New strain of malaria reported in Africa
Scott Gottlieb / British Medical Journal 2001;323:251 4aug01
[ New Malaria Strain Hits Africa Herb May Fight Disease - Dow Jones Newswires 29jul01 ]
A deadly new strain of Plasmodium falciparum, the parasite that causes malaria, has arrived in Africa, according to an article in the Wall Street Journal (below) on 26jul01.
Four different plasmodium species cause malaria, but P falciparum is the most deadly. Several years ago a fourth mutation of P falciparum emerged in parts of Asia and South America. Since then scientists have been waiting for its appearance in Africa, where 90% of the world's estimated one million deaths related to malaria occur each year.
The article stated that about six months ago, while studying nine blood samples taken from Tanzanian children infected with malaria, Carol Sibley, a geneticist at the University of Washington in Seattle, found that three samples had the mutated parasite. Until now her discovery was not widely known, even among malaria specialists.
P falciparum has a long history of resisting drugs through changes in its DNA. In Thailand the species has evolved resistance to chloroquine, sulfadoxine-pyrimethamine, and mefloquine in succession. But the latest mutation in Africa is especially alarming because it shields the parasite from sulfadoxine-pyrimethamine, one of the most affordable and widely used medicines in Africa. Scientists predict that if sulfadoxine-pyrimethamine becomes ineffective the human toll from malaria could escalate.
Most drugs target dihydrofolate reductase, a key enzyme in the synthesis of deoxythymidine, histidine, and methionine. Sulfonamides target dihydropteroate synthase, which is required for the synthesis of folate. These drugs have been extremely effective in the past. In most cases combinations of these drugs have been used because the drugs act synergistically.
However, because the antimalarial drugs are only marginally effective, the incredibly rapid development of resistant P falciparum strains has made these drugs virtually useless in many regions. The parasites are resistant to the drugs because they carry alleles of the dihydrofolate reductase or dihydropteroate synthase genes that encode mutant forms of the target enzyme. Combination therapy has been advocated as the standard treatment to prevent the spread and development of resistance to antimalarial drugs.
Roger Thurow / Wall Street Journal 26jul01
UBOMBO, South Africa -- Quiet and lonely, the isolation ward of Bethesda Hospital is living up to its name as Francois Delcourt begins his rounds. "A few cases of cholera. A few cases of malaria," he says. "None of them serious."
A year ago, a malaria epidemic was raging here, flooding the 30-bed ward with as many as 120 patients at a time. Racked with fever and chills, they lay shivering on almost every inch of floor space, even under the beds. There were "10, 20, 30 malaria cases a day," says Dr. Delcourt, a tropical-medicine specialist. "People were dying."
Now his caseload is so light that he can return to his nearby house during his days on call and lounge on the couch, smoking cigarillos and watching TV. What's made the difference? "DDT," he says.
Yes, those three infamous initials are back. Decades ago, the developed world used DDT to win its own battle against the malaria-carrying mosquito and to kill agricultural pests. By the 1970s, however, Western countries were banning the chemical after witnessing the harm it did to the environment, principally from its use on crops.
But in this highland outpost and elsewhere in the tropical reaches of the developing world, malaria's ravages have worsened in recent years as the mosquito and the malaria parasite it spreads have evolved more resistance to DDT alternatives and to drugs. With the disease, one of the world's deadliest, now striking more than 300 million people a year and killing about a million of them, the pendulum appears to be swinging back toward DDT. Today, in South Africa and the two dozen other nations that use it, the pariah pesticide -- still effective and cheaper than anything else on the market -- is seen as the lesser of two evils.
"It's against our conscience to use DDT. But so is watching people die from malaria," says Rejoice Mabudafhasi, South Africa's deputy minister of environmental affairs and tourism. "It's a horrible choice we have to make in our country."
And it raises a painful quandary for Western governments and relief agencies, which recently found themselves pushing for a global ban on DDT at the same time they were seeking to raise an international fund to eradicate malaria: How far should rich nations go in imposing their own values and risk standards on the scourges of poor ones?
Deadly Mutant Strain of Malaria Appears to Have Reached Africa
South Africa yielded to those values in 1996, when a new democratic government, sensitive to international opinion and alarmed by evidence of DDT residues in breast milk, swore off the pesticide and switched to more environmentally friendly sprays. The country had used DDT for 50 years, and had wiped out its most pernicious distributor of malaria, a mosquito species known as Anopheles funestus.
But two years ago, South Africa's malaria rates suddenly skyrocketed to 50,000 cases a year from just a few thousand, outstripping even the number of new HIV/AIDS cases in parts of the country. The funestus was back -- and it was resistant to the newer chemicals. So, South Africa went back to DDT. Now it is leaning on its eastern neighbor, Mozambique, to follow suit.
"It has been our saving grace," says Keith Hargreaves, a South African entomologist in the Ubombo region, who caught malaria four times in four months during the recent epidemic. Since South Africa resumed spraying DDT in early 2000, Mr. Hargreaves, who monitors the mosquito population, hasn't caught malaria in months. Nor has he caught a single funestus in his traps.
"Until we find something else that works, we must keep all our options open," says Mr. Hargreaves. "To ban DDT completely would be tragic."
Yet that was just what the developed world recently set out to do with a proposed treaty to ban 12 of the world's nastiest environmental pollutants. For many nations, dichloro-diphenyl-trichloroethane was at the top of the list. Though scientists have yet to agree on whether there's a conclusive link between DDT and any human illness, its toxicity and its persistence in the environment make it a deadly threat to many forms of wildlife.
Only India and China still produce the pesticide, mainly for domestic use. A secretive network of brokers fills most of the rest of the world's demand for the fine white powder from supplies warehoused in Asian and Latin American countries that have ceased making and using it. In South Africa, for example, a local company, working through a European broker, says it imports about 80 tons of DDT per spraying season, mostly from stockpiles in Asia.
But over the past year, as negotiators hammered out the details of the environmental treaty, emotions reached a boiling point over the developing world's insistence that the use of DDT for malaria control be exempted from the ban. True, the exemption's advocates conceded, DDT kills birds and other wild species, but, they argued, malaria kills children -- about one every 40 seconds in sub-Saharan Africa.
"It was getting to the stage of 'Look at these environmentalists, they don't care about black babies dying in Africa,' " says one negotiator, who backed an all-out ban.
In the end, the human-health argument prevailed. When government officials from around the globe met in Stockholm in May to sign the treaty, 31 of the more than 90 nations that participated, including South Africa, registered for the malaria-control exemption. From a Swedish convention hall, a harsh reality emerged: The world wouldn't be free of DDT until it was free of malaria.
"If we get the global community to take malaria as seriously as it needs to be taken, then we can find alternatives to DDT," says Brooks Yeager, a Washington-based vice president of the global threats program at the World Wildlife Fund.
And so, the push is on to "Roll Back Malaria," the new battle cry of the World Health Organization. Philanthropists, such as Microsoft Corp.'s Bill Gates, are donating millions to research and to the quest for a possible vaccine, drug companies are studying more effective treatments for the disease, and scientists are probing the mosquito's genome, hoping to unlock some useful secrets. Meanwhile, international relief agencies are working to develop and distribute cheap repellent-treated bed nets to protect children in malarial areas at night, when the mosquito is most voracious.
Their efforts have yet to help people like Vasco Abilio Cumaio, who recently returned to the regional hospital in Boane, Mozambique, seeking treatment for another bout of malaria. Last year, the hospital, where flies and mosquitoes buzz around the waiting room, had 65,723 malaria cases -- about 180 a day. The 34-year-old Mr. Cumaio showed up last month and the month before. Now, he is back with two cousins also gripped by the chills, fever and aches that indicate the onset of the disease.
"The drugs didn't work last month," says Mr. Cumaio. "I'm not sure the medicine will work this time either."
If malaria isn't treated promptly, and with the proper drug, it can kill quickly as the parasite clogs the circulatory system of its victim, impeding the flow of blood. Children under five and pregnant women are most at risk. Children who survive can end up mentally or developmentally impaired.
As Mr. Cumaio waits in a long line to get his prescription filled, he studies a tattered poster illustrating ways to prevent malaria -- spraying, bed nets and cleaning up standing water. "I don't know what, but they need to spray with something," he says, swatting away mosquitoes.
In southern Africa, Mozambique is alone in its refusal to use DDT, but South Africa is pressuring it to use the pesticide as part of a concerted regional attack on the disease. South Africa suspects its recent epidemic was started by mosquitoes arriving from Mozambique, but Mozambique is skeptical of that theory and leery of the pesticide.
"If a product like DDT isn't being used in developed countries because it is dangerous, why should we use it in our country?" asks Francisco Songane, Mozambique's health minister. "Are you saying we are somehow different than other people?"
"For some, DDT is an evil word, like apartheid," explains Andre van der Bergh, an environmental management executive at Billiton PLC. The London-based mining and metals company recently led construction of a $1.4 billion aluminum smelter in Mozambique, the biggest foreign investment yet in the impoverished nation. The company was hit with nearly 7,000 cases of malaria during the smelter's two years of construction, and 13 of its expatriate workers died from the disease. Ever since, Billiton has been urging Mozambique to join South Africa in adding DDT to the rotation of pesticides it uses to fight the disease.
But 20 miles down the road in the capital of Maputo, where photos of mosquitoes hang like wanted posters on the walls of the Health Ministry, the answer remains firm. "No DDT," says Avertino Barreto, chief of infectious disease control.
Both he and Mr. Songane recount malaria's tragic toll on their country's 17 million citizens. Two-thirds of all admissions to pediatric wards in the nation's hospital and 40% of all outpatient consultations are malaria-related. Last year, there were more than three million reported cases of malaria and at least 2,000 deaths. The government says the numbers understate the problem, since many who get malaria don't seek treatment or die before they can get it.
Even so, Dr. Barreto maintains that using DDT to save lives now "is a shortsighted vision. I need a long vision." While South Africa argues that its strategy of spraying DDT only indoors limits the pesticide's contact with the environment, Dr. Barreto asks, "Do we know what impact DDT use will have 10 years from now? Nobody can say what you need to pay tomorrow to deal with the consequences of DDT use today."
DDT proponents insist it's more effective and much cheaper than the alternatives, such as synthetic pyrethroids. According to a study by a Johannesburg-based group called Africa Fighting Malaria, DDT costs the South African government about one cent per square yard of coverage, compared with nearly two cents per square yard for the cheapest pyrethroid it uses and about four cents for a carbamate spray. The overall saving can be even greater: some DDT alternatives need to be sprayed more than once a year.
Mozambique spends about $2 million a year for malaria control, only a quarter of what Dr. Barreto figures is needed to cover the entire population and one-fifth of what South Africa spends. Officials at Billiton, which spent more than $600,000 to finance the more-expensive sprays, says DDT use would increase the area Mozambique could treat for the same amount of money or free up funds for other uses.
But the Mozambicans say they aren't convinced by South African studies showing mosquito resistance to the alternative sprays the country is using. And they argue that they shouldn't have to use DDT just because it costs less.
"It's not fair to say we should use DDT because it's cheap and we're poor," says Mr. Songane, an obstetrician. "My call to the world is to lower the prices of the other chemicals. Or put up the money and develop other alternatives."
Because it relies heavily on foreign aid, Mozambique is susceptible to pressure from the developed world's relief agencies not to use DDT. Some of these agencies, including the foreign-aid arms of some Western governments, in the past have refused to fund DDT spraying programs elsewhere, claiming that they can't use public money to support the use of something that's banned in their own countries. And they fret that Mozambique, invoking the exemption in the Stockholm treaty, might begin using DDT and ask them to fund it.
But Dr. Barreto says Mozambique's opposition to DDT is homegrown. The spray stains the walls of houses, its smell lingers, and it agitates bedbugs and other pests, making them more active. He says that South Africa sprays DDT only inside traditional huts made of mud, sticks and thatch, not in Western-style houses.
'Your House First'
"They only want us to use DDT on poor, rural black people," he says. "So whoever suggests DDT use, I say, 'Fine, I'll start spraying in your house first.' "
The South Africans find Mozambique's objections baffling. "We don't want to use DDT until the cows come home. But it needs to be in our arsenal, because we know it works," says Brian Sharp, the head of malaria research at South Africa's Medical Research Council.
Mr. Sharp believes that the best way to keep mosquitoes from becoming pesticide-resistant is for the entire region to hit them with a coordinated rotation of sprays that include DDT. Otherwise, he says, resistant mosquitoes will cross borders to areas where they can thrive.
Mr. Sharp unfurls a map of the Mozambique-South Africa-Swaziland border area, where he has charted the prevalence of the malaria parasite in children under 15. In South Africa and Swaziland, where DDT is sprayed inside houses, most rates are in the single digits, with the highest, 41.8%, recorded in a South African village near Mozambique. In southern Mozambique, where a more expensive carbamate insecticide is used, the rates rarely fall below 70% and often approach 90%.
"No doubt about it, malaria's the most common illness here," says Antonio Gumende, sliding behind his desk in the one-room clinic in the small southern Mozambican village of Mahubo. "In the summer, it's about 100 cases a week."
On Mr. Sharp's map, Mahubo is in an area where three-quarters of the children are thought to have the malaria parasite. "Last month, the government introduced nets for beds, but I don't think it's enough," Dr. Gumende says, adding that he doesn't remember any spraying locally. Should DDT be used? "Whatever works," he says.
'Many, Many Times'
As he hands out malaria tablets to his patients -- mostly mothers with small children -- Dr. Gumende holds back some pills for himself and his staff. How many times has Dr. Gumende had malaria? He laughs at the question. "Many, many times," he says. He asks his nurse if she has had malaria. "Many, many times," she replies.
Across the border in South Africa, it's another quiet afternoon at Bethesda Hospital. The waiting room is empty. Dr. Delcourt, praising the wider use of bed nets as well as DDT, says with satisfaction that some days pass with no new malaria cases at all.
On a neighboring hilltop, in the village of Jozini, Mr. Hargreaves, the entomologist, is hoping to keep it that way. He opens a screen door and enters a room filled with traps teeming with mosquitoes. He pokes a straw into one trap, sucks up several insects and blows them out into a test tube lined with DDT-impregnated paper. After an hour, he transfers them to a second, untreated test tube. One by one, they die, and Mr. Hargreaves breathes easier. The DDT is still working: no resistance yet.
He unlocks the door to another room and points to the back to a stack of cardboard boxes filled with sachets of DDT. "Only for use by the Department of Health," it says on each box. "Toxic to fish, bees and wildlife. Add water and stir well."
The next round of spraying will commence in several weeks.
Gautam Naik / Dow Jones Newswires 29jul01
Five years after Carol Sibley started her quest, she has found what she was looking for - and dreaded finding: evidence that a deadly strain of malaria, plasmodium falciparum, has arrived in Africa.
"Scientifically, this is very exciting," says Prof. Sibley, a geneticist at the University of Washington in Seattle, "but I'm also depressed."
Four parasites cause malaria, but falciparum is the biggest killer of all. Several years ago, a fourth mutation of falciparum emerged in parts of Asia and South America. Since then, scientists have been bracing for its appearance in Africa, where 90% of the world's estimated one million malaria-related deaths occur each year.
About six months ago, while studying nine blood samples taken from malaria-infected children from Tanzania, Prof. Sibley found that three had the mutated parasite. Her discovery isn't widely known even among malaria specialists. It is still in the early stages and must go through the normal rigors of scientific verification by others before it is widely accepted. How long that will take is difficult to determine. If verified, it is certain to cause alarm.
Falciparum has a long history of resisting drugs by undergoing changes in its DNA. But the latest mutation is especially alarming because it shields the parasite from SP, one of the most affordable and widely used medicines in Africa. If SP turns ineffective, the human toll from malaria could surge.
Scientists have long been "terrified that this is going to show up in Africa," says Nick White, a malaria expert funded by Britain's Wellcome Trust, a health-care charity, who works in Thailand. That is where the fourth mutation first emerged, before moving to South America - and now, apparently, Africa.
Scientists have one hope: An ancient Chinese herb called qinghaosu is proving to be a remarkably effective killer of falciparum. In several large trials in Africa, whose results are yet to be published, qinghaosu-based drugs cured more than 90% of malaria cases in certain countries, according to the World Health Organization, which spearheaded the effort. Similar qinghaosu trials in Thailand have shown equally promising outcomes. Scientists backed by WHO and other aid agencies are racing to combine qinghaosu with existing drugs and unleash a double whammy against the mutant malaria parasite.
The new therapies are "the most exciting and positive development we've had in treating malaria for quite a while," says Steven Meshnick, an expert on antimalarial drugs at the University of Michigan, Ann Arbor.
But getting them to Africa won't be easy. Many cash-strapped countries there still distribute inexpensive chloroquine - it costs just 10 cents per treatment - even though that drug has lost its effectiveness against malaria in most places. The new qinghaosu-based drugs will be more expensive, averaging about $1 per treatment, according to Mr. White.
Big pharmaceutical companies have taken a back seat, partly because, unlike AIDS, malaria no longer occurs in the West, and drugs to treat the disease aren't that lucrative. Novartis AG is an exception. In May, the Swiss drug company agreed to provide its newly developed combination drug Coartem at sharply reduced prices to poor nations. A Coartem treatment, which includes a qinghaosu derivative, can cost as much as $40 in the West; Novartis will supply it for $2.40 to WHO, which will help distribute it to poor countries.
Scientists have been playing cat and mouse with falciparum for years. The one-celled protozoan hitches a ride in the salivary glands of a female mosquito and enters a person's body via a mosquito bite. The disease can spread rapidly: If a mosquito attacks an already infected person, it picks up the parasite and passes it along when biting its next victim. That is why a mutated parasite that appears in Thailand eventually can travel halfway around the world.
Chloroquine, derived from quinine, was extremely effective against the disease until resistant strains emerged in the early 1960s. Although newer drugs were developed, they were mainly based on the original quinine molecule, so falciparum could easily mutate and overpower them. By the 1970s, Western researchers desperately were seeking a new drug.
Unknown to them, the answer lay in China. In the late 1960s, Chinese scientists also were looking for a new malaria medicine. After testing scores of traditional medicines, they zeroed in on qinghaosu, a 2,000-year-old fever cure, also known as sweet wormwood. The Chinese used an extract from the plant, artemisinin, to treat malaria in mice and later in people. The results were published in 1981, and caused a stir: It was clear that the Chinese had found a potent killer of the malaria parasite.
But many Western scientists were skeptical. Some questioned the research methods used by the Chinese; others fretted that artemisinin could be toxic. When they tried to import the herb from China, they were rebuffed. Faced with these hurdles, WHO decided not to pursue human trials.
Dan Klayman, a U.S. army chemist, was more persistent. Although unable to get the plant from China, he found it growing on the banks of the Potomac River in Washington. Mr. Klayman obtained artemisinin but never managed to turn it into a proper drug. He died in 1992. (Today, the army continues to experiment with qinghaosu derivatives.)
The Chinese were more successful. They devised a water-soluble form of artemisinin, called artesunate. In the 1980s, armed with artesunate tablets and other methods, they started a massive antimalarial drive. It was a big success. In the 1970s, several million Chinese got the disease each year. Now, fewer than 100,000 do.
Artemisinin acts like a bomb. It has two oxygen atoms that break up in the presence of iron. The malaria parasite inhabits its victims' red blood cells, which are rich in iron. When an artemisinin molecule encounters the parasite, it explodes, releasing lethal toxins that destroy the parasite.
Artemisinin is also effective against the fourth mutation in falciparum. Scientists in Thailand noticed years ago that falciparum had mutated and become increasingly resistant to mefloquine, a drug used widely there. So local companies began to import artesunate from China. In 1994, researchers made the medication more powerful by combining mefloquine with artesunate.
With the help of funds provided by the Wellcome Trust, the combination drugs were provided to 10 refugee camps in northwest Thailand, an area of forests, rice paddies and mosquitoes. The results: Infection rates fell by 90% between 1994 and 2000, according to the trust. In the early 1990s, as many as 100 people in the camps succumbed to malaria each year. So far this year, no one has.
One survivor is Ma Shwe, a housewife who got falciparum malaria in early June. The parasite invaded her liver and clogged the tiny blood vessels in her brain. A week later, the 35-year-old slipped into a coma.
Ms. Shwe was taken to a nearby hospital. "One more day and she definitely would have died," says Arjen Dondorp, the Dutch physician who injected her with a qinghaosu-based drug and a modern medicine. In a phone interview from her hospital bed in Thailand, Ms. Shwe says she still feels weak, "but at least I'm alive."
The goal is to get similar combination drugs to Africa before the new mutation spreads widely there. But many scientists aren't hopeful. "We may be already too late," says Prof. White, one of the few scientists who knows about Prof. Sibley's discovery of the fourth mutation in Africa. "We're running as fast as we can to beat resistance, but I feel resistance is winning."
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