| dc.description.abstract | Drug resistance continues to undermine malaria control, threatening malaria elimination efforts.
Resistance to artemisinin has now been confirmed in Southeast Asia and quinine monotherapy
clinical failure, although rare, has been reported as well. Studies in Kenyan coast have reported
parasite reduced sensitivity to quinine and artemisinin, indicating an urgent: need for surveillance
of the first-line drugs in Kenya. Quinine and Artemether-lumefantrine are the first-line treatment
for complicated and uncomplicated falciparum malaria respectively in Kenya. The present
study established the association between in vitro quinine and dihydroartemisinin (the active
metabolite of artemisinin) sensitivity and micro satellite polymorphism within P. falciparum
sodium/hydrogen exchanger-l (Pfnhe-l) and multidrug resistance-6 (Pfmdr-6) genes in samples
collected from western, highlands and coastal regions of Kenya. In vitro activity was assessed as
the drug concentration that inhibits 50% of parasite growth (IC50) and parasite genetic
polymorphisms were determined by DNA sequencing. Associations between the in vitro quinine
and dihydroartemisinin sensitivity [phenotypic] with the polymorphisms of the Pfnhe-I and
Pfmdr-6 genes [genotypic] were established using regression method. The median (Interquartile
range) IC50svalues in nM for quinine and dihydroartemisinin were 65.56 (18.19-337.7) and 8.18
(3.39-13.48), respectively. Data revealed significant association between 1 and 2 DNNND repeat
and parasite susceptibility to quinine (p=0.014 and p=0.043, respectively). In addition,
significant association .was seen between DNNND single repeat and parasite response to
dihydroartemisinin (p=0.04).While No significant different between quinine and
dihydroartemisinin IC50with DDNHNDNHNND and DDNNNDNHNDD repeats (p=0.199 and
p=O.S7).On the other hand, due to variation in Nand NIN microsatellite repeat of Pfmdr-6 ten
haplotypes was established, there was significant association between 8, 9 and 13 Pfmdr-6
R1repeat and parasite susceptibility to quinine (p=0.02, p=0.012 and p=0.041). Out of 87 and 34
isolates tested against quinine and dihydroartemisinin 29% and 44% contained high IC50s, which
are considered quinine and dihydroartemisinin resistance based on World Health Organization
cut-off points (quinine IC50 > 31SnM and dihydroartemisinin IC50 > lOnM), respectively. This
indicates quinine and dihydroartemisinin resistance may be emerging in Kenya. Clinical efficacy
studies are required to confirm the validity of these markers and the importance of parasite
genetic background given the importance of these drugs in the management of malaria. To
further validate our observation and conclusions, it will be important isolates from different
malaria ecological zones and malaria endemicity regions of Kenya are analyzed. | en_US |
