Spread of Malaria Strain Feared as Drug Loses Potency

By Thomas Fuller, The New York Times

TASANH, Cambodia - The afflictions of this impoverished nation are on full display in its western corner: the girls for hire outside restaurants, the badly rutted dirt roads and the ubiquitous signs that warn "Danger Mines!"

But what eludes the naked eye is a potentially graver problem, especially for the outside world. The parasite that causes the deadliest form of malaria is showing the first signs of resistance to the best new drug against it.

Combination treatments using artemisinin, an antimalaria drug extracted from a plant used in traditional Chinese medicine, have been hailed in recent years as the biggest hope for eradicating malaria from Africa, where more than 2,000 children die from the disease each day.

Now a series of studies, including one recently published in The New England Journal of Medicine and one due out soon, have cemented a consensus among researchers that artemisinin is losing its potency here and that increased efforts are needed to prevent the drug-resistant malaria from leaving here and spreading across the globe.

"This is something we can't just slide under the carpet," said R. Timothy Ziemer, a retired admiral in the United States Navy who heads the President's Malaria Initiative, the $1.2 billion program started by the Bush administration three years ago to cut malaria deaths in half in the countries affected worst.

Admiral Ziemer met with Thai and Cambodian officials last month to assess the resistance problem, which affects the same 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.

Though the studies show relatively early signs of resistance to artemisinin, the drugs were judged to have failed in only two patients in the recently published study. Even they were eventually cured.

But malaria experts note that several times in the past, this same area around the Thai-Cambodian border appears to have been a starting point for drug-resistant strains of malaria, starting in the 1950s with the drug chloroquine.

Introduced immediately after World War II, chloroquine was considered a miracle cure against falciparum malaria, the deadliest type. But the parasite evolved, the resistant strains spread, and chloroquine is now considered virtually useless against falciparum malaria in many parts of the world, including sub-Saharan Africa.

It took decades for this resistance to spread across the world, so by the same token artemisinin-based drugs are almost sure to be useful for many years to come.

To protect against artemisinin resistance, the global health authorities are trying to assure that it is sold only as a combination pill with other antimalaria medicines that linger longer in the blood, mopping up any artemisinin-resistant parasites.

The two most recent tests showing artemisinin resistance were done with pills that had no combination drug. But if resistance spreads, there are no new drugs to take the place of artemisinin-based combinations and no immediate prospects under 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 led a study of drug resistance in Cambodia and is co-author of a coming study on the subject. "We know it's not yet in Bangladesh," he said. "It's not yet in India."

Scientists have documented how malarial parasites that were resistant to chloroquine in the 1950s spread across Thailand, Burma, India and over to Africa, where a vast majority of the nearly one million annual malaria-related deaths occur.

To prevent a recurrence with artemisinin therapies, the United States has put aside political considerations and approved a malaria monitoring center in military-run Myanmar, formerly Burma. The Bill and Melinda Gates Foundation, one of the largest donors to malaria research, is giving $14 million to the Thai and Cambodian governments to help pay for a containment program.

That program includes efforts to supply the area with mosquito nets, a screening program for everyone living in affected areas and follow-up visits by health workers to assess the effectiveness of the drugs, said Dr. Duong Socheat, director of Cambodia's National Malaria Center. On the Thai side of the border, the government has "motorcycle microscopists" who take blood samples from villagers and migrant workers, analyze them on the spot and distribute antimalaria drugs.

But some experts would like to see an even more aggressive approach.

"Many of us think this should be treated on the same order as SARS," said Col. Alan J. Magill, a researcher at the Walter Reed Army Institute of Research in Maryland. "This should be a global emergency that is addressed in a global fashion." SARS, the respiratory disease that spread rapidly through Asia and beyond in 2003, killed more than 700 people.

The falciparum parasite is one of four types of malaria and by far the most virulent. It enters the bloodstream through a mosquito bite, and after incubating about two weeks, it multiplies and takes over red blood cells. There it causes fever, chills, headaches and nausea, among other symptoms. If untreated, the infected cells can block blood vessels and fatally cut off blood supply to vital organs.

The recent studies show that artemisinin-based drugs are becoming less effective in removing the parasite from the bloodstream. While a few years ago it took the drugs 48 hours to clear the bloodstream of parasites, it now can take 120 hours."What our study demonstrates is that therapy for some patients fails - the malaria goes away and comes back," said Lt. Col. Mark M. Fukuda, a United States Army doctor whose study was published in The New England Journal of Medicine in December.

Different regions rely on different artemisinin combinations. The Cambodian government recommends that artemisinin be combined with mefloquine, which was developed by the American military and is known commercially as Lariam. Artemether, a derivative of artemisinin, is often combined with another antimalarial drug, lumefantrine. This was recently judged to be the most effective combination in a study of children in Papua New Guinea.

The same combination is also expected to be approved for sale in the United States soon, marketed by Novartis and mainly intended for people traveling overseas or for those who arrive in the United States with malaria.

The mosquito responsible for transmission of malaria is still endemic in the United States. But modern housing, better access to health care and the use of insecticides have virtually eradicated the disease in wealthier countries.

Here in Tasanh, a village 20 miles east of the Thai border, Dr. Fukuda and a team of researchers work in what is euphemistically called a more challenging environment. Tasanh is served by a dirt road and has no running water and no public supply of electricity.

In a small, spartan clinic, Chet Chen, an 18-year-old malaria patient, lies listlessly on an old metal-framed bed next to a sample of his urine in a used water bottle. The male nurse who examines blood samples is out helping to fix the weed whacker, which has broken.

In a small but newer annex to the clinic, Dr. Fukuda and his researchers work in a trilingual environment - Khmer (Cambodian), Thai and English - that sometimes sows confusion.

Americans in the clinic recently chuckled when a Thai researcher described a patient as having a "hot body" - a literal translation of "fever" in Thai, but one that evoked nightclub images.

Dr. Fukuda calls this region of Cambodia the "canary in the coal mine" for drug resistance.

In the past, migrant workers in plantations and gem mines are believed to have helped spread drug-resistant strains westward. A history of civil unrest, counterfeit drugs and a weak and underfinanced government has made it difficult to control malaria. In the case of chloroquine, preventive use of the drug - including putting it in table salt to protect a wide swath of the population - might have actually encouraged resistance to the drug, Dr. Fukuda and others say.

It was not until the 1990s that mefloquine, the American army drug, was combined with artemisinin, made from a Chinese herb.

Artemisinin-based combinations turned out to be fast-acting and seemed to slow transmission of the disease, said Dr. John MacArthur, an infectious disease expert with the United States Agency for International Development in Bangkok.

Dr. MacArthur and others say resistance to malaria drugs is a natural consequence of widespread use of the drug. "In the case of malaria, it's the Darwinism of the parasite," he said. "It likes to survive."

Still, some researchers remain concerned about sending the wrong message to the public about the efficacy of artemisinin-based drugs.

"This is not the death knell of artemisinin," said Dr. Nicholas White, a malaria expert who is chairman of a joint research program between Oxford University and Mahidol University in Thailand. "The drug still works in Cambodia, maybe not as well as before."

But given the history of drug failures here, there appears to be a consensus on the solution.

"Get rid of all malaria from Cambodia," Dr. White said. "Eradicate it. Eliminate it."

http://www.nytimes.com/2009/01/27/health/27malaria.html?_r=1&hp