Studies reveal markers of malaria resistance
Plasmodium falciparum
Image from CDC/Mae Melvin
Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.
Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.
Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.
However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.
The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.
About resistance
The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.
However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.
Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.
Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.
Plasmepsin genes
In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.
The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.
The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.
The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.
Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.
Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.
“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”
“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”
Exo-E415G variant
The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.
The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).
The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.
