Artemether-lumefantrine treatment failure in nonimmune European travelers with P. falciparum malaria: 5.3% now and 5.3% then - need to reconsider dosing in patients from non-endemic regions?

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1466 • CID 2017:64 (15 May) • CORRESPONDENCE
Clinical Infectious Diseases® 2017;64(10):1465–6
to a population vulnerable to VPDs in the
United States.
Finally, in Mr. Trump’s vision of
“America rst,” economic aspects tend to
be prioritized, and global challenges such
as climate change tend to be neglected.
However, Mr. Trump’s doubts about cli-
mate change [8] must be discussed from
a scholarly point of view because if coun-
termeasures to control climate change are
not taken, mosquito-borne diseases may
be le untreated. As a fact, we should take
note that since 2015, 220 cases of locally
acquired mosquito-borne Zika infec-
tion have been reported in some parts of
Florida and Texas [9]. We believe that any
policies and orders should be announced
aer the due deliberation of several
aspects including the scienticfacts.
Our challenge is to control possible
outbreaks of infectious diseases, and Mr.
Trump’s challenge is to protect his coun-
try and the children of the United States
from the view of a “globalized world.”
We believe that not only the guarantee of
vaccine service to all children irrespective
of their nationality, ethnicity, or race but
also addressing climate change honestly
will create a stronger wall than any that
might be built at a border.
Notes
Contributions. K.T.and Y.M.made signif-
icant contributions to the synthesis of the man-
uscript. T.T., E.K., and M. K.made signicant
contributions to organizing the discussion. All
the authors read and axpproved this manuscript
for submission.
Potential conicts of interest. All authors
certify no potential conicts of interest. All
authors have submitted the ICMJE Form for
Disclosure of Potential Conicts of Interest.
Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.
KenzoTakahashi,1,3,a YokoMotoki,2,a
TetsuyaTanimoto,3 EijiKusumi,3 and MasahiroKami4
1Teikyo University Graduate School of Public Health, Tokyo,
2Yokohama City University, Department of Obstetrics,
Gynecology and Molecular Reproductive Science, Yokohama,
and 3Navitas Clinic, and 4Medical Governance Research
Institute, Tokyo, Japan
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© The Author 2017. Published by Oxford University Press for
the Infectious Diseases Society of America. All rights reserved.
For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/cix225
aK.T.and Y.M.contributed equally to this correspondence.
Correspondence: K. Takahashi, Associate Professor, Teikyo
University Graduate School of Public Health, 2-11-1 Kaga,
Itabashi, Tokyo 173–8605, Japan (kenzo.takahashi.glbh@
gmail.com)
CORRESPONDENCE
Artemether-Lumefantrine
Treatment Failure in
Nonimmune European Travelers
With Plasmodium falcipar-
um Malaria: Do We Need to
Reconsider Dosing in Patients
From Nonendemic Regions?
We read with interest the recent article
by Sóden and colleagues [1], which de-
scribes 310 imported Plasmodium fal-
ciparum malaria cases in Sweden treat-
ed with oral regimens: 95 of 310 with
artemether-lumefantrine (AL), 162 of
310 with meoquine, 36 of 310 with
atovaquone-proguanil, and 17 of 310 with
other regimens. Among patients treated
with AL, a high rate of late treatment fail-
ures was observed: 5.3% (5/95) of patients
showed recrudescence of P. falciparum
20–28 days aer completion of treat-
ment, whereas no late treatment failures
were seen in patients treated with other
oral regimens. While genotyping did not
reveal any evidence of underlying drug
resistance, pharmacokinetic data suggest
that the observed treatment failures may
be attributable to subtherapeutic lume-
fantrine plasma concentrations [1].
As the area under the curve of plasma
lumefantrine concentration vs time is the
main determinant for eradication of resid-
ual parasites not cleared by artemether, and
thus the determinant of clinical ecacy
[2–4], this explanation appears plausible.
Sóden and colleagues also provide
a review of published reports on AL
treatment, which includes the only pro-
spective study on the ecacy of AL
including nonimmune European travel-
ers published in 2008 [5]. In this study,
165 nonimmune patients from Europe
and nonmalarious regions of Colombia
with uncomplicated falciparum malaria
were treated with the standard 6-dose
AL regimen. We would like to highlight
that, although the cited overall failure
rate of AL treatment in this study was
3.6% (6/165), the failure rate in the sub-
group analysis of European travelers (not
shown) was 5.3% (3/57), and thus identi-
cal to the rate now reported by Sóden and
colleagues in Swedish patients.
Considering that (i) the currently used
6-dose regimen of AL was a consequence
of the unacceptably high recrudescence
rates following the initially recom-
mended 4-dose regimen of AL [6, 7], that
(ii) nonimmune patients lacking acquired
partial immunity have a higher risk of
treatment failure compared with patients
from endemic regions [3], that (iii) at the
time of AL registration, almost no data
from nonimmune patients were available,
that (iv) the observed treatment failures
with AL are very likely attributable to low
lumefantrine plasma levels, and that (v)
the now reconrmed failure rate of 5.3%
in nonimmune patients challenges the
current treatment strategy, reconsidera-
tion of the dosing strategy of AL in this
patient population is warranted.
To achieve suciently high lumefantrine
plasma levels over time, either the extension
of the current 3-day AL regimen to a 5-day
“augmented regimen” [3] or the spreading
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CORRESPONDENCE • CID 2017:64 (15 May) • 1467
Clinical Infectious Diseases® 2017;64(10):1466–7
of the 6-dose regimen from currently 3days
(0, 8, 24, 36, 48, 60 hours) to 5days (0, 8, 24,
48, 72, 96 hours) may be discussed [8]. e
question of whether a higher cumulative
dose of lumefantrine in an augmented reg-
imen may increase the rate of gastrointesti-
nal side eects (primarily vomiting [3]) will
be answered once the results of the “AL3vs5”
study, comparing the 3-day AL regimen
with a 5-day regimen, are published [9].
Note
Acknowledgement. e original study on
artemether-lumefantrine (Hatz et al [5]) was
sponsored by Novartis Pharma.
Potential conicts of interest. B.G.has re-
ceived institutional grant support from Novartis
for compensation for a clinical trial. All other
authors report no potential conicts. No report-
ed conicts of interest. All authors have submit-
ted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors
consider relevant to the content of the manu-
script have been disclosed.
AndreasNeumayr,1,2 Daniel HenryParis,1,2
BlaiseGenton,2,3 and ChristophHatz1,2
1Swiss Tropical and Public Health Institute, Basel; 2University
of Basel; and 3Infectious Disease Service and Department of
Ambulatory Care, University Hospital, Lausanne, Switzerland
References
1. Sondén K, Wyss K, Jovel I, etal. High rate of treat-
ment failures in nonimmune travelers treated
with artemether-lumefantrine for uncomplicated
Plasmodium falciparum malaria in Sweden: retro-
spective comparative analysis of effectiveness and
case series. Clin Infect Dis 2017; 64:199–206.
2. Price RN, Uhlemann AC, van Vugt M, et al.
Molecular and pharmacological determinants of
the therapeutic response to artemether-lumefan-
trine in multidrug-resistant Plasmodium falci-
parum malaria. Clin Infect Dis 2006; 42:1570–7.
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artemether-lumefantrine: a systematic review and
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4. WorldWide Antimalarial Resistance Network
(WWARN) Lumefantrine PK/PD Study Group.
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concentrations and therapeutic response using
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5. Hatz C, Soto J, Nothdurft HD, et al. Treatment
of acute uncomplicated falciparum malaria
with artemether-lumefantrine in nonimmune
populations: a safety, efficacy, and pharmacokinetic
study. Am J Trop Med Hyg 2008; 78:241–7.
6. van Vugt M, Brockman A, Gemperli B, et al.
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comparative efficacy and tolerability of CGP 56697
(artemether + lumefantrine) versus halofantrine in
the treatment of uncomplicated falciparum malaria in
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and France. Int J Antimicrob Agents 1999; 12:159–69.
8. Ezzet F, van Vugt M, Nosten F, Looareesuwan S,
White NJ. Pharmacokinetics and pharmacody-
namics of lumefantrine (benflumetol) in acute fal-
ciparum malaria. Antimicrob Agents Chemother
2000; 44:697–704.
9. ClinicalTrials.gov. Optimising operational use of
artemether-lumefantrine comparing 3 day ver-
sus 5 day (AL3vs5). Available at: https://clinical-
trials.gov/ct2/show/NCT02020330. Accessed 17
February 2017.
© The Author 2017. Published by Oxford University Press for
the Infectious Diseases Society of America. All rights reserved.
For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/cix262
Correspondence: A. Neumayr, Swiss Tropical and Public
Health Institute, PO Box, Socinstrasse 57, CH-4002 Basel,
Switzerland (andreas.neumayr@unibas.ch).
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