primaquine therapy for malaria. Clin Infect
86. Baird JK, Louisa M, Noviyanti R et al. Association of impaired Dis 2004; 39:1336–45.
cytochrome P-450 2D6 activity genotype and phenotype with 104. Chu CS, White NJ. Management of relapsing Plasmodium vivax
therapeutic efficacy of primaquine treatment for latent malaria. Expert Rev Anti Infect Ther 2016; 14:885–900.
Plasmodium vivax malaria. JAMA Open Network 2018; 1: 105. Baird JK, Valecha N, Duparc S, White NJ, Price RN. Diagnosis
e181449. and treatment of Plasmodium vivax malaria. Am J Trop Med Hyg
87. Marcisisin SR, Sousa JC, Reichard GA et al. Tafenoquine and 2016; 95:35–51.
NPC-1161B require CYP2D metabolism for antimalarial activity: 106. Ashley EA, Recht J, White NJ. Primaquine: the risks and benefits.
implications for the 8-aminoquinoline class of antimalarial com- Malar J 2014; 13:418.
pounds. Malar J 2014; 13:2. 107. Baird JK. Resistance to therapies by Plasmodium vivax. Clin
88. St Jean PL, Zue Z, Carter N et al. Tafenoquine treatment of Microbiol Rev 2009; 22:508–34.
Plasmodium vivax malaria: suggestive evidence that CYP2D6 108. White NJ, Imwong M. Relapse. Adv Parasitol 2012; 80:113–42.
reduced metabolism is not associated with relapse in the Phase 2b 109. Sutanto I, Tjahjono B, Basri H et al. Randomized, open-label trial
DETECTIVE trial. Malar J 2016; 15:97. of primaquine against vivax malaria relapse in Indonesia.
89. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan T, Magill AJ. Antimicrob Agents Chemother 2013; 57:1128–35.
Primaquine: report from CDC expert meeting on malaria chemo- 110. Llanos-Cuentas A, Lacerda MV, Rueangweerayut R et al.
prophylaxis I. Am J Trop Med Hyg 2006; 75:402–15. Tafenoquine plus chloroquine for the treatment and relapse pre-
90. Nasveld PE, Edstein MD, Brennan RM et al. Randomized, double- vention of Plasmodium vivax malaria (DETECTIVE): a multicen-
blind study of the safety, tolerability, and efficacy of tafenoquine ter, couble-blind, randomized, phase 2b dose-selection study.
versus mefloquine for malaria prophylaxis in nonimmune subjects. Lancet 2014; 383:1049–58.
Antimicrob Agents Chemother 2010; 54:792–8. 111. Krintafel™ package insert. Washington, DC: GlaxoSmithKline
91. Shanks GD, Oloo AJ, Aleman GM et al. A new primaquine analog, Pharmaceuticals; 2018. Reference ID: 4294835. https://www.
tafenoquine (WR 238605), for prophylaxis against Plasmodium fal- accessdata.fda.gov/drugsatfda_docs/label/2018/210795s000lbl.pdf
ciparum malaria. Clin Infect Dis 2001; 33:1968–74. 112. Baird JK. Resistance to chloroquine unhinges vivax malaria thera-
92. Hale BR, Owusu-Agyei S, Fryauff DJ et al. A randomized, double- peutics. Antimicrob Agents Chemother 2011; 55:1827–30.
blind, placebo-controlled, dose-ranging trial of tafenoquine for 113. Dow GS, Gettayacamin M, Hansukjariya P et al. Radical curative effi-
weekly prophylaxis against Plasmodium falciparum. Clin Infect cacy of tafenoquine combination regimens in Plasmodium cynomolgi-
Dis 2003; 36:541–9. infected Rhesus monkeys (Macaca mulatta). Malar J 2011; 10:212.
93. Dow GS, McCarthy WF, Reid M, Smith B, Tang D, Shanks GD. A 114. Alving AS, Arnold J, Hockwald RS et al. Potentiation of the cura-
retrospective analysis of the protective efficacy of tafenoquine and tive action of primaquine in vivax malaria by quinine and chloro-
mefloquine as prophylactic antimalarials in non-immune individuals quine. J Lab Clin Med 1955; 46:301–6.
during deployment to a malaria-endemic area. Malar J 2014; 14:49. 115. Miller AK, Harrell E, Ye L et al. Pharmacokinetic interactions and
94. Dow GS, Liu J, Lin G et al. Summary of antimalarial prophylactic safety evaluations of coadministered tafenoquine and chloroquine
efficacy of tafenoquine from three placebo-controlled studies of in healthy subjects. Br J Clin Pharmacol 2013; 76:858–67.
residents of malaria-endemic areas. Malar J 2015; 14:473. 116. Green JA, Mohamed K, Goyal N et al. Pharmacokinetic interac-
95. Shanks D. The conundrum of malaria chemoprophylaxis. J Travel tions between tafenoquine and dihydroartemisinin-piperaquine or
Med 2016; 23(6). pii: taw065. PMID: 27694470. artemether-lumefantrine in healthy adult subjects. Antimicrob
96. Brueckner RP, Coster T, Wesche DL, Shmuklarsky M, Schuster B. Agents Chemother 2016; 60:7321–32.
Prophylaxis of Plasmodium falciparum infection in a human chal- 117. Clyde DF. Clinical problems associated with use of primaquine as
lenge model with WR238605, a new 8-aminoquinoline compound. a tissue schizontocidal and gametocytocidal drug. Bull World
Antimicrob Agents Chemother 1998; 42:1293–4. Health Organ 1981; 59:391–5.
97. Dow G, Smith B. The blood schizontocidal activity of tafenoquine 118. Recht J, Ashley EA, White N. Safety of 8-aminoquinoline antimal-
makes an essential contribution to its prophylactic efficacy in nonim- arial medicines. Geneva: World Health Organization, 2014, 222.
mune subjects at the intended dose (200mg). Malar J 2017; 16:209. ISBN 978 92 4 150697 7.
98. Lell B, Faucher J-P, Missinou MA et al. Malaria chemoprophylaxis 119. Carson PE, Hohl R, Nora MV et al. Toxicology of the 8-
with tafenoquine: a randomized study. Lancet 2000; 355:2041–5. aminoquinolines and genetic factors associated with their toxicity
99. Thakkar N, Green JA, Koh GC, Duparc S, Tenero D, Goyal N. in man. Bull World Health Organ 1981; 59:427–37.
Population pharmacokinetics of tafenoquine, a novel antimalarial. 120. Gething PW, Patil AP, Smith DL et al. A new world malaria map:
Antimicrob Agents Chemother 2018. doi:10.1128/AAC.0711-18. Plasmodium falciparum endemicity in 2010. Malar J 2011; 10:378.