New England Journal of Medicine,
Journal Year:
2023,
Volume and Issue:
389(8), P. 722 - 732
Published: Aug. 23, 2023
Partial
resistance
of
Plasmodium
falciparum
to
the
artemisinin
component
artemisinin-based
combination
therapies,
most
important
malaria
drugs,
emerged
in
Southeast
Asia
and
now
threatens
East
Africa.
resistance,
which
manifests
as
delayed
clearance
after
therapy,
is
mediated
principally
by
mutations
kelch
protein
K13
(PfK13).
Limited
longitudinal
data
are
available
on
emergence
spread
We
performed
annual
surveillance
among
patients
who
presented
with
uncomplicated
at
10
16
sites
across
Uganda
from
2016
through
2022.
sequenced
gene
encoding
13
(pfk13)
analyzed
relatedness
using
molecular
methods.
assessed
metrics
longitudinally
eight
Ugandan
districts
2014
2021.
By
2021-2022,
prevalence
parasites
validated
or
candidate
markers
reached
more
than
20%
11
where
was
conducted.
The
PfK13
469Y
675V
were
seen
far
northern
2016-2017
increased
thereafter,
reaching
a
combined
54%
much
Uganda,
other
regions.
469F
mutation
38
40%
one
district
southwestern
2021-2022.
561H
mutation,
previously
described
Rwanda,
first
2021,
23%
441L
12
three
western
Genetic
analysis
indicated
local
mutant
independent
those
Asia.
observed
predominantly
areas
effective
control
had
been
discontinued
transmission
unstable.
Data
showed
partial
artemisinins
multiple
geographic
locations,
increasing
regional
over
time.
(Funded
National
Institutes
Health.).
The Lancet Infectious Diseases,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 1, 2025
Adding
a
single
dose
of
primaquine
to
artemisinin-based
combination
therapy
(ACT)
for
the
treatment
falciparum
malaria
can
reduce
transmission
Plasmodium
and
could
limit
spread
artemisinin
partial
resistance,
including
in
Africa,
where
disease
burden
is
greatest.
We
aimed
compare
safety
efficacy
single-dose
plus
ACT
between
young
children
(aged
<5
years)
older
5
years
<15
adults
≥15
years),
low
moderate-to-high
areas.
For
this
systematic
review
individual
patient
data
meta-analysis,
we
searched
PubMed,
Embase,
Web
Science,
Cochrane
Central
Register
Controlled
Trials,
WHO
Global
Index
Medicus,
OpenGrey.eu,
ClinicalTrials.gov,
International
Clinical
Trials
Registry
Platform,
from
database
inception
April
3,
2024,
with
no
language
restrictions.
included
prospective
studies
on
against
that
enrolled
at
least
one
child
younger
than
15
involved
study
group
given
(≤0·75
mg/kg)
ACT.
Studies
involving
mass
drug
administration,
healthy
volunteers,
or
patients
severe
mixed
(with
non-falciparum)
infections
were
excluded.
inclusion
analysis,
potential
(as
determined
by
gametocytaemia,
infectivity,
both)
enrolment
follow-up
(day
day
7,
14)
required;
analysis
required
haemoglobin
concentrations
haematocrit
values
more
visits
any
adverse
events,
both.
After
independent
screening
search
results
two
reviewers,
investigators
eligible
invited
contribute
data.
quantified
7
gametocyte
carriage,
probability
infecting
mosquito,
decreases
(>25%)
concentration
associated
anaemia,
events
until
28
using
regression
analyses,
random
study-site
intercepts
account
clustered
These
analyses
registered
PROSPERO,
CRD42021279363
(safety)
CRD42021279369
(efficacy).
Of
5697
records
identified
search,
30
analysis.
these,
shared
23
studies,
6056
16
countries:
1171
(19·3%)
2827
(46·7%)
2058
(34·0%)
years).
(0·2-0·25
ACTs
reduced
positivity
(adjusted
odds
ratio
[aOR]
0·34,
95%
CI
0·22-0·52;
p<0·001)
infectivity
mosquitoes
over
time
(aOR
per
0·02,
0·01-0·07,
p<0·001).
No
difference
was
found
effect
low-dose
both
compared
(1·08,
0·52-2·23;
p=0·84)
(0·50,
0·20-1·25;
p=0·14)
low-transmission
settings
(1·07,
0·46-2·52;
p=0·86),
(1·36,
0·07-27·71;
(0·31,
0·01-8·84;
p=0·50)
(0·18,
0·01-2·95;
p=0·23).
Gametocyte
clearance
also
similar
different
(dihydroartemisinin-piperaquine
vs
artemether-lumefantrine)
when
combined
target
0·25
mg/kg
(1·56,
0·65-3·79;
p=0·32
7).
However,
less
0·2
dihydroartemisinin-piperaquine
likely
have
gametocytaemia
those
treated
artemether-lumefantrine
(5·68,
1·38-23·48;
p=0·016
There
increase
anaemia-associated
declines
mg/kg,
regardless
age
group,
setting,
glucose-6-phosphate
dehydrogenase
status.
The
risks
grade
2
higher
serious
no-primaquine
groups,
children.
Regardless
intensity
safe
efficacious
reducing
P
transmission.
findings
underscore
need
formulations
suitable
children,
provide
supportive
evidence
expand
use
regions
rate
are
threatened
resistance.
EU
Bill
&
Melinda
Gates
Foundation.
medRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 1, 2025
Abstract
Background
The
treatment
and
control
of
malaria
in
Africa
is
challenged
by
drug
resistance,
including
Plasmodium
falciparum
transporter,
folate
pathway,
PfK13
mutations
that
mediate
resistance
to
aminoquinolines,
antifolates,
artemisinins,
respectively.
Characterization
susceptibility
informs
optimal
strategies.
Methods
We
characterized
ex
vivo
susceptibilities
nine
drugs
isolates
collected
from
individuals
presenting
with
uncomplicated
eastern
(2019-2024)
northern
(2021-2024)
Uganda
using
a
growth
inhibition
assay
the
dihydroartemisinin
(DHA)
ring
survival
(RSA).
Genetic
polymorphisms
were
molecular
inversion
probe
dideoxy
sequencing.
assessed
over
time
evaluated
associations
between
potential
markers
for
samples
studied
since
2016.
Results
Of
1,297
collected,
724/828
390/469
successfully
susceptibilities.
Median
half-maximal
inhibitory
concentrations
(IC
50
s)
low-nanomolar
chloroquine,
monodesethylamodiaquine,
piperaquine,
pyronaridine,
lumefantrine,
mefloquine,
DHA,
but
higher
quinine
pyrimethamine.
Over
time,
improved
decreased
unchanged
other
drugs.
Changes
prevalences
known
altered
followed
same
patterns.
Genotypes
associated
those
previously
identified
aminoquinolines
For
was
wild-type
PfCRT
K76T
or
PfMDR1
N86Y,
mutant
C469Y
A675V,
newly
PfCARL
D611N
mutation,
which
increased
prevalence
number
polymorphisms.
RSA
results
not
mutations,
based
on
IC
s
parasites
A675V
Y500N
mutation.
Interpretation
Susceptibilities
antimalarial
mostly
excellent,
activities
lumefantrine
DHA
suggest
loss
efficacies
leading
regimens.
Funding
National
Institutes
Health,
Medicines
Malaria
Venture,
Gates
Foundation.
Research
Context
Evidence
before
this
study
searched
PubMed
combinations
terms
“antimalarial
resistance”,
“malaria”,
“
”,
“Africa”,
“ex
vivo”,
“pfmdr1”,
“pfcrt”,
“kelch”,
“K13”
papers
published
Jan
1,
2020,
Dec
30,
2024
sensitivity
Africa.
A
prior
identical
search
conducted
2000
31,
2020
preparation
an
earlier
publication.
reviewed
included
any
relevant
articles
cited
references.
Our
many
studies
few
combining
genotyping
results.
Added
value
This
provides
comprehensive
assessment
Ugandan
July,
2019
June,
2024.
It
also
genotype-phenotype
these
data
sequencing
80
genes
as
mediators.
findings
add
existing
literature
providing
Uganda,
>1100
two
regions
country,
description
changes
characterisation
associations,
considering
genetic
various
antimalarials
novel
Implication
all
available
evidence
circulating
past
five
years
sensitive
commonly
used
However,
parasite
genotypes
phenotypes
have
changed
time.
Most
importantly,
components
first-line
therapy
although
magnitudes
decreases
are
modest,
clinical
implications
uncertain.
Continued
performance
parasitological
genomic
surveillance
institution
policy
limit
selection
failure
should
be
high
priorities.
medRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: May 1, 2024
Abstract
In
Africa,
the
first
Plasmodium
falciparum
Kelch13
(K13)
artemisinin
partial
resistance
mutation
561H
was
detected
and
validated
in
Rwanda.
Surveillance
to
better
define
extent
of
emergence
Rwanda
neighboring
countries
as
other
mutations
arise
East
Africa
is
critical.
We
employ
a
novel
scheme
liquid
blood
drop
preservation
combined
with
pooled
sequencing
provide
cost-effective
rapid
assessment
frequencies
at
multiple
collection
sites
across
countries.
Malaria-positive
samples
(n=5,465)
were
collected
from
39
health
facilities
Rwanda,
Uganda,
Tanzania,
Democratic
Republic
Congo
(DRC)
between
May
2022
March
2023
sequenced
199
pools.
K13
675V
90%
65%
an
average
frequency
19.0%
(0-54.5%)
5.0%
(0-35.5%),
respectively.
had
high
while
it
absent
DRC
although
seen
low
frequency.
Conceringly
candidate
observed:
441L,
449A,
469F
co-occurred
suggesting
they
are
arising
under
same
pressures.
Other
markers
associated
artemether-lumefantrine
common:
P.
multidrug
protein
1
N86
98.0%
184F
47.0%
(0-94.3%)
chloroquine
transporter
76T
14.7%
(0-58.6%).
Additionally,
sulfadoxine-pyrimethamine-associated
show
frequencies.
Overall,
rapidly
expanding
region
further
endangering
control
efforts
potential
engendering
partner
drug
resistance.
The Journal of Infectious Diseases,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 5, 2024
Abstract
Background
In
Africa,
the
first
Plasmodium
falciparum
artemisinin
partial
resistance
mutation
was
Kelch13
(K13)
561H,
detected
and
validated
at
appreciable
frequency
in
Rwanda
2014.
Surveillance
to
better
define
extent
of
emergence
neighboring
countries
is
critical.
Methods
We
used
novel
liquid
blood
drop
preservation
with
pooled
sequencing
provide
cost-effective
rapid
assessment
frequencies
multiple
collection
sites
across
regions
Uganda,
Tanzania,
Democratic
Republic
Congo.
Malaria-positive
samples
(N
=
5465)
from
39
health
facilities
collected
between
May
2022
March
2023
were
sequenced
199
pools.
Results
Rwanda,
K13
561H
675V
90%
65%
sites,
an
average
19.0%
(range,
0%–54.5%)
5.0%
(0%–35.5%),
respectively.
had
high
sites.
appeared
1.6%
Uganda.
absent
Congo,
although
seen
low
frequency.
Concerningly,
candidate
mutations
observed:
441L,
449A,
469F
co-occurred
mutations,
suggesting
that
they
are
arising
under
same
pressures.
Other
markers
for
decreased
susceptibility
artemether-lumefantrine
common:
P
multidrug
protein
1
N86
98.0%
63.3%–100%)
184F
47.0%
(0%–94.3%)
chloroquine
transporter
76T
14.7%
(0%–58.6%).
Additionally,
sulfadoxine-pyrimethamine–associated
show
frequencies.
Conclusions
rapidly
expanding
region,
further
endangering
control
efforts
potential
engendering
partner
drug
resistance.
