Authors

Patrick Tumwebaze, Infectious Diseases Research Collaboration, Kampala, Uganda
Melissa D. Conrad, Department of Medicine, University of California, San Francisco, California, USA
Andrew Walakira, Infectious Diseases Research Collaboration, Kampala, Uganda
Norbert LeClair, Department of Medicine, University of California, San Francisco, California, USA
Oswald Byaruhanga, Infectious Diseases Research Collaboration, Kampala, Uganda
Christine Nakazibwe, Infectious Diseases Research Collaboration, Kampala, Uganda
Benjamin Kozak, Department of Medicine, University of California, San Francisco, California, USA
Jessica Bloome, Department of Medicine, University of California, San Francisco, California, USA
Jaffer Okiring, Infectious Diseases Research Collaboration, Kampala, Uganda
Abel Kakuru, Infectious Diseases Research Collaboration, Kampala, Uganda
Victor Bigira, Infectious Diseases Research Collaboration, Kampala, Uganda
James Kapisi, Department of Medicine, University of California, San Francisco, California, USA
Jennifer Legac, Department of Medicine, University of California, San Francisco, California, USA
Jiri Gut, Department of Medicine, University of California, San Francisco, California, USA
Roland A. Cooper, Department of Natural Sciences and Mathematics, Dominican University of CaliforniaFollow
Moses R. Kamya, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
Diane V. Havlir, Department of Medicine, University of California, San Francisco, California, USA
Grant Dorsey, Department of Medicine, University of California, San Francisco, California, USA
Bryan Greenhouse, Department of Medicine, University of California, San Francisco, California, USA
Samuel L. Nsobya, Infectious Diseases Research Collaboration, Kampala, Uganda
Philip J. Rosenthal, Department of Medicine, University of California, San Francisco, California, USA

Document Type

Article

Journal or Conference Title

Antimicrobial Agents and Chemotherapy

ISSN

1098-6596

Volume

59

Issue

6

First Page

3018

Last Page

3030

Publication Date

3-9-2015

Department

Natural Sciences and Mathematics

Abstract

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.

Rights

Copyright © 2015 American Society for Microbiology. All rights reserved.

Publisher Statement

Originally published as Tumwebaze, P., et al. (2015). Impact of antimalarial treatment and chemoprevention on the drug sensitivity of malaria parasites isolated from ugandan children. Antimicrobial Agents and Chemotherapy, 59(6). 3018-3030.

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