Even with ample ACT options, chang-
ing up the treatments typically given
in a particular area is easier said than
done, says Amato. For many patients in
difficult-to-access regions of endemic
countries with poor access to clinics,
simply rolling out rotating partner drugs
every time ACT resistance pops up is not
always practical. In cases of delayed clear-
ance, researchers are experimenting with
tweaking the dose of artemisinin deriv-
ative, but this can be equally tricky to
implement—for instance, if the deriva-
tive can’t be easily separated from its ACT
partner because it normally comes in a
single pill or blister pack. “There are vari-
ous strategies on the table,” he says. “The
question is, which ones are actually logis-
tically implementable?”
And while the evidence says that
partial artemisinin resistance doesn’t
cause ACT failure on its own, Alonso
acknowledges that, with an ever-evolving
parasite, the situation could change
tomorrow. “In public health, one learns to
never say never.” g
Natalie Slivinski is a freelance science
journalist living in Seattle, Washington.
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THE SEARCH FOR A BETTER ANTIMALARIAL
While experts debate the relevance of ACT resistance to the fight against malaria, researchers are always looking for alternatives. One
option is to combine existing drugs in new ways. For instance, a Phase 2 clinical trial monitoring more than 2,000 patients throughout the
Greater Mekong, southern Asia, and the Democratic Republic of the Congo is investigating whether the partner drug mefloquine can be com-
bined with the ACT dihydroartemisinin-piperaquine (DHA-PP), as the mechanisms by which P. falciparum evades mefloquine and piperaquine
appear to be mutually exclusive.
Simply recombining existing drugs may not be sufficient, however, and the search for antimalarial drugs with new mechanisms of action—
such as damaging the parasite’s digestive vacuole membrane or disrupting its ability to stick to red blood cells—is also underway. A dozen or
so drugs, including both alternative partner drugs and novel artemisinin derivatives, are currently in early- to mid-stage clinical development.
One new combination therapy, which has shown promise in Phase 2 trials against parasites that exhibit partial resistance to artemisinin, part-
ners the chloroquine-like drug ferroquine with artefenomel, the first potential synthetic alternative to artemisinin. Artefenomel has a much lon-
ger half-life than artemisinin-derived drugs, allowing it to be given as a single dose. It has also shown high activity against the resistance-prone
ring stage of the parasite.
Most of the antimalarials in development attack blood-stage schizonts, the stage that causes illness. However, a handful instead target
the gametocyte stage picked up by the mosquito. Such drugs would not cure an existing infection, but could control transmission, a critical
aspect of malaria elimination. Tw o of these, tafenoquine and primaquine, have advanced through Phase 3 trials, but they can’t be used broadly,
because they can cause severe damage to red blood cells in patients with a genetic condition called G6PD deficiency that is common in Africa.
Another leading candidate, KAF 156, which doesn’t carry the same risk, is currently being tested in Phase 2b trials in combination with the
partner drug lumefantrine.
With a parasite that continues to evade many existing antimalarial treatments, says David Kaslow, director for the PAT H Malaria Vaccine
Initiative, “we’ve got to continue to invest in new drugs.”