30 THE SCIENTIST | the-scientist.com
until DHA-PP–resistant PLA1 parasites
emerged in 2008 that things started to
get bad, he says.
Of all the kelch13 mutants, one
haplogroup, called the KEL1 lineage,
appeared to have the potential to spread
more aggressively than others. When par-
asites started picking up resistance alleles
from both KEL1 and PLA1 together, those
KEL1/PLA1 parasites came to dominate
the landscape in Cambodia. The so-
called co-lineage soon spread to Thai-
land, Laos, and Vietnam.^15 Frequencies of
both the PLA1 and KEL1 parent lineages
shot up—KEL1, from 4 percent in 2007
to 63 percent in 2013; PLA1, from zero
to a whopping 79 percent in that same
period. By 2013, more than 90 percent
of DHA-PP resistant parasites carried
resistance alleles from both lineages.^16
“That’s when people really started shout-
ing at each other,” says Amato, with some
arguing that ACT resistance could pose
serious problems in the fight to eradicate
malaria, and others maintaining that the
concern was overstated.
By 2017, DHA-PP treatment failure
had reached 30 percent in Vietnam and
a staggering 90 percent in western Cam-
bodia.^17 It’s thought that the KEL1 lineage
allowed parasites to persist in patients
two or three days longer after the artemis-
inin pulse than in other endemic areas,
while the PLA1 lineage made them resis-
tant to P P. Currently, Amato says, “KEL1/
PLA1 has basically replaced the indige-
nous population [of P. falciparum]. So
the situation is not great.”Misplaced concern?
Experts caution against sensationalizing
partial artemisinin resistance, as there is
some debate over the role that it plays in
ACT failure. Indeed, there are no known
cases in which delayed clearance has led
to treatment failure on its own, says Mesh-
nick at the University of North Carolina—
resistance to the partner drug, not arte-
misinin, is the primary driver for an ACT
failing. For this reason, he adds, the term
“resistance” should not be conflated with
delayed clearance. “I think it’s misleading.
When you say everybody’s ‘artemisininresistant.’... All it means is that everybody
has delayed clearance times, but they’re
still responding to the drug.” If the therapy
uses an effective partner drug, it will still
be successful—and currently, if one ACT
fails, another will still be effective.
It is also reassuring that, so far, P. falci-
parum’s ability to resist artemisinin treat-
ment is restricted to the ring stage, says
Krishna. Ongoing research into the effects
of adjusting the artemisinin dose could
yield a solution, adds Meshnick. “I’ve
heard people talk about giving artemis-
inin for longer periods of time, or maybe
giving it twice a day versus once a d a y,” he
says. “I think all of those things should be
on the table.”
Cases involving delayed clearance
in Southeast Asia and South Amer-
ica are on the rise, but actual clearance
times have not increased further since
they first appeared, says Pascal Ring-
wald, who leads the Drug Efficacy and
Response unit for the WHO Global
Malaria Program. Thus, the parasites do
not appear to be moving toward more
complete resistance—at least not yet, he
says. “We are concerned, we are watch-
ing it, and we are trying to find alterna-
tives. But we can still cure 100 percent of
people if we have a good partner drug.”
Ultimately, most experts agree that
ACT resistance needs to be monitored,
but when it comes to extinguishing
malaria—which has stubbornly main-
tained a constant global burden since
2015—there are bigger fish to f r y. Drug
resistance has thankfully not played a role
in the current stall, says Pedro Alonso, the
director of the WHO Global Malaria Pro-
gram: it seems A C Ts are enough to keep
resistance from affecting mortality rates
for the time being, including in Africa.
Despite occasional reports of artemis-
inin resistance markers popping up there,
none have stuck around, suggesting there
is no selective pressure for the parasites to
survive the initial blast of the compound’s
derivatives. Since the mid-2000s, there
have been signs of selection for resis-
tance to lumefantrine, the partner drug
of Africa’s frontline AC T, but for now it
remains 100 percent effective when com-bined with a blast of artemether. “There is
no drug resistance of any significance in
the entire continent,” says Alonso.
Rather, Alonso says, logistical chal-
lenges of delivering ACT therapies, diag-
nostic tools, and other life-saving inter-
ventions such as insecticide-treated bed
nets have caused declining mortality
rates to stall at about 400,000 per year.Furthermore, funding has not increased
apace with population growth, mean-
ing that bed nets and on-site clinics are
in short supply. “We’re probably seeing
the limits of what can be achieved with
the tools and the funding that we have.”
He and other experts also express greater
concern about the evolution of DDT-resis-
tant mosquitoes that could thwart addi-
tional efforts to prevent transmission.
Some, however, continue to sound
the alarm. Even if delayed clearance
doesn’t directly lead to treatment failure,
it puts more pressure on partner drugs to
succeed in mopping up lingering para-
sites, says Nicholas White, a professor of
tropical medicine at Mahidol University
and the University of Oxford. Parasites
even developed resistance to lumefan-
trine, which was never used as a mono-
therapy before its release in an ACT
with artemether in the late 1990s, in the
Greater Mekong within just five or six
years. And the newest AC T, which pairs
artesunate with the partner drug pyro-
naridine, was already failing in 10 per-
cent of cases in western Cambodia at the
time of its release in 2012, and artemis-
inin clearance times were already two to
three days longer.I really caution
us against
complacency.
-David Kaslow, PAT H Malaria
Vaccine Initiative