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Concerns Over Potential Drug Resistant Malaria

January 27, 2009

The afflictions of impoverished Cambodia can be seen in the nation’s western corner:  girls for hire standing outside restaurants, uneven dirt roads dotted with signs that warn “Danger Mines!”

But a potentially greater danger lurks there, particularly for the outside world. The parasite that causes the most lethal form of malaria is showing initial signs of resistance to the best new drug that treats the disease, the New York Times reports.

Combination treatments using the antimalaria drug artemisinin, which comes from a plant used in traditional Chinese medicine, have been praised in recent years as the best hope for eradicating the disease from Africa, where the a vast majority of the nearly one million annual malaria-related deaths occur.

However, a number of new studies, such as one that will soon be published in the New England Journal of Medicine, are convincing researchers that artemisinin is losing its potency in Cambodia, and that additional work is required to prevent the drug-resistant malaria from spreading elsewhere to other parts of the world.

“This is something we can’t just slide under the carpet,” R. Timothy Ziemer, a retired Navy admiral who leads the President’s Malaria Initiative, told the New York Times.  

The $1.2 billion program was started by the Bush administration three years ago to halve malaria deaths in the most affected countries.

Last month, Admiral Ziemer met with Cambodian and Thai officials to assess problem, which also affects drugs used by the malaria initiative in Africa.

“We feel that we not only have to beat the drum but shake the cage: guys, this is significant,” he said.

The research showed relatively early signs of resistance to artemisinin, according to the recently published study, and only failed in two patients who were eventually cured.

However, malaria experts point out that at several times in the past, this same area around the Thai-Cambodian border has served as a starting point for drug-resistant strains of malaria, beginning with the drug chloroquine in the 1950s.

The drug, introduced shortly after World War II,  was considered a miracle cure against the deadly falciparum malaria.  But the parasite evolved and resistant strains spread, and chloroquine is now considered useless against falciparum malaria in many areas, including sub-Saharan Africa.  However, it took generations for this resistance to spread, and scientists believe artemisinin-based drugs will be useful for many years to come. 

Nevertheless, to protect against any potential artemisinin resistance, health authorities across the world are working to ensure the drug is only sold in combination with other antimalaria medicines that remain longer in the blood, so that any artemisinin-resistant parasites are killed off. 

The recent study showing artemisinin resistance was conducted with pills that had no combination drug.

The danger is that if resistance spreads, there are no new drugs to take replace artemisinin-based combinations, and no immediate prospects are in development.

“This could spread in any direction; we have to make sure it doesn’t,” said Pascal Ringwald, malaria coordinator at the World Health Organization (WHO). 

Three years ago, the WHO led a study of drug resistance in Cambodia.  The organization is also co-authoring an upcoming study on the issue.

“We know it’s not yet in Bangladesh,” he said.

“It’s not yet in India.”

Scientists have documented how chloroquine-resistant malarial parasites spread across Thailand, Burma, India and Africa during the 1950s. 

To prevent a recurrence with artemisinin, the United States has approved a malaria monitoring center in Myanmar, formerly Burma. The Bill and Melinda Gates Foundation is providing $14 million to Thailand and Cambodia to help fund a malaria containment program, which includes supplying the area with mosquito nets, initiating a screening program for those living in affected areas and providing follow-up visits by health workers to assess drug effectiveness.

On the Thai side of the border, the government has “motorcycle microscopists” who obtain and analyze blood samples from villagers and migrant workers and distribute antimalaria drugs if needed, said Dr. Duong Socheat, director of Cambodia’s National Malaria Center.

But some are hoping for more aggressive efforts.

“Many of us think this should be treated on the same order as SARS,” Col. Alan J. Magill, a researcher at the Walter Reed Army Institute of Research, told the New York Times, referring to the respiratory disease that spread quickly through Asia and beyond in 2003, killing more than 700 people.

“This should be a global emergency that is addressed in a global fashion.”

The falciparum parasite is the most virulent of the four types of malaria.   It enters the bloodstream through a mosquito bite, and after incubating about two weeks begins multiplying.  It eventually takes over red blood cells,  causing fever, headaches, chills and nausea, among other symptoms.   Left untreated, infected cells can block blood vessels and cut off blood supply to vital organs, killing the victim.

The recent research indicates that artemisinin-based drugs are becoming less effective in removing the falciparum parasite from the bloodstream.  Indeed, a few years ago the drug took 48 hours to clear the bloodstream of parasites, but it can now take 120 hours.

“What our study demonstrates is that therapy for some patients fails “” the malaria goes away and comes back,” Lt. Col. Mark M. Fukuda, a U.S. Army  physician whose study was published in December in The New England Journal of Medicine.

Combinations of artemisinin differ by region.  The Cambodian government recommends artemisinin combined with mefloquine, which is known commercially as Lariam and  developed by the U.S. military.   Artemether, an artemisinin derivative, is often combined with the antimalarial drug lumefantrine in a combination recently deemed the most effective combination in a study of children in Papua New Guinea.

The same combination is also expected to soon be approved for sale in the U.S., mainly for citizens traveling overseas.

Although the mosquito responsible for transmission of malaria is still endemic within the U.S., modern housing, better health care access and the use of insecticides have nearly eradicated the disease in developed nations.

In the village of Tasanh, 20 miles east of the Thai border, Dr. Fukuda and his team work in places without running water or electricity and served by only by dirt roads.  In a small, spartan clinic, he and his team work in a trilingual environment “” English, Khmer, Thai”” that often sows confusion.

Dr. Fukuda calls this region of Cambodia the “canary in the coal mine” in terms of drug resistance.

In the past, migrant workers are thought to have helped spread drug-resistant strains westward in the past.  And a history of civil unrest, counterfeit drugs and a weak government has made it difficult to control malaria.

Preventive use of the drug chloroquine, including adding it to table salt to protect large portions of the population, might have actually promoted resistance to the drug, Dr. Fukuda says. 

It was not until the 1990s that the American army drug mefloquine was combined with artemisinin, a combination that turned out to be fast-acting and appears to have slowed transmission of the disease, said Dr. John MacArthur, an infectious disease expert with the United States Agency for International Development in Bangkok.

Dr. MacArthur told the New York Times that resistance to malaria drugs is a natural consequence of the drug’s widespread use.

“In the case of malaria, it’s the Darwinism of the parasite,” he said.

“It likes to survive.”

Nevertheless, some experts worry about sending the wrong message to the public about the efficacy of artemisinin-based drugs.

“This is not the death knell of artemisinin,”  Dr. Nicholas White, a malaria expert and chairman of a joint research program between Mahidol University in Thailand and Oxford University.

“The drug still works in Cambodia, maybe not as well as before,” he told the New York Times.

However, considering the history of drug failures in Cambodia, there appears to be agreement on the solution.

“Get rid of all malaria from Cambodia,” Dr. White said.

“Eradicate it. Eliminate it.”

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