AIDS research rarely escapes the klieg lights of controversy, but now a whole new set of contentious ethical questions loom over the field as more studies take place in the developing world. The shifting of AIDS scientific work to the developing world, particularly clinical trials of therapies and vaccines, is inevitable because of the changing demographics of the disease; AIDS is increasingly a Third World disease for which solutions must be found and applied to the poorest countries. But many of the lead investigators and organizations in AIDS still come from the West, setting in motion debates about exploitation and equity that are not easily resolved.

Much of the current focus is on vaccine trials, with one of the key questions being the standard for antiretroviral therapy for people in the trials who become infected with HIV. Last year, there was a major controversy about the use of placebos in mother-to-infant transmission trials.

Dean Designate Barry Bloom has been in the thick of the vaccine trials ethics debate as chair of the Vaccine Advisory Committee of the Joint United Nations Programme on HIV/AIDS (UNAIDS). As a major proponent for AIDS vaccine research in and for the developing world, Harvard AIDS Institute Chair Max Essex has also been outspoken.

The issue of antiretroviral therapy comes up in AIDS vaccine trials for several reasons. Any control group is bound to have infected individuals. Much of the current thinking about aids vaccines is that they will work by dampening HIV replication, not by completely blocking infection. Even if a vaccine is effective, it seems likely that some vaccines may eventually need therapy if their immune response is incomplete or wears off. Also, from a pure research perspective, starting someone on treatment right after the first evidence of infection will make it much harder for investigators to assess whether a vaccine is working because the vaccine and early treatment serve, in effect, the same purpose, which is to keep virus levels low.

Taking his cue from language in the World Health Organization's charter and the International Convention on Economic, Social, and Cultural Rights, Bloom has argued for requiring the "highest attainable standard" of care for people in vaccine trials. But there has been sharp criticism of this formulation--particularly from some outspoken AIDS activists and scientists in Brazil--as a dangerous departure from the World Medical Association's Declaration of Helsinki, which set forth guidelines for clinical trials. The Helsinki document says every patient in a clinical trial, including those in the control group, should be given "the best proven" care. The problem with AIDS is that the "best proven" therapy is generally viewed as treatment with so-called drug cocktails that include protease inhibitors. Such therapy is expensive, needs to be monitored closely, and taken for a long time- perhaps the rest of an infected person's life. African health officials have been especially vocal in criticizing the "best proven" care standard. They have said it is impractical in their AIDS-ravaged countries and very possibly harmful because it might undermine aids vaccine research in the Third World, where an effective vaccine is needed most.

To give researchers, ethicists, and some AIDS activists a chance to air their opinions, UNAIDS organized a series of meetings around the world last year. That effort culminated with a June gathering in Geneva in which Bloom played a key role. At the end of the intense, sometimes acrimonious two-day meeting, the group apparently (news accounts and other accounts of the meeting had a Rashomon quality and varied tremendously) agreed to a procedural recommendation that countries participating in trials should set the standard of care but that standard should not be anything less than the "highest practicable attainable," which was very close to Bloom's formulation. Some have said this compromise is a laudable attempt to end dated Western paternalism in clinical trials while others have criticized it as a dodge around taking a firm stand to provide everyone with combination antiretroviral drug therapy.

Essex argues that there are both ethical and practical reasons to push for AIDS research in the developing world. He notes that for vaccine trials, the relatively low rates of infection in the West are a major disadvantage: "If you are working with some rate of infection that is southern African-like, which means that one-third of all pregnant women are infected, does it make any sense just from the point of view of trial design to test your vaccine in the West? The answer is "no.'"

Essex has also staked out the position that any experimental vaccine must be as immunologically relevant as possible to whatever kind of virus is circulating in the test population. Thus a vaccine being tested among intravenous drug users in Thailand should be based on the subtype of HIV circulating in that population, which happens to be HIV1-E. "You should test their virus," he insists. This creates problems, however, for vaccine developers who understandably have an eye on a vaccine that will work in the United States, where HIV1-B is the prevailing subtype. Vaccine developers may have found a way out of this problem by cleverly manipulating vaccines so they are combinations of a number of different antigen subtypes. When Don Francis, SD '79, and his South San Francisco-based company, VaxGen, got Food and Drug Administration permission in June to do the first large-scale testing of an AIDS vaccine, Francis said the Thai part of the trial would be testing a vaccine with both HIV1-B and HIV1-E antigens. Meanwhile, there is now some active debate on just how immunologically meaningful HIV subtypes will turn out to be in vaccine development. Some researchers believe, for example, that a HIV1-B vaccine will work fine against HIV1-C, which is the subtype of the virus found in India and much of Africa.

Another ethical quandary lurking in AIDS vaccine research is the obligation to make the product of the trial, if it is successful, "reasonably available." Thus sponsors, researchers, and companies have to provide a working vaccine to the country where it was tested. But if a company tests a vaccine in India, is it ethically obligated to make the vaccine available to the whole country, to a particular state, or just to the people who live in the cities or villages where the trial was conducted? And what does make "reasonably available" mean? At the meeting in Geneva, the ethicists agreed that vague promises weren't enough and that researchers must have definite plans about making a working vaccine available before a trial starts. Francis says VaxGen has given the Thai government a written promise to make any proven vaccine as inexpensive as possible in Thailand and to take steps to manufacture it in the country. Peter Lurie, a researcher with Public Citizen's Health Research Group, the Washington, D.C.-based watchdog organization, and an outspoken critic of the design of the mother- to-infant transmission trials that included placebos, says developing countries need to drive hard bargains and get specific guarantees: "These are rich companies. You have to get the best deal possible."

- Peter Wehrwein