It’s not quite 8 am in Mae Sot, Thailand, and Francois Nosten’s team is loading up trucks with medical supplies bound for clinics and Burmese refugee camps along the Thai-Myanmar border.
“We’re in a bit of a rush,” says Francois Nosten MD, PhD, from his wood-paneled office in Mae Sot. The French-born, former-Médecins Sans Frontières doctor has run this Mahidol Oxford University Research post—known as the Shoklo Malaria Research Unit (SMRU)—since 1986.
Although malaria deaths in the region have decreased from 10% to less than 1% in the past 30 years, his team is in a race against time. They have moved into Myanmar to eliminate an emerging and worrisome drug resistant parasite in the Karen (Kayin) state before it spreads west.
Fearing that the resistant malaria will reach Africa, Nosten and team are among those scientists who are scrambling to stop it while they still can. Drug resistance to artemisinin has been steadily increasing in Southeast Asia. Having emerged in Cambodia in 2007, it since has been recorded in Thailand, Vietnam and Myanmar. Artemisinin is the last remaining effective drug against the resistant falciparum strain, and there are no suitable replacements yet.
In a $5-million pilot project in the Karen region funded by the Global Fund and the Gates Foundation, Nosten’s team is giving artemisinin, along with two other drugs, to entire villages of people whether or not they have malaria symptoms. Known as mass drug administration (MDA), this malaria control and elimination tactic has long been used in the field, though rarely with any major, long-term efficacy.
Yet within the last few years, MDA as a means to eliminate malaria has reemerged as a potentially viable intervention.
This week, Nosten and other experts are presenting data as WHO meets to revise its current position on malaria and MDA.
“We’re hoping to prevent the catastrophic resurgence of untreatable malaria,” says Chris Plowe, MD, MPH, president of the American Society for Tropical Medicine and Hygiene and director of the University of Maryland's new Institute for Global Health. He and his wife, Myaing Myaing Nyunt, MD, PhD, MPH, are also launching an MDA project this year in 12 locations throughout Myanmar.
MDA projects since the 1940s have a history of mixed results. Engaging the community to make sure enough of the population receives the drugs, as well as limiting new malaria cases after the project finishes is key, says Jimee Hwang, MD, a clinician and epidemiologist at the CDC’s Malaria Branch who works with the Malaria Elimination Initiative at the University of California at San Francisco (UCSF).
While Nosten’s 3-decade legacy of field research and strong community ties create a solid foundation for the effort, it’s unclear if MDA will be able to be scaled up on a national level in Myanmar or elsewhere.
“Every time you have a success and a new drug, people tend to be complacent,” says Laurent Réina, PhD, director of the government funded Singapore Immunology Network at the Agency for Science, Technology, and Research. “That’s when people forget the urgency to treat the disease and the parasite comes back.”
Even successful models of MDA can’t be entirely replicated from one locale to the next, as what works in one community may not in another. “Malaria is just complicated,” says Ingrid Chen, PhD, a research colleague of Hwang’s at UCSF’s Malaria Elimination Initiative. “We have no recipe in any given place to get rid of the disease.”
Nosten is starting almost from scratch, epidemiologically speaking. Up until this point, the Karen state lacked reliable census data and malaria prevalence information. Much of rural Myanmar remains a relative wilderness, lacking roads, cell phones and electricity, following decades of military rule and civil conflict.
Since July 2014, Nosten’s team has been using geographic mapping systems to determine where approximately 250,000 people live and how many of them have malaria. Because many migrants in the Karen region move back and forth to Thailand, keeping track of population and disease prevalence is difficult.
“It’s kind of like orchestrating a big symphony,” says Daniel Parker, PhD, an anthropologist who has supervised a team of mappers for Nosten’s malaria elimination project since May 2014. Often with no more than a backpack—and sometimes a motorbike—Parker and colleagues have traversed thousands of miles throughout the Karen state, creating population and epidemiology maps.
Moving from village to village, they’re in the process of setting up 800 malaria testing and treatment centers. Sometimes private homes double as centers; other times a new building is constructed. Parker’s team personally delivers rapid diagnostic tests (RDTs) and artemisinin combination drugs. Smart phones are also distributed where cell networks exist for the rapid collection of data from each post.
Working with hundreds of paid community health workers throughout the region, Parker and a group of Karen locals—some who have worked for Nosten for years—train regional health care workers to test for malaria using rapid diagnostic tests and more sensitive polymerase chain reaction assays (PCRs).
Though PCRs require more blood than rapid diagnostic tests, they can detect malaria with fewer parasites; specifically, asymptomatic cases. This matters in the region, where, in some areas, the majority of malaria infections are asymptomatic. Though the PCR results are read using a machine located at the Mae Sot headquarters, the near-real time data exchange is used to monitor each post’s malaria activity.
If 40 percent or more of a village tests positive for malaria via PCR—and 20 percent of those with the falciparum parasite—then everyone in the village is eligible for mass treatment, sick or not. This threshold was determined by mathematical modeling.
So far, Nosten’s team has established 400 centers and started drug treatment in about 2,000 people living in 11 villages.
“Everyone is awaiting the results of the MDA trials being conduced by Francois and the Mahidol Oxford Research Unit,” says Hwang. Working with the CDC and the Malaria Elimination Initiative, Hwang authored a Cochrane review in 2013 analyzing 32 past mass drug administration projects.
“It wasn’t that long ago that the malaria community really didn’t believe that elimination could be done,” says Hwang.
Perhaps the best example of an MDA success story is on Vanatau’s island of Aneitym. In 1991, all 718 residents received mass drug regimens for both falciparum and vivax strains, along with bed nets. Aside from a vivax outbreak in 2002, the island has maintained a strong community commitment and remained malaria-free for over two decades.
Aneitym’s case is an unusual one, benefitting from its geographic isolation and small size.
“If you’re in a landlocked village with a constant influx of infected people, it’s going to be a huge challenge,” says Hwang.
In the management of malaria, the WHO is moving “towards elimination” as the strategy in the greater Mekong region, says Pascal Ringwald, MD, PhD, who heads the malaria drug resistance and containment unit for WHO. Understanding how well it works in the field is crucial to future projects. “If you start to press the button on MDA you need to go to the end,” he says. “How many years do you need to maintain MDA to reach the end?”
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The ride to Wang Pa, Nosten’s border clinic, is about 20 minutes from Mae Sot. Farms cover most of the land, and Myanmar’s nearby mountain ranges are hazy in the distance. Wang Pa sits at the bank of the Thye Moei River, which divides Thailand from Myanmar. Migrants frequently cross between the two countries.
The WHO’s MDA meeting doesn’t concern Nosten too much; he’s more focused on the urgency of his team’s work in the field.
“Something has to be done,” he says. “We know what will happen if we do nothing. It’s happened twice before, with the drugs chloroquine and Fansidar. And in those cases, resistance from Southeast Asia reaches Africa and millions of children die.”
Yet Nosten’s project has a long way to go. The rainy season lasts from May to October, making travel nearly impossible. There’s also the matter of making sure eligible villagers complete 3 doses of artemisinin when they’re supposed to.
To manage this, Nosten’s organization plans to set up a moving caravan. Workers will camp out and supervise drug treatment in one village, before moving on to the next.
“Malaria resistance is a serious global threat that needs quick action,” says Ibon Villelabeitia Jaureguizar, media specialist at the Global Fund, which has committed $1.4 million to Nosten’s elimination project. “If resistance were to reach India or sub-Saharan Africa, where most malaria cases occur, the public health consequences could be disastrous.”
Nosten is acutely aware of this possibility. In February 2015, Mahidol researchers published cases of resistant malaria on the western borders of Myanmar in The Lancet Infectious Diseases.
“It’s literally knocking on the door of India,” Nosten says.
If resistance reaches India or Bangladesh, it may be too late to stop the spread of resistance. With a combined population of over 1.4 billion, those countries’ public health systems aren’t strong enough to track, treat and eliminate drug-resistant strains.
“The parasite is very smart,” says Réina, alluding to the fact that during the 20th century, malaria evolved its way around every drug used to treat it. Drug-resistant malaria not only spreads through movement of infected people, including migrant workers, but also independently arises through genetic mutation.
Artemisinin resistance is only the most recent example, but the drug is the last effective one available while others are being developed. The next generation of treatment could be 10 years away before it’s approved and available.
“If resistance can pop up anywhere, all you can do is eliminate it everywhere,” says Plowe who, along with Myaing Myaing Nyunt, is independently validating Nosten’s work throughout Myanmar at the request of the Gates Foundation. In addition to MDA, Plowe will test a new PCR technique that doesn’t require a large volume of blood or that the sample be kept cold. If it works, this could help make the intervention a more viable option.
After the conclusions from the WHO meetings are finalized in the coming months, new recommendations will be published.
As for Nosten, he’ll keep taking malaria treatment directly to clinics, camps and remote mountainous regions otherwise untouched by modern medicine. “Resistance doesn’t remain in Asia. It spreads,” he says. “How we deal with resistance is important for the rest of the world.”