Graduation Date

12-2017

Document Type

Master's Thesis

Degree Name

Master of Science

Department or Program

Biological Sciences

Department or Program Chair

Maggie Louie, PhD

First Reader

Roland A. Cooper, PhD

Second Reader

Philip J. Rosenthal, MD

Abstract

Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns, ex vivo sensitivities were assessed and genotypes previously associated with altered drug sensitivity were characterized for 58 isolates collected in Tororo, Uganda from subjects presenting in 2016 with malaria from the community or as part of a clinical trial comparing DP chemoprevention regimens. Compared to community isolates, those from trial subjects had lower sensitivities to the aminoquinolines chloroquine, monodesethyl amodiaquine, and piperaquine, and greater sensitivities to lumefantrine and mefloquine, consistent with DP selection pressure. Compared to results for isolates from 2010-13, sensitivities of 2016 community isolates to chloroquine, amodiaquine, and piperaquine improved (geometric mean IC50s 248, 76.9, and 19.1 nM in 2010-13 and 33.4, 14.9, and 7.5 nM in 2016, respectively, P50 3.0 nM in 2010-13 and 5.4 nM in 2016, P50 1.4 nM). These changes were accompanied by decreased prevalence of transporter mutations associated with aminoquinoline resistance and low prevalence of polymorphisms recently associated with resistance to artemisinins or piperaquine. Antimalarial drug sensitivities are changing in Uganda, but novel genotypes associated with DP treatment failure in Asia are not prevalent.

Comments

The abstract and paper section (pages 10-21) of the thesis are Copyright © American Society for Microbiology, [Antimicrobial Agents and Chemotherapy, 61, 2017, e01516-17 and doi:10.1128/AAC.01516-17].

Available for download on Saturday, December 15, 2018

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