Changing Antimalarial Drug Sensitivities in Uganda

Abstract

None of the work contained in this thesis would have been possible without the help and support of the members of the Cooper and Rosenthal Labs, the TOLAB team members, or the study participants and their families. Special thanks to Frida Ceja for helping me collect the phenotypic drug sensitivity data in Uganda; Patrick Tumwebaze, Oswald Byaruhanga, and Thomas Katairo for their support collecting and analyzing data in Uganda; Melissa Conrad for being a great genotyping and research mentor; and Jenny Legac for her constant guidance and support. I am extremely grateful to Dominican University and the UC Berkeley Minority Health/Global Health Disparities Research Fellowship for helping support my travel to Tororo, Uganda in 2015, 2016, and 2017 to gather data critical to this thesis. Lastly, I would like to thank my mentors, Roland Cooper and Philip Rosenthal, for letting me work in their labs, travel to Uganda, and helping me grow as a research scientist.

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda.

“…Previous studies indicated that dihydroartemisinin-piperaquine treatment selected the N86Y allele in pfmdr1 in Uganda [48,[52][53][54], albeit one study questioned this association [55]. Approximately one third of parasites possessed the N86Y in 2010-2013 in Tororo [9], which was much higher than that found in our study area (2%). Since N86Y is associated with chloroquine resistance, it might be plausible that the N86Y mutation selected by piperaquine played a role in the slower recovery of chloroquine sensitivity in Tororo.…”

“…In contrast to chloroquine, average lumefantrine IC 50 values in the present analysis (21-29 nM) were considerably higher than those in Eastern Uganda (3.0-5.4 nM) [9,24]. It has been suggested that decrease in lumefantrine susceptibility are associated with wild type alleles in pfcrt and pfmdr1 [48,[56][57][58][59].…”

“…In this study higher IC 50 s to lumefantrine were observed in K76 sequences than those with K76T. The higher prevalence of K76 allele in our study area than that in Eastern Uganda [9,23,42] may partly explain the observed lumefantrine susceptibility.…”

“…It is of note that recovery of chloroquine sensitivity after its withdrawal occurred much earlier in Gulu than in other regions in Uganda [9,[22][23][24]41]. In 2013, as much as 65% of parasites displayed ex vivo chloroquine resistance [24] and 60-80% carried K76T allele in Tororo, Eastern Uganda [42].…”

“…However, with widespread discontinued use, numerous molecular-epidemiological studies showed that there was return of chloroquine susceptibility in P. falciparum field isolates [4]. This is supported by ex vivo [5][6][7][8][9][10][11][12][13][14][15][16] and in vivo drug-susceptibility studies [5,17,18]. Findings suggest that chloroquine might be reused in the future as an option for the treatment and/or chemoprophylaxis on the condition that chloroquine sensitivity is maintained in the area.…”