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Multidrug-Resistant Strain of Malaria Spread Undetected in Cambodia For Years

Researchers from the Wellcome Sanger Institute and collaborators find that a multidrug-resistant strain of malaria spread throughout Cambodia 5 years before clinical resistance was even reported.

*Updated on 2/12/2018 at 6:10 PM EST

A genetic study conducted by researchers from Wellcome Sanger Institute suggests that Plasomodium parasites in Southeast Asia have rapidly developed multidrug resistance to first-line malaria treatments in Cambodia.

In fact, 1 resistant strain, in particular, is thought to have spread 5 years before clinical resistance was even reported, according to a recent press release issued by the Wellcome Sanger Institute. According to the investigators, the study underscores the need for ongoing genomic surveillance, as delays in detecting antimicrobial resistance could hinder efforts to eliminate the disease on a global scale.

Malaria, a mosquito-borne disease caused by Plasomodium parasites, is estimated by the Centers for Disease Control and Prevention to have caused 216 million illnesses globally in 2016. The disease claimed 445,000 lives that same year. Although malaria is treatable, many regions are noticing an increasing number of infections that are resistant to available drugs.

Currently, first-line malarial treatment for several regions around the world includes a combination therapy of dihydroartemisinin and piperaquine (DHA-PPQ). Although DHA-PPQ appeared to be effective when it was first introduced in Cambodia in 2008, clinical trials conducted in 2013 found that some malaria parasites had already developed resistance to both drugs.

"There is a big and important ongoing debate on whether the current outbreak of multidrug-resistant malaria could spread outside of SEA and on what risks it poses to the global population and the successes so far obtained in the elimination of this disease," Dr. Roberto Amato told Contagion®. "As scientists, our duty is to provide objective data and knowledge that can help this decision process. While it is hard to look into the future, we can look at the past and gather as much information as we can about this strain to inform risk management strategies."

Taking this into account, they tasked themselves with gleaning insight into the initial emergence and spread of malaria resistance in Cambodia.

“We analyzed genome sequence data on 1492 samples collected at 11 locations across southeast Asia, including 464 samples collected between 2007 and 2013 in Cambodia,” the authors write. “This collection allowed a detailed longitudinal genetic analysis of the Plasomodium falciparum population of western Cambodia in the period leading up to the first clinical reports of [DHA-PPQ] resistance in 2013.”

The results of the study showed that in the same year that DHA-PPQ was made the official first-line antimalarial treatment in Cambodia, a multidrug-resistant strain of the malaria parasite emerged. The parasite strain then went on to rapidly spread and, eventually, health care practitioners were seeing complete treatment failure in Cambodia.

“This strain, called KEL1/PLA1, has a number of features that might have contributed to its success. For a start, it is resistant to both artemisinin derivatives and piperaquine, the combination of drugs used at that time. We don't know whether resistance to piperaquine originally arose on that strain or not, but the success of KEL1/PLA1 was sealed when the two forms of resistance combined," Dr. Amato said.

"The other aspect is what appears to be its ability to change its 'resistance profile.' We don't know yet what causes that, but this strain appeared originally to be resistant to mefloquine [a drug used in the past as mono-therapy and more recently in combination with artemisin derivatives] before becoming resistant to piperaquine. In that process, it lost resistance to mefloquine, perhaps because the drug wasn't used anymore, perhaps because incompatible with resistance to piperaquine. Whichever way, the good news is that artesunate and mefloquine are now effectively used in the region. The bad one is that if this strain can really switch so rapidly this stroke of luck might not last," he added.

The question of whether or not the rapid spread of resistance to DHA-PPQ throughout southeast Asia will hinder global progress made against malaria is still up for debate, according to the study authors. The World Health Organization has not deemed this as a public health emergency, but some malaria experts disagree.

“Our data show that the KEL1/PLA1 co-lineage emerged in 2008, the same year that DHA-PPQ officially became the first-line antimalarial in western Cambodia, and then spread rapidly for 5 years before the first clinical reports emerged,” the study authors write. “It would be catastrophic if the same were to happen for the last remaining antimalarials that are effective in Southeast Asia.”

The study underscores the need for ongoing genomic surveillance in order to monitor the spread of resistance and inform control strategies.

"In short, the situation is very fragile and any technology we have to keep it under control must be used. Drug efficacy monitoring is always ongoing in this and other regions, in various way or forms," Dr. Amato said. "However, these studies can require time in order to accumulate enough evidence. For example, in very low transmission areas, it might take a long time to acquire enough cases to draw significant conclusions. While these methods are irreplaceable, we showed that genomic surveillance can effectively supplement and complement them with important information."

"We can't afford to have another outbreak going on unnoticed for years," he continued. "Surveillance can at very least ring a warning bell when we see changes in the parasite that are unusual or unexpected, such as the rise in frequency of a specific strain as in this case, demanding at very least a closer monitoring and further investigation. With time we also hope to be more proactive rather than reactive, by predicting the effect interventions could have, optimizing them and limiting their risks."