April 2019 digital edition

estimated 3.5 million more malaria cases in 2017 than a year
ago. While the African region claimed 92% of the cases, the
South East Asian Region shared 5% and 2% of the disease
burden respectively, according to The World Malaria Report
2018 by the WHO.
Children aged under 5 years accounted for 61% of the
number of 435,000 deaths from malaria globally.
Evidently, the human toll of malaria, and the global risk it
still poses, remains unacceptably high.
Experts cite several reasons for the stalled progress
in eliminating the mosquito-borne disease in spite of the
fact that the parasitic infection is completely curable and
preventable.
Resistance or ‘partial’ resistance?
The threat of pathogens emerging resistant to artemisinin
is one of the most challenging issues faced by some of the
high-burden countries today. Artemisinin, a plant-derived
lactone, is the cornerstone of global efforts to control malaria.
Drug combinations with artemisinin as the anchor drug have
shown over 95% efficacy in malaria caused by Plasmodium
falciparum — the most commonly found infectious agent.
The WHO recommends ACTs as the first and secondline
treatment for uncomplicated P. falciparum malaria as
well as for chloroquine-resistant P. vivax malaria. There are
many advantages to using ACTs. The
artemisinin quickly and drastically reduces
the majority of malaria parasites by killing
the protozoan at all stages of its life-cycle
within the host, while the partner drugs
in the combo clear the small number of
parasites that remain. Tackling in different
ways, ACTs, which are considered the
most effective anti-malarial treatment
today, ensure that no trace of the
pathogen remains in the system posttherapy.
The resilience of the malarial parasite
is well known. In the late 1950s and
1960s, the emergence of P. falciparum
strains resistant to chloroquine and
sulfadoxine–pyrimethamine was reported
on the Thai–Cambodian border and
spread across Asia and Africa, resulting in
millions of deaths from malaria.
Resistance to artemisinin class of
drugs was first documented in Southeast
Asia in 2008 and has been particularly
menacing in the Greater Mekong
Subregion (GMS) comprising Cambodia,
Kelch 13 propeller domain mutations:
The abode of resistance
Drug combinations with artemisinin
as the lead have become the
first and second line treatment
against malaria caused by Plasmodium
falciparum. ACTs helped to bring down
the incidence of malaria cases by 18%
from 2010 to 2016. However, reduced
clinical efficacy of artemisinin due to the
emergence and spread of resistance
raises the risk of retraction of recent
gains achieved in reducing worldwide
malaria burden.
In regions where artemisinin
resistance is prevalent, ACTs are failing
fast. If the trend continues, malaria
could become practically untreatable, at
least in those parts of the world.
Though there is no consensus on
the biochemical targets of artemisinin
or on the mechanism of action, the
drug is considered a potent
inhibitor of P. falciparum
phosphatidylinositol
-3-kinase (PfPI3K).
Genome-wide association
studies (GWAS) have
revealed the genetic loci
in P. falciparum parasite
associated with artemisinin
resistance. The resistance is
caused by single nucleotide
polymorphisms in the
parasite›s kelch 13 gene.
Single point mutations
in the propeller domain of
kelch13 after position 440 were
associated with a mean increase
in the parasite clearance half-life
of 116%, studies revealed. Mutations
in kelch13 gene are associated
20 / FUTURE MEDICINE / April 2019