By Douglas Birch
July 9, 2000
The reason? The rise of resistance to anti-malarial drugs. First came the collapse of chloroquine -- one of the wonder drugs of the 20th century -- as a reliable treatment. Now health officials are turning to their second line of defense, a drug called Fansidar. But resistance to Fansidar has already appeared, and if it spreads too fast, there may be no cheap, safe and effective drug to take its place.
"It's really a human disaster waiting to happen," says Dr. Kevin Marsh, an Oxford University scientist working at Kenya Medical Research Institute labs on Kenya's coast.
The failure of Fansidar would be a disaster piled on top of an existing disaster. Malaria already kills 1.1. million people a year, most of them children, in the tropics. Drug resistance threatens to add to the horrendous losses, especially in Africa, where 90 percent of the deaths occur.
"Malaria remains out of control in Africa, causing massive problems," says Dr. Charles Newton, a pediatric neurologist also working in Kilifi. "And the most urgent problem is the spread of resistance to cheap anti-malarial drugs."
Chloroquine's erosion has been keenly felt. One 1998 study found that the risk of death from malaria in two regions of Senegal more than doubled as chloroquine resistance rose over an 11-year period. In a third region, the risk of death for children under the age of 5 shot up eight times.
Kenya banned the use of chloroquine last year because, says Dr. John Odandi, head of the Nyanza Provincial Hospital in Kenya, the drug was "useless" and too often caused fatal delays in effective treatment.
The veteran physician knows a lot about the treatment of malaria. His sparsely equipped, 359-bed hospital, located in the dusty city of Kisumu, is flooded with a quarter of a million patients each year. In four cases out of 10, the primary diagnosis is malaria.
Chloroquine resistance has probably contributed to the death toll in a series of recent outbreaks in Kenya. After the Long Rains of late April and May last year, people were dying so fast in the hospital in a town called Kisii -- in the highlands of western Kenya -- that some corpses lay for hours before they were discovered. More than 18,000 people were stricken, and some 600 died. This year, more than 100 people died in Kisii, although the malaria season was considered moderate.
Doctors working at Kilifi were overwhelmed last year as twice the normal number of malaria patients arrived. During the height of the outbreak, three children died in the pediatric intensive care ward in a 24-hour period. Dr. Faith Osier, a 27-year-old Kenyan physician, says she had to teach herself to shut off her emotions. "You have to have some distance, or you would be crying every day," she says.
Health officials in many African countries have been reluctant to give up chloroquine because it is so cheap. The drug costs only a few cents for a course of treatment. Fansidar costs about 40 cents a pill, a significant amount of money in countries where per capita spending on health is around $3 to $5 a year. The next drugs in line cost $6 to $10 a pill. In Africa, expensive drugs are as bad as no drugs at all.
Resistant organisms appear through the overuse and misuse of drugs. Patients who don't finish their treatment kill all but the hardiest parasites, which survive and spread. The indiscriminate use of anti-malarial drugs to treat other illnesses makes it more likely that resistance will arise.
Drugs work by gumming up a microbe's working parts, blocking one or more vital biochemical reaction. Some malaria parasites have evolved new chemicals that work despite the presence of chloroquine. Others have developed the ability to pump the drug out of their cells.
Resistance to chloroquine first appeared in South America in the early 1960s, during a doomed World Health Organization campaign to eradicate malaria in most of the world. Chloroquine was a key to the eradication strategy. (In Brazil, the health minister ordered the drug put in table salt.) As American troops gobbled drugs during the Vietnam War, strains resistant to chloroquine and other drugs appeared. Chloroquine resistance spread to the coast of East Africa by the early 1980s.
One of the first documented victims of chloroquine-resistant malaria in Africa was an American -- a secretary to the U.S. ambassador in Dar es Salaam, Tanzania. A physician gave her chloroquine after she complained of severe fever and chills. Then she disappeared. Friends broke into her apartment a few days later and found her in a coma on the floor.
She was flown to a Nairobi Hospital, where Dr. Jeffrey Chulay, then a Walter Reed Army Institute of Research scientist working in Kenya, put some of her blood in a petri dish, added some chloroquine and watched the parasites swim undisturbed in their chemical bath. Five days later the woman died. "She basically never woke up from her coma," Chulay recalls.
Today, for reasons no one understands, Central America is the only tropical region on earth without chloroquine resistance. But no one expects drug-resistant parasites to remain south of the Panama Canal forever.
Back in 1993, Malawi became the first African nation to restrict the use of chloroquine and required doctors to use Fansidar. In a not-yet-published study, Dr. Christopher Plowe, chief of the malaria section of the University of Maryland's center for vaccine development, found that from 15 percent to 20 percent of malaria cases in one Malawi township were Fansidar resistant.
The good news, Plowe says, was that after seven years of Fansidar use, 80 percent of the patients still responded to it. The bad news was that Fansidar resistance was firmly established, and growing each year. "We still need urgently to identify the next drug and to have it on deck and affordable," Plowe says. "Things haven't deteriorated as quickly as was predicted, but clearly Fansidar resistance is increasing."
Strains of malaria aren't just adapting to the cheapest drugs. The parasite is increasingly able to evade the most powerful and expensive compounds.
Quinine, the first anti-malarial, was discovered by Jesuit missionaries in South America in the 1600s. Today, intravenous quinine is the therapy of last resort for severe malaria in many tropical hospitals. Disturbingly, malaria has developed some resistance even to this difficult-to-administer, and potentially toxic drug. "Quinine is becoming less and less effective," says Dr. Wil Milhous of the Walter Reed Army Institute of Research near Silver Spring, one of the world's leading centers for malaria research.
Resistance has also appeared in recent years to a drug called mefloquine -- first developed to treat chloroquine-resistant malaria during the Vietnam War. Mefloquine is widely prescribed to Americans traveling to tropical areas, and is a drug of last resort for some victims. While still effective in most areas, mefloquine is losing its power over parasites in southeast Asia. In areas of Thailand, 60 to 70 percent of the parasites are mefloquine resistant.
If there were profits to be made in making new malaria drugs, drug companies would be scrambling to discover them. But most of the disease's victims live in desperately poor countries. Only a handful of nonprofit groups, the World Health Organization and the U.S. military are pushing the search for new drugs. Only a few drug companies are interested in taking newly discovered drugs from the lab to the marketplace.
"There aren't a lot of people working on malaria drugs," Milhous says. Scientists at the Walter Reed Army Institute of Research, he notes, "have been been pretty much doing it solo for the last 20 years."
There are drugs in development that could replace Fansidar. Most are so-called "me-too" drugs -- compounds that are closely related to Fansidar chemically, but differ enough to evade the parasite's defenses. One is a compound nicknamed "Lap-Dap." It's being tested by the World Health Organization and SmithKline Beecham, the drug giant.
Another new malaria drug is malarone, being tested by Glaxo Wellcome. It is highly effective, and the manufacturer has offered to donate the drug on a large scale. But malaria experts fear that the donation program won't continue indefinitely. The demand for malaria drugs is huge: there are an estimated 300 million to 500 million cases a year. Even if a new, affordable malaria drug appears, the decades-old arms race between man and malaria isn't about to end. (Resistance to Lap-Dap has already appeared in parts of South America, even though the drug is not yet approved for global use.)
"If you use it frequently enough and long enough, resistance will develop to any drug," says Newton, the pediatric neurologist in Kilifi.
In the meantime, malaria experts say, perhaps the best way to keep malaria in check is with multi-drug treatments, the same strategy used for AIDS and for tuberculosis. The long-term hope for malaria control is a vaccine.
Progress has been made, notably by a team of U.S. Army scientists working at Walter Reed. But a practical vaccine is probably at least eight years away. "A malaria vaccine will not cure all the problems of the Third World, "says Marsh. "But it could cure one of the biggest, and simplify some of the others."
Odandi at Nyanza Provincial Hospital has seen malaria beaten back, only to resurge. The struggle, he predicts, will be a long one. "The war against malaria started a long, long time ago," he says. "Just when you think that you're winning, the enemy emerges from behind you and stabs you in the back."