Download Reply to Ferreira and Culleton To the Editor—We thank Ferreira and

Reply to Ferreira and
Culleton
To the Editor—We thank Ferreira and
Culleton [1] for their insightful comments.
These authors are interested in helping to
explain our unexpected finding that therapy for Plasmodium falciparum malaria
with artemether-lumefantrine selected in
subsequent infections for key polymorphisms in pfmdr1 up to approximately
2 months after prior therapy, well beyond
the period of selection predicted by the
pharmacokinetics of artemether and lumefantrine. We suggested that clinical
impacts might be seen well after the
period of selection because new illnesses
in semi-immune children may follow extended periods of asymptomatic infection.
Ferreira and Culleton additionally offer
a model to help explain our results, demonstrating increased selection over the
course of a clinical trial, based on the
impact of the trial itself on parasites in
the study community.
The authors suggest that researchers
should consider the impact of study drugs
on the selection of resistance-mediating
polymorphisms over the course of a clinical trial. In our study, we compared genotypes between each initial and recurrent
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malaria infection, in contrast to comparison with prevalence at a set time; thus,
secular trends leading to changes in
population-wide prevalence of polymorphisms over time were expected to have
a minor impact on our results. In addition, our cohort study enrolled only
a small proportion of children living in
the study area, and thus it is unlikely that
the use of artemether-lumefantrine in the
study children had a marked impact on
the population of P. falciparum in the
area. On the other hand, artemetherlumefantrine is now the first-line therapy
for uncomplicated falciparum malaria in
Uganda, and increased population-wide
use of the drug might explain some of
the selection of the pfmdr1 86N and
1246D genotypes in our study. However, as noted above, because our assessments of selection were over the
course of a single recurrence, overall
trends in population prevalence would
be expected to play a minor role. In
any event, we agree with Ferreira and
Culleton that our results highlight the
importance of long-term follow-up to
assess selection of drug resistance mediators after treatment for malaria. Indeed,
because selection was seen over a period
of 2 months after a regimen containing
lumefantrine, it would be expected to last
even longer after a regimen containing
amodiaquine, mefloquine, or piperaquine,
all of which are artemisinin partner drugs
with half-lives considerably longer than
that of lumefantrine.
Frederick N. Baliraine and Philip J. Rosenthal
Department of Medicine, University of California,
San Francisco
Reference
1. Ferreira, Culleton. Dynamics of Plasmodium falciparum selection after artemetherlumefantrine treatment in Africa. J Infect
Dis 2012; 205:1473–5.
Received and accepted 28 November 2011; electronically
published 27 March 2012.
Correspondence: Philip J. Rosenthal, Box 0811, University
of California, San Francisco, CA 94143 (prosenthal@medsfgh.
ucsf.edu).
The Journal of Infectious Diseases 2012;205:1475–6
Ó The Author 2012. Published by Oxford University Press on
behalf of the Infectious Diseases Society of America. All rights
reserved. For Permissions, please e-mail: journals.permissions@
oup.com
DOI: 10.1093/infdis/jis222
Notes
Financial support. This work was supported by the National Institutes of Health
(grant numbers AI52142, AI075045, and
TW01506 to P. J. R.) and the Doris Duke
Charitable Foundation, with which P. J. R. is
a Distinguished Clinical Scientist. F. N. B. was
supported by a National Institutes of Health
T-32/Ruth L. Kirschstein National Research
Service Award (5T32AI060537).
Potential conflicts of interest. All authors:
No reported conflicts.
All authors have submitted the ICMJE Form
for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have
been disclosed.
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