This story is part of a partnership between MedPage Today and VICE News.
A two-hour drive outside Cambodia's bustling capital of Phnom Penh, at a market with dozens of tiny storefronts open to the tropical heat, Rung Bunkok's patients patiently sit on red plastic chairs waiting to see him. Bunkok holds a secondary nursing degree, but he's as close to a doctor as anyone here is likely to find.
Po Theam, a 29-year-old logger who lives about 12 miles away, arrives on the back of his brother's motorcycle. He says he tested positive for malaria last month, but he isn't sure what drugs he took — and he stopped taking them as soon as he felt better.
Now, however, his skin glistens as he tells Bunkok that he is "hot in [his] body" and dizzy.
When the malaria test comes back positive, Theam appears unconcerned that he was just diagnosed with a parasitic disease that killed nearly half a million people around the world last year. Instead, he simply hands over about a day's wages to pay for the visit, test, and more drugs.
"It's not expensive as long as it cures my disease," he says before hopping onto his brother's motorcycle and pulling away.
The World Health Organization (WHO) announced this month that more than half the countries where malaria still occurs have reduced their cases by at least 75 percent since 2000. There have also been promising recent studies about a potential malaria vaccine and the use of gene-editing technologies on mosquitos that would keep them from transmitting the disease.
But not everyone is celebrating. Malaria experts in southeast Asia fear history is about to repeat itself.
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With only a few hundred reported malaria deaths in southeast Asia last year, the region is not usually the first place people associate with the disease. But it is the so-called "cradle" of drug-resistant malaria. When the parasite has previously mutated and rendered medicines all but useless — subsequently killing millions of people around the world — it has started here.
Inside a border clinic in Mae Sot, Thailand, dozens of patients and their families sit on the long wooden benches of the Wang Pha Clinic just up the hill from a river crossing where a small motorized canoe ferries patients from Myanmar for 250 baht — about $7 — per person.
"They come for fever," says Aung Pyae Phyo, who works at the Wang Pha clinic. "None of them worry about malaria."
Rung Bunkok tests 29-year-old logger Po Theam for malaria in Steung Market in Cambodia. (Photo by Sydney Lupkin/MedPage Today/VICE News)
Although the Wang Pha clinic was established to treat the disease, it hasn't had a malaria case in several days. Instead, patients tend to come with other ailments or to visit the maternity ward.
"When no one is worried, that's when we have to worry," says Dr. Francois Nosten, director of the Shoklo Malaria Research Unit, which includes Wang Pha and four other clinics along the Thai-Myanmar border.
Nosten founded the unit in 1986, when malaria was the leading cause of death and disease in the region.
"If you go to a place, and you see nobody in the hospital with malaria, then of course it's difficult to worry about," Nosten says. "It doesn't mean everything is settled and solved. We know from the past that it's not going to stay that way."
Today, the parasite that causes malaria is showing signs of resistance to drugs once essentially guaranteed to defeat the disease when correctly administered. This is similar to what health workers witnessed in southeast Asia in the late 1950s and again in the 1980s with two other malaria drugs.
Resistance to the drug chloroquine emerged in 1957, causing the drug to take longer and longer to eliminate the parasite from patients' bodies until, eventually, it didn't work at all, Nosten says. By the 1970s, the drug-resistant parasite had traveled to Africa, but Nosten says doctors there kept using chloroquine into the mid-2000s even though it didn't work any better than treating patients with nothing at all. (It's unclear why they did so, though theories include corruption and an unwillingness to spend money on new drugs.)
People cross from Myanmar into Thailand to visit the Wang Pha Clinic. (Photo by Sydney Lupkin/MedPage Today/VICE News)
In Africa, malaria is much more transmittable because mosquitos are more aggressive, live longer, and bite more people, Nosten says. Without effective drugs, millions of people died, most of whom were children under 5 years old. Now Nosten and other malaria health workers are seeing resistance in southeast Asia to the current drug of choice, artemisinin.
"We have fewer malaria cases than ever, but the remaining malaria cases are extremely difficult to treat," says Dr. Aung Pyae Phyo of the Wang Pha clinic. "There's increasing resistance to all remaining malaria drugs, including artemisinin."
When the parasite resisted drugs in the past, there was always another drug waiting in the wings. But Nosten says he fears artemisinin combination therapies — known as ACTs, they involve treating a patient with artemisinin along with one other antimalarial drug — could become useless long before a new drug is available to replace them.
"This time," Nosten says, "we don't have a backup."
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Malaria is a disease caused by a parasite that spreads from human to mosquito and back again.
Mosquitos aren't born with malaria. Instead, the females, who need meals of blood to lay their eggs, contract the parasite when they bite an infected human. The parasite multiplies in the mosquito's gut and spreads to its salivary gland, making it possible for the parasite to exit into a human's bloodstream the next time the mosquito attacks a human.
"You wonder how on earth that parasite has maintained itself having such [a] complex lifecycle," says Arjen Dondorp, deputy director of the Mahidol Oxford Research Unit in Bangkok. "But malaria has been with us as long as humans have existed."
When a human is bitten by an infected mosquito, only about 10 parasites enter the human's bloodstream. They make a beeline for the liver, where they spend a portion of their life cycle, and within about two weeks, there can be 100 million parasites in the host, causing flu-like symptoms.
The parasites then re-enter the bloodstream, invading red blood cells and continuing to multiply. By the time someone has more than 10 billion parasites — just a few weeks after the initial mosquito bite — the illness can be fatal. That's in part because normal red blood cells are able to squeeze through tiny capillaries to carry oxygen throughout the body, but red blood cells carrying malaria parasites are unable to do so because they're too big and unyielding.
"It gets stuck like something gets stuck in the sink of your bathroom," Nosten said. "Malaria does that in many small parts of the brain. In the end, it switches off the brain completely. It also does that to the lungs, liver, and kidneys."
Drug resistance can develop when the parasite is exposed to levels of a medication insufficient to kill it — either a dose that is too low or a course of the medicine that has been halted too soon. Instead of killing the parasite, an ineffective amount of a drug can effectively teach the stronger parasites to thwart that drug, leading them to evolve and infect another person.
"The real problem now is that [Plasmodium] falciparum malaria is almost untreatable," Dondorp says, referring to one of the most dangerous species of malaria parasites.
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Chiara Andolina stands in front of dozens of plastic trays filled with tiny white tadpole-like mosquito larvae.
"They're like fetuses — they're pretty cute," she says before moving to a room where a few hundred mosquitoes are feeding on human blood in a contraption made up of interconnected Cup Noodles containers.
Andolina, who works at the Shoklo Malaria Research Unit in Mae Sot, is one of many researchers at various organizations studying the parasite in an effort to help develop new treatments and prevention methods.
But research takes time. The three drugs currently being studied — OZ 439, spiroindolones, and imidazolopiperazine — are still at least four years away from being ready for use by the general population, Dondorp says. For now, health providers are treating patients with ACT, but as artemisinin resistance spreads, scientists may try other stopgaps, like triple drug therapies.
Thim Eng Sreang tests people for malaria on the outskirts of the Memot Rubber Plantation in Cambodia. (Photo by Sydney Lupkin/MedPage Today/VICE News)
"Treatment options are getting very limited because of the increasing problem of concomitant partner drug resistance," Dondorp says, meaning there's resistance to artemisinin as well as occasional resistance to the drugs used in combination with it.
To prevent the Plasmodium falciparum species of malaria parasite that's often fatal in Africa, a vaccine called RTS,S is undergoing clinical trials. In a study published earlier this year in the medical journal the Lancet, researchers at the Imperial School of London predicted the new vaccine will save thousands of lives in its first 15 years.
"The parasite is still ahead, but it's better than nothing," Nosten says.
The Bill and Melinda Gates Foundation have contributed $93 million for malaria elimination in the countries around the Mekong River, and it hopes to eliminate Plasmodium falciparum there by 2020 and all malaria strains by 2030.
Nosten, however, says neither the WHO nor local governments worry enough about the disease, in part because malaria doesn't incite the same fear in decision makers as other diseases.
"When the TV shows people dying of Ebola, everybody gets scared," Nosten says. "With malaria, it's different. We don't have people dying all over the place… it's below the radar screen, below what we can see. Still those parasites evolve, and one day will re-emerge. And when they re-emerge, there will be catastrophic consequences."
Follow Sydney Lupkin on Twitter: @slupkin