MALARIA: Two decades of research in Vietnam

24 August 2010.
The Wellcome Trust Vietnam Major Overseas Programme is a flourishing clinical research unit embedded in the Hospital of Tropical Diseases in Ho Chi Minh City. Its groundbreaking work on malaria, typhoid, avian flu and other major infectious diseases in Vietnam have given it an outstanding international reputation, and it collaborates with research institutions throughout Vietnam, Asia and the rest of the world.However, as Professor Tran Tinh Hien, Vice Director of the Programme explains, just 20 years ago the environment was very different.
On 30 April 1975, Tran Tinh Hien, then a young medical intern working at Cho Quan Hospital in Saigon, looked up to see hundreds of US helicopters filling the sky above the city. The Vietnam war was over. The Americans were retreating, and Saigon had fallen to the North Vietnamese army.
The next day, an eerie silence enveloped Saigon. It was a stark contrast to the constant background sounds of war - bombs, gunfire and jets and helicopters passing overhead - that had been part of his daily life for as long as he could remember. "Suddenly everything stopped. Everything disappeared. There were no more guns, only the silence," he recalls.
Professor Tran Tinh Hien, Vice Director of the Wellcome Trust Vietnam Major Overseas Programme. Credit: Oxford University Clinical Research Unit
The end of the war meant the severance of South Vietnamese ties with America, making it hard for Professor Hien and his colleagues to access medical information and supplies from the West. The problem was compounded by the global embargo that followed Vietnam's invasion of Cambodia in 1979.
Now totally isolated from the rest of the world, Professor Hien and colleagues found themselves trying to deliver a medical service in a war-torn developing country. They resorted to unusual methods to compensate for their severely restricted access to clinical and scientific developments in the rest of the world.
Looking for answers
"After 1975 we didn't have any source of information," he says. "So sometimes, if someone managed to bring one or two articles or books from abroad, we used to copy them by hand. I remember copying an article on cerebral malaria from the 'Transactions of the Royal Society of Tropical Medicine and Hygiene'. And one friend of mine, a doctor, hand-copied a book on liver disease, two or three hundred pages, by hand." They also memorised textbooks and journals by heart.
Main gateway to the Hospital for Tropical Diseases. Credit: Mads Monsen
To keep up to date with medical developments in the wider world, Professor Hien took a considerable personal risk by illicitly tuning into foreign radio stations. "At that time, it was illegal to listen to the BBC and foreign radios. But I didn't get caught," he smiles. "I got a very small earphone."
Working in intensive care in Cho Quan Hospital - now the Hospital for Tropical Diseases in the renamed Ho Chi Minh City - Professor Hien saw around 500 patients die from malaria each year. He knew that clinical research into new therapies could save lives, but was frustrated by the lack of resources to conduct such research.
A new treatment for malaria
That changed at the end of the 1980s when, following Vietnam's retreat from Cambodia, the international embargo was lifted, making travel to and from the country easier. He received a visit from an old friend from medical school, pharmacologist Professor Keith Arnold, who had spent the past 20 years teaching medicine in China and working for the Roche Asian Research Foundation in Hong Kong.
Professor Arnold had brought with him an ancient herbal remedy for malaria used by the Chinese, which appeared to have remarkable effects in treating malaria - artemisinin. "At that time we called it qinghaosu, Chinese for 'green leaf'," says Professor Hien.
Artemisia annua (Sweet wormwood), source of artemisinin, used to treat chloroquine-resistant cerebral malaria. Credit: Wellcome Images
"Very few countries knew about it then - only China, Vietnam and Thailand. Keith Arnold wanted to set up a large-scale comparative randomised control trial to test it in China, but the Chinese didn't want to do that. They prefer to just treat 50 or 100 cases and analyse the data. So he came to Vietnam to do it."
Professor Arnold had bought a supply of artemisinin to test in patients, and he and Professor Hien collaborated on a small-scale clinical study - the first to test the efficacy of artemisinin in treating malaria outside China.
Setting priorities
In 1990, Professor Arnold arranged for Professor Nick White, a clinician and researcher working at the Wellcome Trust's research unit in Bangkok (later to become the Thailand Major Overseas Programme), to visit Vietnam and meet Professor Hien, with a view to forging a research collaboration. "Nick White asked what the first priority was, and I said malaria," says Professor Hien, recalling that first, auspicious meeting.
That meeting turned out to be the first step in extending the Trust-funded research programme in Thailand to Vietnam - ultimately establishing what is now the Wellcome Trust Vietnam Major Overseas Programme (MOP). Professor Hien is Vice Director of the programme, a flourishing clinical research unit, embedded in the heart of the Hospital for Tropical Diseases in Ho Chi Minh City. It boasts an outstanding international reputation for clinical research to treat, prevent and diagnose infectious disease.
Over the last two decades, Profs Hien and White worked together to tackle malaria and other pressing local infectious diseases. They examined different forms of artemisinin - suppositories, oral and injected artesunate - in malaria patients in Vietnam, Thailand and elsewhere in South-east Asia. After a series of groundbreaking clinical trials, WHO recommended artemisinin-based combination therapies as first-line treatments of falciparum malaria.
Tackling typhoid
After malaria, typhoid fever was the next priority. In the south of the country, the incidence was very high because the waters of the Mekong river, which flows along the Mekong Delta, are infected with the bacterium. "The Mekong river has many canals, and the people living there used the water for washing, drinking and cooking - everything. Now people are better educated and they boil the water or use clean water from a pump," explains Professor Hien.
Professor Hien's demonstration that the fluoroquinolone class of antibiotic should be used as first-line treatment for typhoid led to that treatment likewise being recommended by WHO. He also sent samples of the Salmonella typhi bacterium to the Wellcome Trust Sanger Institute, so that its genome could be sequenced to help identify the mechanism by which it evolves to become resistant to antibiotics.
The first case of flu
In addition to his work on malaria, Professor Hien is at the forefront of research on the deadly strain of avian flu (AI), H5N1.
He recalls the moment when he first learnt that the flu had spread from north Vietnam to the south, and reached the Hospital for Tropical Diseases.
"It was 2004, the eve of the Lunar New Year, and I was with my wife watching the fireworks on the river bank of Ho Chi Minh City. Jeremy Farrar [Director of the Vietnam MOP] called me to say the sample I took from the eight-year-old girl was positive for H5N1; it is the first positive case in the south, in my hospital. We made preparations for a pandemic - making sure we had enough laboratory equipment to confirm diagnosis - but in the end, fortunately, there wasn't a pandemic."
He was involved in the management of the first human cases of AI in south Vietnam, and gave the first clinical description of the infection - showing that fatal infection is associated with tissue damage due to high viral replication and the inflammatory response to virus - which was published in the 'New England Journal of Medicine' in 2005.
In addition to that work, he has published research papers on dengue, tuberculosis, meningitis, diphtheria, plague, making national and global contributions to these and other tropical diseases.
He believes collaborations are essential for research to flourish in a developing country like Vietnam and to that end works in partnership with other research groups and hospitals locally and internationally, as well as with the Vietnamese government. He has personally been the key figure in ensuring and sustaining the successful international research collaboration between Vietnam and the UK.
Earlier this year, Professor Hien was awarded the 2010 Mackay Medal by the Royal Society of Tropical Medicine and Hygiene (RSTMH) for his outstanding work in infectious diseases in Vietnam for over 20 years.
In the Hospital for Tropical Diseases itself, Professor Hien has gradually built up around him a group of young doctors and nurses fully versed in clinical research, and hopes the next generation of clinicians will continue to carry out research alongside their hospital duties. "I have been involved in clinical research for 25 years. Now we have to train the new generation to continue that."
By Penny Bailey
http://www.wellcome.ac.uk/News/2010/Features/WTX062544.htm