MAE SOT (Thailand) • Dr Aung Pyae Phyo drives his old car at breakneck speed from Mae Sot up the winding road between gently undulating bean and sugar cane fields, now mostly harvested and bare, to the village of Wang Pha, where the Moei River, narrow and deep, marks the Thai-Myanmar border.
The 39-year-old Myanmar national, who studied medicine at Rangoon University, is now working at the Mae Sot-based Shoklo Malaria Research Unit (SMRU) and doing his PhD on drug-resistant malaria. SMRU is a field station of the Faculty of Tropical Medicine of Mahidol University in Bangkok, and is part of the Mahidol-Oxford Tropical Medicine Research Unit (Moru) supported by the United Kingdom-based Wellcome Trust.
On the 25km drive to Wang Pha, where Dr Aung works at its SMRU clinic, he talks non-stop, excited at his work. And, shaking his head, he remembers well the case of the 29-year-old patient who, last Nov 26, visited the clinic from Myanmar.
The man had malaria, a disease caused by parasites transmitted by the female Anopheles mosquito. The parasite in this case was falciparum - the most lethal.
The treatment for malaria is straightforward - a drug called artemisinin which is administered in combination with a partner drug. Artemisinin kills most of the parasites quickly; over a longer period the partner drug mops up what's left of them. This has worked for years, driving down the number of malaria cases.
Globally, there were 214 million new cases of malaria last year, which killed an estimated 438,000 people, mostly little children. Africa accounted for 90 per cent of the deaths, followed by South-east Asia with 7 per cent. Since 2000, deaths from malaria have declined by 85 per cent in South-east Asia.
Nowadays, SMRU's four clinics, strung along the Thailand side of the border, do not get many malaria cases; last year they registered 369.
At risk: Nearly half the world's population - about 3.2 billion people - across the tropics.
Death toll: In 2015, there were roughly 214 million malaria cases and an estimated 438,000 deaths.
Sub-Saharan Africa bears a disproportionately high share of the global malaria burden - with 89 per cent of malaria cases and 90 per cent of malaria deaths last year. South-east Asia came next with 7 per cent of deaths.
Good news: Increased prevention and control has led to a 60 per cent reduction in malaria mortality rates globally since 2000. Deaths from malaria in South-east Asia have declined by 85 per cent. Singapore has been malaria-free since 1981, but there have been cases acquired abroad. In 2014, there were 62 notified cases of malaria, all acquired overseas.
Bad news: Parasite resistance to artemisinin, the core compound of the best available anti-malarial medicines, has been detected in Cambodia, Laos, Myanmar, Thailand and Vietnam. There is no alternative drug available to treat multidrug-resistant malaria.
Previous drug-resistant strains emerged in South-east Asia and spread through South Asia to Africa, killing millions, mostly children. Scientists fear history is repeating itself, and with more rapid human mobility, the multidrug-resistant parasite could spread more rapidly.
But this case - just three months ago - was different. Two oral doses and one injection of an artemisinin/partner drug combination, and then a dose of an old remedy, quinine, failed to remove the parasite from the young man's blood.
He had arrived in the morning. "At dinner that evening he was okay," Dr Aung remembers. "He ate the food. Then just a couple of hours later, he became confused. And then he died."
DANGEROUSLY OFF THE RADAR
Malaria as a life-threatening tropical disease has fallen off the media radar in recent years as other tropical, mosquito-borne diseases such as dengue and Zika have been on the rise.
Zika, in particular, has caught global attention in recent months with the outbreak in Brazil thought to be linked to a rash of microcephaly - or abnormal smallness of the head often related with incomplete brain development - cases among newborns.
Dengue has become a fact of everyday urban life across South and South-east Asia and is bound to get worse as the conditions that the virus thrives on spread - more urbanised environments, greater and more rapid mobility of people, and faster breeding of mosquitoes on a warming planet, meaning more mosquitoes.
Malaria, by contrast, has seen a steady decline. Yet, that masks the deadly booby trap of drug resistance that has been building up and, if it gains ground, could kill millions.
The dreaded multidrug-resistant parasite is spreading in Myanmar and Cambodia, raising red flags among those in the scientific and medical community working in the field. Researchers have found that the resistant parasite has one particular molecule that they call a "marker" and named K13.
If the genome of the parasite were laid out like a map, K13 - a mutation - would be present in one section of it.
In the scientific equivalent of dark clouds building up on the horizon, more and more blood samples from malaria patients and carriers are showing up with K13 markers.
"Before 2008, SMRU had 1 to 2 per cent of blood samples with K13," said Dr Aung. "In 2013, they had 85 per cent."
Additionally, once treatment begins, the doctors time the clearance of the parasite from the bloodstream of an infected person. On the Thai-Myanmar border, they have found it takes longer and longer. Last year, the amount of time it took for the parasite to be cleared from the bloodstream of patients there converged with that for patients in Cambodia, where the drug-resistant parasite had emerged earlier, said Dr Aung.
"In 2012 we thought we would be the same as Cambodia - the cradle of drug-resistant parasites - in five years. But it has taken less time."
A paper published last February in the medical journal Lancet - co-authored by more than 20 researchers and scientists, and funded by the Wellcome Trust, Moru and the Bill and Melinda Gates Foundation - concluded from a study in Myanmar that artemisinin resistance extends across much of the country.
Overall, 39 per cent of 940 samples had a K13 mutation, the study showed. In Homalin, an area in Sagaing region 25km from the Indian border, 21 out of 45 - or 47 per cent - of parasite samples had K13 mutations.
RACE TO ELIMINATE PARASITE
Two drugs are being developed to counter the parasite, and SMRU is helping to test them. But the best estimate is that the drugs will be available in four to five years; they could take even longer to be actually deployed and used. And this is only if all goes according to plan.
"It seems everything is okay," Dr Francois Nosten, 59, head of SMRU, said in an interview at his office in Mae Sot. "You see there is no case of malaria in the clinic, and you think everything is fine. But what history tells us is that when this parasite becomes resistant, then sooner or later, the number of patients is going to increase again.
"We are in a race, because the only thing we are pretty sure of is if the parasite is too resistant to drugs then patients won't get better, they will continue to transmit the disease, there will be more and more cases, and eventually more and more people will die."
Historically, the malaria parasite's resistance to drugs has always first emerged in South-east Asia and spread to South Asia and on to Africa.
The fear is that this history is repeating itself.
SMRU has started a pilot malaria- elimination programme which involves old-fashioned slogging through mosquito- infested forests, navigating among rebel militias and gaining the trust of remote rural communities.
The programme covers 300,000 people in 1,200 villages across four townships of eastern Myanmar and Karen state. The tactic: Treat the entire population, whether or not they have malaria symptoms.
"The rationale is if you want to stop the spread of resistance and control the programme early on, you have to get rid of the last parasite," said Dr Lorenz von Seidlein, who runs the Targeted Malaria Elimination Programme at Moru in Bangkok, which partners with the SMRU on the border. "No more transmission means no more resistance."
Dr Nosten hopes that by the end of this year it will be clear whether the programme has worked or not - and why - so that it can be replicated elsewhere if it was successful.
But these scientists in the field, who are seeing drug resistance building first-hand, are frustrated at the lack of attention to the looming problem.
"Here we are on the edge of the cliff, but where is the international outrage, where is the political leadership and dynamism?" said Professor Nick White, 64, chairman of Wellcome Trust's tropical medicine research programmes in South-east Asia, and a world authority on malaria.
"It's the third time around," he said, referring to two previous surges of malaria as the parasite developed resistance to earlier drugs. "But I'm not sure we are going to win this one. There isn't enough political interest.
"We can see this looming emergency but until it's around, the newspapers, the politicians, the donors, I'm afraid, unfortunately, international agencies won't react."
What the experts at Moru and SMRU want is "a more concentrated effort", said Dr von Seidlein. "If people would react to what is happening in the field and focus their efforts, go to the sites and try to ramp up control, perhaps you could control it."
In his rudimentary office at the SMRU clinic on the border, where Myanmar workers and families cross the river into Thailand in the hundreds and thousands every day, Dr Aung was straightforward.
He logged into his computer and pulled up the data on the patient who died last November. The lines on the graph showed clearly how the parasite was almost unaffected by the treatment. He shook his head again.
"If we have more cases like this, we are doomed," he said.
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