The Coming Plague (80 page)
Authors: Laurie Garrett
In 1992, having concluded that WHO policies were inadequate and the CDC's analysis better reflected their situation, scientists within Malawi's Ministry of Health recommended a change in policy. And Malawi became the first African nation to abandon chloroquine.
Fortunately, Africa still had options. Though resistances to other antimalarials had emerged, they were not widespread, and alternative, albeit considerably more expensive, medications were available.
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In southern Asia, however, where chloroquine resistance first appeared in the 1950s,
175
the malarial parasites were often multiply resistant to
all
the readily available drugs.
175
the malarial parasites were often multiply resistant to
all
the readily available drugs.
Though most Asian malaria was due to the less dangerous
P. vivax
parasite, the sheer density of parasite-carrying mosquito populations in tropical southern Asian areas was far greater than was seen in Africa with
Anopheles gambiae
and
P. falciparum.
In addition, many Asian nations had lively pharmaceutical black markets and/or over-the-counter sales of antimalarials as early as the 1950s. Finally, in some Asian regions both
P. falciparum
and
P
.
vivax
were present, creating a mixed malarial population.
P. vivax
parasite, the sheer density of parasite-carrying mosquito populations in tropical southern Asian areas was far greater than was seen in Africa with
Anopheles gambiae
and
P. falciparum.
In addition, many Asian nations had lively pharmaceutical black markets and/or over-the-counter sales of antimalarials as early as the 1950s. Finally, in some Asian regions both
P. falciparum
and
P
.
vivax
were present, creating a mixed malarial population.
It wasn't long after the first laboratory reports of chloroquine-resistant strains in Asia that treatment failures were correlated with the emerging mutants. In 1962, for example, three members of an American medical research team working in western Cambodia came down with severe malaria, despite taking prophylactic chloroquine. Analysis of the Cambodian
P. falciparum
strain, as well as a Malaysian strain, showed that they were resistant not only to chloroquine but also to pyrimethamine and proguanil.
176
P. falciparum
strain, as well as a Malaysian strain, showed that they were resistant not only to chloroquine but also to pyrimethamine and proguanil.
176
A team of National Institutes of Health researchers tested the drug-resistance capabilities of several Cambodian and Malaysian
P. falciparum
strains directly by injecting samples into prisoners confined in the federal penitentiary in Atlanta, Georgia. In this ethically questionable manner (due to the strong potential of coercion among alleged research volunteers in a
research environment), the NIH scientists demonstrated that only one of the six Asian strains remained susceptible in 1963 to chloroquine and three strains were resistant to all four of the leading antimalarials of the day (chloroquine, proguanil, mepacrine, and pyrimethamine).
177
P. falciparum
strains directly by injecting samples into prisoners confined in the federal penitentiary in Atlanta, Georgia. In this ethically questionable manner (due to the strong potential of coercion among alleged research volunteers in a
research environment), the NIH scientists demonstrated that only one of the six Asian strains remained susceptible in 1963 to chloroquine and three strains were resistant to all four of the leading antimalarials of the day (chloroquine, proguanil, mepacrine, and pyrimethamine).
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A decade laterâstill five years before the first resistant parasites emerged in East Africaâchloroquine resistance was widespread in Thailand, Burma, Bangladesh, India, Indonesia, the Philippines, Cambodia, Sri Lanka, Malaysia, Vietnam, Australia, Laos, Japan, Singapore, Papua New Guinea, the Solomon Islands, Vanuatu, and China.
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To counter the trend toward nearly universal
P. falciparum
chloroquine resistance in Asia, WHO recommended the use of multiple-drug treatments. The thinking, which paralleled contemporary approaches to antibiotic resistance in bacteria, was that emerging resistance could be snuffed with simultaneous use of other drugs, one of which was sure to kill off the mutant strains.
179
P. falciparum
chloroquine resistance in Asia, WHO recommended the use of multiple-drug treatments. The thinking, which paralleled contemporary approaches to antibiotic resistance in bacteria, was that emerging resistance could be snuffed with simultaneous use of other drugs, one of which was sure to kill off the mutant strains.
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But it wasn't long before multiple resistance expanded in the
P. falciparum
parasites. In the wake of widespread social disruption, a mass refugee exodus, and a genocidal campaign conducted by the Khmer Rouge, a new malaria strain emerged in Cambodia that was strongly resistant to both chloroquine and Fansidar. The mutant strain struck a refugee camp located along the Thai-Cambodian border, causing widespread disease. The CDC responded by recommending a switch from standard chloroquine plus Fansidar treatments for malaria in the region to a combination of quinine and tetracycline.
180
P. falciparum
parasites. In the wake of widespread social disruption, a mass refugee exodus, and a genocidal campaign conducted by the Khmer Rouge, a new malaria strain emerged in Cambodia that was strongly resistant to both chloroquine and Fansidar. The mutant strain struck a refugee camp located along the Thai-Cambodian border, causing widespread disease. The CDC responded by recommending a switch from standard chloroquine plus Fansidar treatments for malaria in the region to a combination of quinine and tetracycline.
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Resistance spread and grew stronger all over Asia throughout the 1980s at a pace that was staggering.
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During the same time period many of the
Anopheles
mosquito species that carried malarial parasites in Asia developed resistance to DDT, making insect control both more difficult and costly. Some of the insects expanded their territories, appearing in ecologies not previously thought to be suitable for their breeding and feeding.
Anopheles
mosquito species that carried malarial parasites in Asia developed resistance to DDT, making insect control both more difficult and costly. Some of the insects expanded their territories, appearing in ecologies not previously thought to be suitable for their breeding and feeding.
Even more troubling, the ratio of
P. falciparum
to its less dangerous cousin
P. vivax
changed in many places between the mid-1970s and the late 1980s. In India, where over 90 percent of all malaria was the milder
P. vivax
form in 1976, by 1989 only 65 percent were
vivax
, the remainder
falciparum
. In Sri Lanka, where
falciparum
had been virtually nonexistent, by 1990 close to half of all disease was due to the more dangerous parasite. Burma saw the percentage of
falciparum
jump from 60 percent to more than 90 percent.
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P. falciparum
to its less dangerous cousin
P. vivax
changed in many places between the mid-1970s and the late 1980s. In India, where over 90 percent of all malaria was the milder
P. vivax
form in 1976, by 1989 only 65 percent were
vivax
, the remainder
falciparum
. In Sri Lanka, where
falciparum
had been virtually nonexistent, by 1990 close to half of all disease was due to the more dangerous parasite. Burma saw the percentage of
falciparum
jump from 60 percent to more than 90 percent.
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One of the great tragedies was Nepal, which had been the success story of America's earlier efforts to eradicate malaria. Between 1950 and 1970, Nepal's malaria rate was reduced by an extraordinary 99 percent, from 2 million cases and 300,000 deaths per year to a mere 25,000 cases and fewer than 200 deaths. But by 1985 the country's malaria incidence had
doubled, and mortality had increased due to parasite resistance. Similar patterns were seen throughout southern and western Asia.
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doubled, and mortality had increased due to parasite resistance. Similar patterns were seen throughout southern and western Asia.
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During the Vietnam War the U.S. Army invented mefloquine and in the early 1980s it was tested on civilians as an alternative to chloroquine. By 1987 mefloquine had supplanted most other antimalarials, becoming the drug of choice in much of Asia. It was a highly effective drug, offering minimal toxicity, at a time when no other agent appeared to guarantee protection against
P. falciparum
in Asia.
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P. falciparum
in Asia.
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But in 1986, along the Thai-Cambodia border, malarial strains resistant to mefloquine alone, and in combination with chloroquine and Fansidar, emerged. In addition, strains appeared in the crucial area that were less responsive to quinine, rendering some malaria cases untreatable. By 1990 the mefloquine cure rate in Thailand had plummeted from 98 percent to 71 percent. And the following year halofantrine, the only remaining marketed drug,
which had never even been used in the country,
was rendered close to useless in Thailand by virtue of
P. falciparum resistance
.
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which had never even been used in the country,
was rendered close to useless in Thailand by virtue of
P. falciparum resistance
.
185
When the new mefloquine-resistant
P. falciparum
strain emerged, Cambodia was in a state of civil war, a 16,000-strong United Nations peacekeeping force was poised to enter the area, and 360,000 refugees bivouacked across the border in Thailand were scheduled for imminent repatriation. It was an opportune moment for the microbe.
P. falciparum
strain emerged, Cambodia was in a state of civil war, a 16,000-strong United Nations peacekeeping force was poised to enter the area, and 360,000 refugees bivouacked across the border in Thailand were scheduled for imminent repatriation. It was an opportune moment for the microbe.
The new strain was resistant to chloroquine, Fansidar, mefloquine, and their chemical cousins. That left only two available drugs, quinine and tetracycline. Neither was ideal. Quinine was a poor prophylactic drug, tetracycline a weak treatment.
By March 1992, WHO estimated that more than half of all malaria cases in Cambodia involved the new strain, and control seemed impossible because years of civil war had left the country's public health system in a state of ruin. The National Cambodian Malaria Control Office, such as it was, estimated that some 10,000 people died of the new malaria in that country in 1991. But officials conceded it was just a conservative guess.
At her laboratory in the Harvard School of Public Health, Dyann Wirth worked at a feverish pace in 1992â93, trying to understand the nature of the mutation in the new strain and find a way to defeat it. She concluded that the parasite had produced a large, unique protein that nestled in its membrane. When the drugs entered the parasite's environment, the protein acted as a pump, shunting the chemicals out of the
P. falciparum.
Though such a mechanism had previously been seen for chloroquine resistance, Wirth and several other scientists were convinced that the new strain had a pump that evicted nearly all the antimalarial drugs.
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P. falciparum.
Though such a mechanism had previously been seen for chloroquine resistance, Wirth and several other scientists were convinced that the new strain had a pump that evicted nearly all the antimalarial drugs.
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Evidence that such a pump existed was strong. A heart disease drug called verapamil, which blocked calcium pumping across cellular membranes, could reverse drug resistance. Some scientists urged WHO to release drugs that combined verapamil and chloroquine: one drug would
shut down the pumps, the other would stop the parasite. Researchers saw evidence of such pumps in test-tube studies: when they compared resistant malaria to nonresistant, the resistant strains had forty to fifty times more chloroquine on the
outside
of the parasite.
shut down the pumps, the other would stop the parasite. Researchers saw evidence of such pumps in test-tube studies: when they compared resistant malaria to nonresistant, the resistant strains had forty to fifty times more chloroquine on the
outside
of the parasite.
The pump mechanism was genetically controlled by at least two so-called
mdr
(multidrug-resistance) genes. No one knew how the malaria parasites got
mdr
genesâsuch genes had previously been seen operating in mammalian cancer cells, pumping out chemotherapy drugs. Nevertheless, Wirth was convinced that
mdr
genes not only were present in the super-resistant bugs but were amplified so that the parasite made huge numbers of the pumps.
mdr
(multidrug-resistance) genes. No one knew how the malaria parasites got
mdr
genesâsuch genes had previously been seen operating in mammalian cancer cells, pumping out chemotherapy drugs. Nevertheless, Wirth was convinced that
mdr
genes not only were present in the super-resistant bugs but were amplified so that the parasite made huge numbers of the pumps.
“Once this kind of mechanism occurs, it means resistance will emerge even before the drug can be invented,” Wirth said.
It was tempting to conclude that the pump mechanism explained why the pace of resistance had so accelerated. Though chloroquine resistance first emerged in the 1950s, it and most of the other early antimalarials remained effective worldwide for decades. But in the 1980s resistance emerged at an extraordinary pace, seemingly from the moment drugs were introduced in some Asian areas, particularly Thailand and Cambodia. Most early mutant P.
falciparum
strains resulted from apparently random point mutations, and those strains were resistant to one drug at a time. But by the end of the 1980s, Indochina seemed to be awash in multidrug-resistant parasites.
falciparum
strains resulted from apparently random point mutations, and those strains were resistant to one drug at a time. But by the end of the 1980s, Indochina seemed to be awash in multidrug-resistant parasites.
Perhaps, malariologists whispered nervously, the presence of a pump mechanism provided the parasites with a way to quickly outwit new drugs, by fine-tuning their pumps to adapt to each new agent. If that were so, the resistance trend would only worsen, and accelerate, wherever in the world the malaria parasites possessed such pumps.
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In 1989, after forty years of effective trouble-free use, physicians treating people in Papua New Guinea who were infected with P. vivax parasites noticed that chloroquine no longer cured that type of malaria.
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Though resistance problems had been apparent with
P. falciparum
almost from the beginning of the chloroquine revolution,
P. vivax
had always remained vulnerable to the drug.
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Though resistance problems had been apparent with
P. falciparum
almost from the beginning of the chloroquine revolution,
P. vivax
had always remained vulnerable to the drug.
Malariologists had hoped that the Papua New Guinea
P. vivax
cases were nothing more than an odd flukeâperhaps even a failure due to improper treatmentâbut in 1993 chloroquine-resistant
P. vivax
appeared in Indonesia (Irian Jaya).
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Because
P. vivax
had a more complicated life cycle inside humans, and spent far longer in the liver, the parasite's vulnerability to drugs differed from that of
P. falciparum.
P. vivax
cases were nothing more than an odd flukeâperhaps even a failure due to improper treatmentâbut in 1993 chloroquine-resistant
P. vivax
appeared in Indonesia (Irian Jaya).
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Because
P. vivax
had a more complicated life cycle inside humans, and spent far longer in the liver, the parasite's vulnerability to drugs differed from that of
P. falciparum.
“There is no obvious replacement for chloroquine,” researchers said.
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“We are in a crisis,” declared WHO's parasitic disease expert Tore Godal. “The situation is truly alarming.”
Only one alternative drug remained. For over two thousand years Chinese herbalists had treated malaria with extracts from the sweet wormwood, or
Artemisia annua,
plantâcalled qinghao in Chinese. The plant's chemicals had long been used to bring down fevers. In 1972 Chinese scientists succeeded in isolating the responsible chemical in qinghao, giving it the name qinghaosu (or, alternatively, arteether and artemether). In the 1980s, as they witnessed the rapid rise of drug resistance throughout the malarial world, WHO and the Walter Reed Army Institute of Research teamed up to conduct studies of the drug. And in 1994, with much fanfare, WHO announced completion of successful field trials of the drug in Vietnam.
Artemisia annua,
plantâcalled qinghao in Chinese. The plant's chemicals had long been used to bring down fevers. In 1972 Chinese scientists succeeded in isolating the responsible chemical in qinghao, giving it the name qinghaosu (or, alternatively, arteether and artemether). In the 1980s, as they witnessed the rapid rise of drug resistance throughout the malarial world, WHO and the Walter Reed Army Institute of Research teamed up to conduct studies of the drug. And in 1994, with much fanfare, WHO announced completion of successful field trials of the drug in Vietnam.
WHO possessed the patent. And no drug company was interested. Critics wondered why WHO was embarking on such a mammoth project, given that synthesized slightly altered versions of the chemical were in development elsewhere.
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Meanwhile, WHO officials spoke candidly about the need to “protect” the Chinese drug from the social conditions in Southeast Asia that led to the downfalls of chloroquine, halofantrine, mefloquine, quinine, Fansidar, proguanil, and every other antimalarial. But in late 1993 a French traveler picked up a strain of
P. falciparum
in Mali, West Africa, that was resistant to
everything,
including the new Chinese drug. Researchers discovered four strains of
P. falciparum
in Mali that were resistant to qinghaosu, though the drug wasn't widely available in the country.
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P. falciparum
in Mali, West Africa, that was resistant to
everything,
including the new Chinese drug. Researchers discovered four strains of
P. falciparum
in Mali that were resistant to qinghaosu, though the drug wasn't widely available in the country.
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Insiders like Brinkmann and Campbell were skeptical. They had seen the conditions in Asian malarial regions up close, understood how the mosquitoes and parasites spread, and doubted that without strong political will in key countries any drug could be protected.
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