Important note: Information in this article was accurate in July 2000. The state of the art may have changed since the publication date.The Queen Saovabha Memorial Institute in Bangkok is best known to tourists for its snake farm. People watch in fascination as poisonous venom is extracted from cobras, vipers, and kraits at daily "milking" sessions. The venom goes into snake-bite antidotes which are distributed throughout Thailand.
Less than 100 yards away, in a quiet corner of the institute's grounds, the Thai Red Cross Program on AIDS occupies a modest suite of offices in an unremarkable two-story building. You could say that the program staff is developing another sort of "antidote." They are exploring the question of how to provide the best possible treatment to HIV-positive residents of a country that has minuscule resources compared with financial superpowers like the US.
Some of the answers they are proposing could have significant benefits for millions of people worldwide. Yet most tourists wander by the program site without more than a glance.
Praphan Phanuphak, MD, PhD, a Thai physician and medical professor, has headed the Program on AIDS since its inception in 1989. Phanuphak, an immunologist, was uniquely qualified for the job--he had encountered AIDS for the first time while studying medicine in the US and had drawn on that experience to treat some of Thailand's first AIDS cases in the mid-1980s.
His knowledge accumulated as the number of AIDS cases rose in his country during the next several years. He helped establish an inpatient ward and outpatient clinic for HIV-positive people at Bangkok's Chulalongkorn Hospital, where he continues to maintain a caseload of HIV-positive patients. While aggressive AIDS education has dramatically reduced transmission rates, the estimated number of HIV-infected Thais is approaching one million, which means that Thailand will need strong leadership on HIV treatment for many years to come.
Phanuphak has guided the Thai Red Cross Program on AIDS into an important role in the treatment arena. In his determination to maximize Thailand's limited resources, he has helped generate concrete strategies and practices that hold tremendous promise for other resource-challenged nations. Phanuphak, a member of JIAPAC's Editorial Advisory Board, recently discussed his work with the JIAPAC.
Phanuphak is understandably proud of the HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, which established Thailand's first clinical trials center in 1996. The Thai Red Cross partnered with Australia's National Centre in HIV Epidemiology and Clinical Research and The Netherlands' National AIDS Therapy Evaluation Centre to create HIV-NAT, which has staged several clinical trials since its inception.
An early benchmark for HIV-NAT was an audit of a study by Bristol-Myers Squibb in 1997. The same year, HIV-NAT made its first presentation of trial results at an international AIDS conference in Manila. Since then, HIV-NAT studies have been featured at numerous conferences in Europe, Asia, and the United States.
"This is a successful clinical trial center set up outside of the developed world," stressed Phanuphak, who serves as a codirector of HIV-NAT. While earning the trust of industry and the research community has been one of HIV-NAT's biggest achievements, earning the trust of the Thai people has been equally important.
HIV-NAT's relationship to the Thai Red Cross Program on AIDS bestows invaluable credibility. The Thai Red Cross, an affiliate of the International Red Cross since 1921, is widely trusted by Thais to minister to a range of public health needs. The Red Cross works closely with both the government and the royal family. (Thailand is a constitutional monarchy whose royal family provides strong leadership even though the monarchy does not hold official political power.) Queen Sirikit, in fact, is the President of the Thai Red Cross, and Crown Princess Sirinthorn is the Vice President.
The actions of Crown Princess Sirinthorn's sister, Princess Soamsawali, send a strong message about the royal family's perspective on the AIDS epidemic. An ardent supporter of the Program on AIDS, Princess Soamsawali typically marks World AIDS Day by both making public appearances and spending private time with HIV-positive clinic patients. She also helped spearhead a Thai Red Cross campaign that raises funds to provide zidovudine (ZDV) to pregnant women in a bid to reduce perinatal HIV transmission.
Several Thai clinical trials had preceded the inception of HIV-NAT, including a 1990 ZDV trial that was the country's first antiretroviral study. But with no central organization, the clinical trials effort lacked cohesiveness. HIV-NAT has provided more than a central organization; the structure of the partnership enables the Bangkok-based staff to capitalize on the resources of the Australian and Dutch partners. Phanuphak's two HIV-NAT Co-Directors, David Cooper, MD, DSc, and Joep Lange, MD, PhD, are, respectively, Director of Australia's National Centre in HIV Epidemiology and Clinical Research and Chief Scientific Advisor of the International Antiviral Therapy Evaluation Center. Cooper and Lange, whose home organizations are well known to the pharmaceutical industry, have used their connections to establish an ongoing dialogue with pharmaceutical companies about clinical trial prospects in Thailand.
While Phanuphak is proud that HIV-NAT has earned the international community's respect for its ability to produce reliable trial results, he cares far more about the tangible results for his patients and other HIV-positive Thais. Several of the HIV-NAT trials have delivered double nucleosides into the bodies of trial participants who otherwise would be unable to acquire these drugs. (The best that many HIV-positive Thai people can hope for is treatment for opportunistic infections, because of antiretrovirals' high cost and the inability of many Thai doctors to administer antiretroviral regimens.)
Furthermore, Phanuphak is hopeful that lessons learned from some of the trials of double nucleosides will eventually benefit the citizens of the vast number of countries where state-of-the-art therapy is hopelessly unaffordable.
"I think the trials involving double nucleosides--probably the only combination many countries can afford--are quite significant," he said. The lon gest running trials, he added, are entering their fourth year, providing HIV-NAT with valuable opportunities to explore the efficacy of lower-priced regimens.
Although these regimens have hardly been abandoned in the West, they are so far from the cutting-edge of treatment that Phanuphak realizes the importance of double nucleoside trials can be overlooked by other researchers. "We try to set up studies that will help local situations, instead of doing ‘ivory tower' trials," he said. "That means our trials are not so sexy."
The trials are so unsexy, in fact, that Phanuphak found himself recently defending HIV-NAT's priorities to a well-known medical journal. The journal, Phanuphak explained, had privately criticized HIV-NAT after receiving a submission that described one of the double-nucleoside trials.
"They said that what we were doing was unethical. We wrote back, ‘Can the West provide better treatment?'" The outcome of the exchange was that the journal, after considering what Phanuphak and others had to say about the trial's relevance, agreed to accept the paper, which is currently scheduled for publication.
Even though research shows that triple combination therapy more effectively counters HIV, Phanuphak explained, he and his colleagues are committed to working on what they believe to be the only hope for many HIV-positive people. "We are proud to be doing something that may be valuable to countries like Mexico and the Philippines," he stressed.
And in the past two years, HIV-NAT has begun studying more complex regimens, including several triple-nucleoside combinations, two nucleosides plus interleukin 2, and nucleoside-based regimens including hydroxyurea, a nonnucleoside, or indinavir plus low-dose ritonavir.
It is hardly new for Phanuphak to be speaking his mind about medical ethics. A few years ago he weighed in emphatically on a ZDV placebo controversy that involved trials in Thailand and other countries with limited resources.
The controversy emerged when some researchers and activists pointed out that placebo trials were still being conducted well after the famed ACTG 076 study had conclusively demonstrated that ZDV could reduce the risk of perinatal transmission. The purpose of the trials in question was not to reconsider the 076 regimen--it was to try to identify a shorter regimen, one that would be more affordable to people in developing countries. While critics recognized the need for such a regimen, they found the use of placebos objectionable, given that ZDV's benefits had been conclusively demonstrated.
In the September 18, 1997, New England Journal of Medicine, representatives of the US-based Public Citizen's Health Research Group wrote, "In June 1994, the World Health Organization (WHO) convened a group in Geneva, Switzerland, to assess the agenda for research on perinatal HIV transmission in the wake of ACTG 076. The group, which included no ethicists, concluded, ‘Placebo-controlled trials offer the best option for a rapid and scientifically valid assessment of alternative antiretroviral drug regimens to prevent [perinatal] transmission of HIV.' This unpublished document has been widely cited as justification for subsequent trials in developing countries. In our view, most of these trials are unethical and will lead to hundreds of preventable HIV infections in infants."
The controversy--and the trials--continued into early 1998, when Phanuphak spelled out his position in the March 19, 1998, New England Journal of Medicine. "Scientifically sound alternatives to placebo-controlled trials exist," he wrote. "The investigators or the sponsors may have to enroll more patients, spend more money, or take more time to perform an equivalency study than a placebo-controlled trial. In my view, they ought to do so rather than to risk the lives of the patients (or their offspring) receiving placebo. This is particularly true of trials involving zidovudine, which has been proved effective in preventing mother-to-child transmission of HIV and which has been accepted as the standard of care in all developed countries."
Phanuphak went on to charge that a trial then underway in Thailand was unethical because it provided placebos instead of ZDV to some of its pregnant test subjects.
Researchers had begun revising most placebo-based ZDV trials about a month before Phanuphak's statement was published--but not because of public pressure. Instead, the use of placebos in the trials was halted because one of those trials yielded data that demonstrated the effectiveness of a shorter ZDV regimen. It was a hollow victory for opponents of the trials, which involved thousands of women in several developing countries--many of these women had already missed the opportunity to reduce their chance of transmitting HIV to their babies.
Phanuphak still spoke bitterly about the Thai placebo trial when he was interviewed for this article. "I do not think the infected mothers who participated were told the full story about 076," he said. What makes the wrongdoing even worse in his eyes is that the Thai Red Cross campaign to purchase ZDV for pregnant women had been in full swing since 1996.
"We have never turned down a request for AZT [ZDV]," Phanuphak said. "But these women were not told they could get AZT. I think that was unethical."
Phanuphak is just as forthright about his position on the phase III AIDSVAX vaccine trial currently under way in Thailand. The first AIDSVAX phase III clinical trial, which began in the US in 1998, is looking at 2500 high-risk individuals, most of them gay men. The affiliated Thai trial, which began in 1999, is designed for 2500 Thais who are considered high-risk because of their history of intravenous drug use. (Thai candidates are being recruited from city-run drug rehabilitation clinics in Bangkok.) Both the American and Thai trials are placebo-controlled.
The US Food and Drug Administration's 1998 decision to approve AIDSVAX for phase III testing was a controversial one because of uncertainty about this vaccine's potential. While some proponents of the trials are optimistic that AIDSVAX will significantly decrease the likelihood of HIV transmission, many do not expect much from AIDSVAX. Others have mixed feelings--with no vaccine candidates at such an advanced stage of development, they reason that further study of AIDSVAX may provide some important clues in the search for an effective HIV vaccine.
Phanuphak's feelings about AIDSVAX are decidedly unmixed. "Why Thailand?" he protests. "Why drug addicts?"
As a scientist, Phanuphak is alarmed by the data that call the vaccine's effectiveness into question. And as an advocate for the Thai people, he is wary of the danger that his country's limited resources may invite exploitation.
"There are scientists from various parts of the world who also agree that this vaccine should not be tested," he said. "If you ask them whether or not they would want to test it in their institution, the answer is no. But when it comes to testing in Thailand, they never come out and say it should not be tested."
Phanuphak is particularly critical of researchers whom he suspects of maintaining their silence out of a desire to protect their own professional interests. "They just behave like good boys," he said. "They do not say anything against [AIDSVAX], because they do not want trouble when it comes their turn to have another vaccine tested in Thailand. I do not think that is fair. If you know the truth, you should say it."
Once again, Phanuphak speaks as if he is far more preoccupied with protecting the health of vulnerable people than with scoring points in a debate with his peers. He worries that both the potentially low efficacy of AIDSVAX and the use of a placebo control group spell trouble for trial participants. "We may even be exposing these volunteers to higher risk, because they may think they are superman," he said, referring to the possibility that overly confident trial participants might take fewer precautions against HIV than they otherwise would.
Phanuphak maintained a lonely course during his government's discussion about whether to permit the AIDSVAX manufacturer, VaxGen, to conduct the phase III clinical trial in Thailand. His status as a member of the Thai Ministry of Public Health committee that evaluates such trials gave him ample opportunity to argue against AIDSVAX, but he found few allies.
After being overruled, Phanuphak might have been expected to adopt the protective mechanism of showing token acceptance for the government's decision. Instead, well after the approval of the Thai AIDSVAX trial, Phanuphak has no qualms about publicly stating his views on this controversial issue.
Phanuphak strongly feels that part of his job as a physician is to advocate for what he believes are the best interests of people threatened by the AIDS epidemic. His voice is sorely needed in a nation where public dissent can easily be interpreted as a grave breach of etiquette.
Phanuphak's willingness to speak his mind can be explained to some degree by his professional status. He is a member of the Chulalongkorn University medical faculty, not a government employee, and therefore he does not feel pressure from superiors to toe a party line on AIDS treatment policies.
Even so, he admits, this does not entirely account for his candor. Other Thais in similarly immune positions typically choose to avoid controversy as much as possible. Asked to venture an explanation for his notably different style, he showed a reticence to speak about himself in personal terms, simply observing with a wry grin, "I am not a typical Asian."
While Phanuphak may not be inclined to discuss the forces that have shaped his perspective on practicing medicine, his motivation for speaking out is obvious. Whenever he mentions HIV-positive people in need of help, a note of urgency enters his voice.
"Talking to my patients and to their families makes me realize the difficulty they are facing," he said. "Kids are turned away from school because their parents are infected with HIV. Surgeons are refusing to operate on HIV-positive people. Some HIV-positive women are forced to get abortions. I have hundreds of thousands of stories. These are my patients--I need to do something."
Phanuphak's strategy for attempting to right many of the day-to-day wrongs is typical of his unshowy nature. Rather than aggressively confronting people, "I try to help by writing letters." A letter to a school principal, for example, might persuade the school to re-examine its AIDS-phobic admission policy.
Instead of merely trying to remedy problems, Phanuphak also looks for opportunities to suggest systemic improvements. For example, when Crown Princess Sirinthorn persuaded Chulalongkorn Hospital to eliminate its high overhead charge for already-expensive HIV medications, Phanuphak realized that he might be able to capitalize on Chulalongkorn Hospital's example. He wrote letters to other hospitals proposing that they follow suit by reducing the overhead on their HIV medications.
More than 10 hospitals agreed to the plan, typically lowering the overhead charge for HIV medications from the 12 to 15 percent range to 3 to 5 percent. Eager to show his appreciation, Phanuphak responded by writing to the Minister of Health praising the hospitals that responded.
While writing letters might seem like small potatoes to anyone familiar with the dramatic policy showdowns that characterize the American healthcare arena, the fact remains that Phanuphak's letters get results. And he writes quite a few of them. "This is the thing I love to do," he said.
From Phanuphak's perspective, the tremendous success story of Thailand's HIV prevention education campaign has a down side. "Right now, our policy-makers think AIDS treatment is very expensive compared to prevention, so they are not willing to invest in treatment," he said.
While Phanuphak agrees that the Thai government has needed to make HIV prevention education the top priority in order to contain the epidemic as much as possible, he charges that policy-makers have become too set in their ways. "I would like the government to have a more open mind," he said. "The country needs to consider more seriously how we are going to handle those who are sick. We cannot just say the antiretrovirals are unaffordable."
Phanuphak asserts that a major component of this problem is the government's skepticism about the cost-effectiveness of antiretroviral therapy. "I want people to come to Thailand to show that administering antiretrovirals is cost-effective," he said. "The government does not believe Western data because of the difference in the standard of living."
The current international push to make drugs more affordable to poorer countries gives Phanuphak a sense of hope. In the next year or two, he predicts, lower drug prices will entice the Thai government into making a tangible financial commitment to a policy that will make antiretroviral regimens much more widely available.
When that day comes, do not expect to find Phanuphak resting on his laurels. The HIV-NAT experience to date may very well provide a preview of what is to come in the years ahead. Because most developing countries will continue to lag far behind in the expensive foot race for effective drug regimens, HIV-NAT will have a role to play in investigating affordable regimens well into the future. Unfortunately, there will probably also still be a need for Phanuphak's role as a protector of the interests of the world's more vulnerable citizens. One can only hope that he will be joined by more physicians who agree that to remain silent when faced with healthcare inequalities is against medical ethics, not to mention the most basic human ethics.
Double-nucleoside trials might seem like the other end of the HIV treatment spectrum to people familiar with the most advanced Western standards of care. But any clinic sophisticated enough to administer double nucleosides is light-years ahead of what is truly the far end of the HIV treatment spectrum in Thailand--rural refugee health programs like the one run by Cynthia Maung, MD, in northwest Thailand.
The Mae Tao Clinic lies four kilometers east of the border with Myanmar (still widely referred to as Burma, its name until 1989), on the main road that leads from the Burmese border town of Mya Wa Di to the Thai town of Mae Sot. Every year, thousands of Burmese people take that route into Thailand, many entering illegally in their desperation to find work.
An unpaved lane leads from the main road to the Mae Tao Clinic, which Maung founded in 1989. An American or European visitor who enters the lane for the first time might have the impression of entering a farm--a cluster of haphazardly constructed outbuildings sprawls up ahead. But it turns out that these are not outbuildings. These are the clinic's facilities, housed in several small concrete and wooden structures that are sturdier than they appear.
It is hard to believe that this institution saw 19,471 visits in 1998. The accomplishment is even more remarkable given the size of the permanent staff--in 1998, it consisted of three physicians, including Maung, and 22 healthcare workers. (Visiting physicians and medical students also lend some assistance.) The clinic provides a staggering array of services, including inpatient and outpatient medical treatment, maternal child health programs, eye care clinics, infant nutrition and immunization programs, and mobile medical services across the border, in areas too politically unstable to support permanent clinics.
The Mae Tao Clinic sees two or three AIDS patients every month, most commonly treating them for diarrhea, gastrointestinal ailments, pneumonia, and skin infections. Maung's observation is that her HIV-positive patients generally progress from HIV infection to an AIDS diagnosis within two years and rarely live for longer than six months after that.
It is a story that is all too common in many of the world's poorest populations. Antiretroviral treatments are so far out of reach that Maung's patients do not even think about them. Merely getting to the clinic to seek treatment for opportunistic infections is an accomplishment.
Maung provided a sense of perspective on refugee health care standards by describing the local malaria problem. "Many people around here die of malaria, even though they know they can get free malaria medicine at the clinic," she said. "They do not come in because they cannot get transportation, or because the factory owners and farm owners will not allow them to miss work."
The Mae Tao Clinic does offer something that clinics in developed countries generally do not. Patients who have no place else to go can stay with the physicians and other staff who live on the clinic grounds. When this writer visited the Mae Tao Clinic in late 1999, one resident was an HIV-positive widow who had probably contracted the virus when she was raped by three Thai men.
Recognizing the importance of prevention education, the Mae Tao clinic talks to patients about how to protect themselves from HIV and disseminates HIV information in its public education programs. Unfortunately, Maung points out, education will not help women who are encouraged or forced to participate in risky behavior. Economic crisis, she says, drives many refugee women into the sex industry, where they are often at the mercy of pimps and clients who do not want them to use condoms.
The plight of the Burmese refugees painfully illustrates the inescapable link between healthcare and politics. The withdrawal of British colonial rule from Burma after World War II was followed by a period of political tension that culminated in a military coup in 1962. The military government set the once-prosperous Burma down the road to economic ruin, while at the same time violently repressing opposition to its reign. However, it could not extinguish the spirit of resistance constantly fueled by human rights abuse and economic hardship, and in 1988 this spirit emerged in the form of massive peaceful protests by Burmese people demanding democracy.
As many as 10,000 people may have been killed in the military's brutal response to the protests, and thousands more fled to nearby countries to protect their lives. Maung, a participant in the protests, was among those who fled. When she founded the Mae Tao Clinic the following year, she envisioned it as a short-term venture because she was hopeful that the political situation in Burma would improve.
But the military has refused to loosen its grip, even after ceding to public pressure and holding multi-party elections in 1990. (The country's leadership simply ignored the pro-democracy results.) Since then, the regime has continued to rule by brute force. And Burmese people, driven by both fear of the military and by extreme poverty, have continued to flee.
Asked how she feels about practicing medicine under these circumstances, Maung's grave response was that it is far better than working in Burma. "Here we can do a lot more, even with limited resources and a stressful situation," she said. "We have medicine, we can train more people, and we can provide public education."
Cynthia Maung, MD, can be contacted at (telephone) 66-55-533644; or at (e-mail) win7@loxinfo.co.th; or at (mailing address) Mae Tao Clinic, P.O. Box 67, Mae Sot, Tak 63110, Thailand.
Kelly Safreed Harmon is a Chicago-based writer and editor (safreed@enteract.com).
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