Every day, about 14,000 people worldwide become infected with HIV, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS). In developing countries, where therapies are not readily available, HIV infection is a death sentence.
Of the 3 million deaths attributed to AIDS worldwide in 2001, 2.2 million occurred in Africa1; UNAIDS estimates that in 2002, 3.5 million people in sub-Saharan Africa were newly infected. It is essential that new therapies and preventatives be developed, and that these be made available in clinical trials to populations most at risk. "Right now, the developing world, with the highest HIV burden, needs a vaccine urgently," e-mails Job Bwayo of the Kenya AIDS Vaccine Initiative (KAVI).
While clinical trials with HIV/AIDS drugs or vaccines may be hard to conduct in developed countries, where issues of recruiting and sensitivity to underrepresented minority groups, informed consent, and standard of care can create ethical concerns, similar research and trials in developing nations have additional complexities. Developing nations provide trial researchers with large populations affected with HIV, and social and cultural situations that catalyze HIV's spread. But, conducting trials here is cheaper, and can be completed more quickly than in developed nations.
"HIV/AIDS is affecting people of [the] sub-Saharan region more than any part of the globe," writes Bwayo. "It is therefore appropriate and fair that those affected take part in finding a solution to [the] HIV/AIDS scourge." Bwayo, team leader of KAVI, University of Nairobi, is involved in HIV vaccine clinical trials. The International AIDS Vaccine Initiative (IAVI) in New York sponsors KAVI. IAVI has spent about $4 million (US) for early-stage vaccine clinical trials in developing countries.
Researchers who sponsor, organize, or carry out such trials note numerous problems, including: the absence of a healthcare infrastructure, various definitions of informed consent, decisions about whether illnesses or infections resulting from the drug regimen should be treated, and concerns about giving participants information that may stigmatize them. And sometimes, a researcher sitting in a comfortable office in New York or London may not realize what the physician in the field faces in the midst of a raging epidemic.
"How do we get buy-in from the South?" ponders IAVI president Seth Berkley, referring to developing countries in the Southern Hemisphere. "Obviously, the ethical principles are, in a way, the same anywhere in the world.... The implementation of those principles is based on the local situation."
Courtesy of Ashraf Grimwood
One challenge to these vaccine trials is the standard-of-care definition, says Ashraf Grimwood, a physician who directs the South African HIV Vaccine Action Campaign in Cape Town, South Africa. Grimwood notes that such a definition is pertinent at the initial HIV screening of a potential trial participant. If HIV positive, says Grimwood, that person needs access to healthcare infrastructure. "What happens if none exists?" he asks. Thus, this problem may limit where a clinical trial can be carried out, especially if there is no ability to build infrastructure, Grimwood explains.
NO MORE HELICOPTERS Previously, clinical trials conducted in areas with no healthcare infrastructure were called "helicopter research," says Arthur Ammann, president of Global Strategies for HIV Prevention, an AIDS advocacy organization in San Rafael, Calif. They "come in, drop drugs, [and] when [the] study is done, [they] helicopter everything out .... We've got to provide more of the infrastructure as part of the cost of doing the study." It's an issue of justice, he says: "We have to return something to people in the developing countries almost as a privilege of doing these studies."
Sarah Rowland-Jones, coordinator of the Oxford Centre for Tropical Medicine at Oxford University, UK, says these countries no longer want these drops. She works with African and Asian countries on HIV vaccine trials "specifically linked to technology transfer, capacity building." Rowland-Jones' work is funded by the Wellcome Trust, which supports training of local technical people, helping them to go to the United Kingdom to become research fellows or attain PhDs, and then supporting their work when they return home.
But for National Institutes of Health grantees, it's another story. The NIH now gives the country hosting the trial 8% of the grant's cost for overhead; it provided nothing a few years ago. Wendy Baldwin, who recently left the NIH as its extramural research director, said before leaving, "We are not considering any change to this policy." Remarks Ammann, "I think that needs to increase."
In building the infrastructure, the standard of care for patients must also be considered. If a breakthrough (HIV infection) occurs, say Ammann and Grimwood, the person should be treated. Says Ammann: "Because we are doing the study in a developing country, because it could be done faster, more economically, we should provide the people with combination [antiretroviral therapy] and CD4+ monitoring," which assays the numbers of immune CD4+ T cells. These cell numbers drop as the infection progresses. Grimwood, however, disagrees with Ammann over who should supply the treatment. "Is it [the] research team, sponsors, the government? Legally speaking, it should be the government .... What happens 10, 15, 20 years after the cessation ... of the study? There should be provisions made that these people will be given the best therapies available at the time, which may mean antiretroviral therapies."
Courtesy of Bill and Melinda Gates Foundation
Family Health International (FHI) of Research Triangle Park, NC, has posttrial plans for its upcoming study on the effectiveness of the antiretroviral drug tenofovir as a preventative when given in daily doses to healthy people who, by their behaviors, risk HIV infection. The study sites still need to be chosen. FHI is working with the Bill & Melinda Gates Foundation of Seattle, the study's funder, and Gilead Sciences, the drug's manufacturer. "Gilead has agreed to develop a global access plan to make the drug available in resource-poor countries if the study shows tenofovir to be effective at preventing HIV transmission," says Helene Gayle, director of HIV/AIDS & TB at the Gates Foundation. "Given the urgent need to increase access to prevention interventions, if this proves successful, the foundation is committed to working with FHI, Gilead, and other partners to secure access to tenofovir as broadly as possible."
DEFINING INFORMED CONSENT Lack of infrastructure is only one ethical issue. Informed consent is another. "Here," notes Berkley, "we believe in individual informed consent. In other cultures, there are other consents." Among them are the free consent of women, the male partner's consent, and perhaps the concurrence of the community's local leader. To solve questions of cultural differences, Oxford University in the last year set up "a separate research committee to handle the problems of overseas studies," says Rowland-Jones. The committee includes people who work in and come from those countries, she says.
The countries, too, must have a stake. "It's important we work in sites where the local government will be supportive of an HIV protection program," says Kate MacQueen, a project investigator at FHI. Grimwood explains that the role and participation of the local community need to be unraveled.
Local mores could have a profound effect on individuals in clinical trials. The Nuffield Council on Bioethics report2 relates the story of a woman who did not want to be tested for HIV to prevent mother-to-child transmission before she could participate in a clinical trial. She was afraid of the social opprobrium that would follow if she tested HIV-positive. "What happens once a trial comes to an end?" asks Grimwood, who ticks off social problems associated with an HIV-positive diagnosis: "stigma, discrimination, social harm, [and lack of] access to travel, ... insurance, ... international employment."
Grimwood's South African HIV Vaccine Action Campaign is preparing a position paper for 2004 that will outline standards of care from an ethical and human rights perspective. The Nuffield Council published a large book of recommendations.2 In the United States, the National Bioethics Advisory Commission in Bethesda, Md., also produced a report on ethics of clinical trials in developing countries.3
But would everyone follow these guidelines? One re-searcher, who requested anonymity, says that a recent NIH grant study committee did not seem to understand that a foreign government needs to approve clinical research in its country and that permits are needed to carry samples out of the country.
No matter what the ethical hurdles may be, HIV/AIDS clinical research will continue in developing countries. As Bwayo says, "The many benefits of testing a vaccine in the developing world outweigh the harm caused by HIV/AIDS."
Myrna E. Watanabe is a freelance writer in Patterson, NY.
1. See www.avert.org/aafrica.htm.
2. Nuffield Council on Bioethics, "The ethics of research related to healthcare in developing countries," 2002, available online at www.nuffieldbioethics.org/publications/pp_0000000013.asp.
3. "Ethical and policy issues in international research: Clinical trials in developing countries," Bethesda, Md.: National Bioethics Advisory Commission, 2001, available online at www.georgetown.edu/research/nrcbl/nbac/pubs.html.