Should Western Research Ethics Apply to Fighting AIDS in Africa?
In Uganda, some scientists say they must 'bend the rules' to find appropriate treatments
By BURTON BOLLAG
Rakai District, Uganda
For the past 12 years, Michael Kakooza, a 64-year-old farmer, has regularly welcomed health workers into his neat,
mud-walled house here, nestled among banana trees and coffee plants, to take samples of body fluids including blood, urine,
and saliva from him and his wife. Like most of their neighbors in this rural area, a two-hour drive from the Ugandan capital, the
Kakoozas are volunteers in a research project, led by the Johns Hopkins University, aimed at controlling the spread of AIDS.
Mr. Kakooza says he volunteered for the study hoping that it would hasten the discovery of treatments for a disease that was
killing his friends and relatives. When people started wasting away and dying here in the early 1980's, everyone was terrified,
and many of those who were well rejected those who got ill. "Some sick people took poison to kill themselves," he recalls.
Even though the researchers have not yet found a cure or a preventive vaccine, Mr. Kakooza says, they "have helped people
understand this disease and how to protect themselves.
"Now we are living free from fear."
While the American and Ugandan scientists carrying out a series of AIDS studies here appear to have gained the gratitude of
subjects like Mr. Kakooza, they have drawn the scorn of some other scientists, who accuse the researchers of disregarding
their subjects' welfare. The result is a painful reconsideration of the ethics of medical research in poor countries.
The controversy started when the Johns Hopkins-led team published its latest study in The New England Journal of
Medicine in March. The debate may erupt again next week at the world's largest annual meeting on the disease, the 13th
International AIDS Conference, held this year in Durban, South Africa.
The perspective is often very different here on the front lines of the battle against AIDS in Uganda, one of the countries hardest
hit by the epidemic, than it is in offices in Boston and Washington.
Some in the field say the criticism of the Rakai study and others like it may prevent poor countries from getting crucial help in
fighting the epidemic. "The more this goes on, the less people are going to be willing to carry out research," says Laura Guay, a Johns Hopkins researcher on mother-to-child-transmission of the virus that causes AIDS. She has worked in Uganda for 12
As scientists confront the realities of doing large studies in developing countries, they have moved toward relaxing some of the internationally recognized ethics standards in human-subject research for the sake of results. At the same time, agreement is growing that countries where the research takes place should play a greater role in determining what is proper, and should have a stronger claim to any benefits from the research. One company running a vaccine trial in Thailand, for example, promised to help that country produce the vaccine at affordable prices if the trial is a success.
In the Rakai study, researchers monitored 415 couples in which only one partner was initially infected with the human immunodeficiency virus. Participants were counseled on safe sex, and condoms were distributed free. Those who tested positive for H.I.V. were urged to inform their spouses. But citing the Uganda government's confidentiality policy, the researchers themselves did not inform the AIDS-free partners. After 30 months, 90 of the healthy spouses -- about 22 percent
-- had become infected. The 415 "discordant couples" were part of a study of 15,217 Rakai residents, and the researchers said they didn't know the couples' identities until after the research phase was over.
In an editorial in the same issue of the journal in which the study was published, the executive editor, Marcia Angell, accused the researchers of using Ugandans as guinea pigs in a study that would not have been allowed in the United States. "For up to
30 months," she wrote, "several hundred people with H.I.V. infection were observed but not treated."
Some critics, including a New York-based group called Citizens for Responsible Care & Research, went further, comparing
the Rakai study to the infamous Tuskegee trials.
The Rakai study was approved by scientific and ethics boards in Uganda and the United States. After the controversy broke out, UNAIDS, the United Nations office that coordinates the international response to the epidemic, found no ethics violations.
The debate, meanwhile, has become bitterly divisive. "Many of the critics are armchair academics who are pulling ethical theories out of the air and have not been to the field," says Nelson Sewankambo, the principal Ugandan investigator on the Rakai study and dean of the faculty of medicine of Makerere University, Uganda's largest institution of higher education.
In their defense, the study's researchers point out that the use of multiple antiretroviral drugs, often called "combination therapy," which has turned AIDS from a killer to a manageable disease in developed countries, was proved to be effective only in the summer of 1998, four months before the end of the Rakai study. Besides, the researchers note, with many African countries spending as little as $10 per person annually on health care, combination therapy, which costs thousands of dollars, is out of the question, for all but a few.
Some AIDS activists are nonetheless calling for the study's authors to be banned from this year's AIDS conference. Ronald
Gray, a professor of population and family health sciences at Johns Hopkins and one of those researchers, says the attacks were unexpected. "We have been vilified, compared to the Nazi doctors. This has been a very disappointing experience."
Researchers in Uganda say the critics don't appreciate the urgency of the fight against the epidemic in the field. Uganda, one of the African countries hardest hit in the early years of the epidemic, has been recognized for its success in lowering the infection rate. According to UNAIDS, in the early 1990's an estimated 14 percent of the country's adult population was infected with
Uganda has brought that number down to about 8 percent today.
To be sure, the reduction in the infection rate is due in part to the AIDS-related deaths of about two million people from Uganda's population of 20 million. But many observers attribute the success in reducing new infections to prevention efforts supported by President Yoweri Museveni.
In Kampala, the capital, John Rwomushana works late in the walled compound that houses the Uganda AIDS Commission, the country's top AIDS policy body, where he is director of policy, research, and development. The pathologist is well aware of the responsibilities, under international ethics guidelines, that medical researchers have toward participants in their studies.
Subjects who fall ill have the right to the best treatment known, even if the illness was not caused by the research.
The commission approved the Rakai study as well as other trials, knowing that they fell short of the ethics standards: While researchers have provided treatment for the opportunistic infections that plague AIDS sufferers, they do not provide expensive antiretroviral drugs. "This is bending the rules," concedes Mr. Rwomushana, "but it is not being unethical." Any African country that required Western researchers to provide the costly AIDS therapies would only scare off scientists and slow down research, he says.
Even the usefulness of the Rakai results is a matter of heated debate. The study found that the single most important factor in determining whether an uninfected spouse would contract H.I.V. was the amount of the virus that the infected partner carried in his or her body, a factor known as the viral load. Dr. Angell argues that this finding is of little help to Uganda, because the antiretroviral drugs, which sharply reduce viral load, are too expensive for Africa. But others disagree.
David Kihumuro Apuuli, director general of the Uganda AIDS Commission, says that as Uganda maps its strategy against
AIDS, officials now know that developing a way to reduce viral load, even short of a cure, could be important in slowing the spread of AIDS.
Meanwhile, the debate over research in developing countries is resulting in a second look at international medical-ethics guidelines. It was horror over the medical experiments carried out by Nazi doctors that led to the adoption of an international code of medical ethics, known as the Declaration of Helsinki, by the World Medical Association in 1964. The declaration says
every patient enrolled in a medical study should get "the best proven diagnostic and therapeutic method."
But AIDS is raising new questions. Is it either feasible or fair to provide expensive AIDS treatment to the participants in a study, but not to other people who need it? And who will pay for continuing treatment after the study ends?
A working group established by the World Medical Association has just issued proposed changes to the Declaration of
Helsinki. In any medical study, every patient -- including those in a control group, if there is one -- would be assured of proven effective, prophylactic, diagnostic, and therapeutic methods. That means subjects in a trial would still have a right to the best locally available medical care, but not necessarily the best in the world.
In May, UNAIDS published ethics guidelines for trials of vaccines against AIDS. No vaccine yet exists, and only two large-scale vaccine trials are under way, one in the United States and one in Thailand. Other potentially life-saving vaccines, however, are in the pipeline.
In the vaccine research, too, the most controversial issue was what level of care researchers owe trial participants who become infected with H.I.V. The U.N. guideline requires treatment, with "the ideal being to provide the best proven therapy and the minimum to provide the highest level of care attainable in the host country."
Nancy Dickey, a professor of family medicine at Texas A&M University, is chairwoman of the working group revising the Declaration of Helsinki. She says it has been very difficult to find the right language. "How do you write principles for people
who want to do good research," she asks, "and at the same time take into account differences in standards of care in, say,
Philadelphia and Central Africa?"
Some people think you should not try. The Washington-based advocacy group Public Citizen has opposed the easing of ethics standards. Peter Lurie, a physician with the organization's Health Research Group, says the proposed revisions would "water down the declaration."
"Our solution," he says, "is to step up enforcement of the declaration."
Sophia Mukasa Monico, a lawyer and a leading Ugandan advocate for people with AIDS, accepts the idea that researchers
need only provide subjects with the best level of medical care available in Uganda. "I don't want well-intentioned persons from
the North to impose conditions that, in fact, will prevent the conduct of research that we urgently need," she says.
But at a recent meeting, medical-ethics committees in Thailand surprised observers by taking the opposite point of view and opposing any lowering of the level-of-care requirement.
The ethics debate over AIDS research exploded into the open three years ago, when Dr. Lurie and Sidney M. Wolfe, director
of the Health Research Group, denounced as unethical 15 AIDS studies, most of which were in Africa and were financed by
the U.S. government. The research was intended to find cheap and simple treatments to prevent infected mothers from passing
on H.I.V. to their newborn babies.
Dr. Lurie and Dr. Wolfe criticized the trials because they involved giving some women a new drug to be tested and other women a placebo. The use of a placebo was unethical, the physicians said, because a good treatment already existed: The drug AZT, which cost $1,000 per pregnancy.
In February 1998, when research in Thailand showed that a shorter regimen of AZT was also effective, government agencies ordered an end to the use of placebos.
At the time, Dr. Guay, an assistant professor of pediatric and infectious diseases at Johns Hopkins, had just begun a trial of two new treatments in Kampala. Three months into the trial, the researchers were ordered to discontinue the placebo. They were furious, she says. "We all said it makes no scientific sense. What we needed to do was compare the two new treatments to what was the standard in Uganda -- no treatment at all."
Dr. Guay argues that dropping the placebos pushed back the researchers' work by six months, delaying the development of a simple and cheap treatment for Uganda.
By good fortune, one of the drugs they tested, nevirapine, turned out to be very effective. This spring, Uganda began a large
project intended to provide the cheap -- less than $4 per pregnancy -- and simple-to-use drug to all pregnant women.
Reidar Lie, a professor of ethics at the University of Bergen, in Norway, who has written on AIDS, says the placebo dispute illustrates the epidemic's dilemmas. "I'm sympathetic to the argument that you should not do trials in the Third World that couldn't be done at home," he says. "But doing the mother-to-child-transmission trials without a placebo produces results that are, for statistical reasons, not so useful to the developing countries."
In Kampala, Rose Bossa, 26, sits with her two young sons on a large straw mat on the concrete floor of the clinic where Ms.
Guay works. Ms. Bossa says she volunteered to participate in the drug trial during her second pregnancy, knowing that she might receive a placebo. The chance that she might be given a drug that would help her newborn son was inducement enough.
That boy, now 2½ years old, is healthy. Both Ms. Bossa and her 4-year-old son, however, are infected with H.I.V. "He is often sick, but they give him medicines here," she says with a smile.
"Up to now," Ms. Bossa says, "I'm feeling OK, but I try to plan for the future. I've asked relatives to look after my children when I'm gone."