From the aProgram in Medical Ethics, Center for AIDS Prevention Studies and Division of General Internal Medicine, USA
bGlobal Health Sciences, AIDS Research Institute and the Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, USA
cRopes and Gray LLP, and the Department of Internal Medicine, Yale Medical School, New Haven, Connecticut, USA.
Received 14 June, 2006
Revised 25 October, 2006
Accepted 10 November, 2006
Better HIV prevention is urgently needed in resource-poor countries, which suffer the vast majority of new HIV cases. Increasingly, HIV prevention trials in resource-poor countries are expected to guarantee that antiretroviral therapy (ART) is available to participants who develop HIV infection during the trial [1–6]. HIV prevention trials have been halted because access to ART has not been assured to seroconverters. Although it may be debated as to whether the provision of ART to seroconverters is morally obligatory or merely praiseworthy, a recent article declared ‘Existing social and political realities have now rendered provision of access to care a critical factor in a trial's ability to go forward’ .
There are ethical as well as pragmatic reasons for this expectation of ART for seroconverters. Physicians are trained to help individuals in need, by providing treatment for medical problems that they identify. During a research study, participants come to a study office, receive medical tests and interventions, and interact with study staff. Researchers, knowing that care may not be available elsewhere, have the impulse to help. The more direct, frequent, and prolonged the researcher–participant interaction during an HIV prevention trial, the stronger the researcher's sense of responsibility to provide ART to participants who seroconvert during the study. Moreover, participants in a clinical trial deserve reasonable benefits in return for their participation as a matter of reciprocal justice .
In the light of intense political pressures to provide ART to serocoverters , the discussion should now shift from whether prevention trials must guarantee ART for seroconverters to how to do so. ART should be provided to seroconverters in ways that ameliorate rather than exacerbate disparities in the access to ART in the host country.
If prevention trial participants receive treatment that is not available to others in the country, health disparities in the host country would grow. Large gaps in health resources between rich and poor nations violate the principle of justice and evoke moral outrage [9,10]. Promising ART to only a few individuals widens disparities within a resource-poor country and would therefore be unjust . Furthermore, providing ART only to participants in prevention trials is unfair to individuals who participated in previous HIV research. Ideally, the assurance of ART to seroconverters in a prevention trial should be done in a way that also improves access to ART for others in the country. Justice, as well as beneficence, needs to be considered.
One option is for trials to provide funding to national treatment programmes for participants who seroconvert during the trial to receive ART [2,12]. Funding should be consistent with World Health Organization recommendations for 5 years of ART up to second-line therapy . Working within the national programme, the prevention trial can try to improve the quality of ART services for all HIV-infected individuals in the area, not just for those who participated in the trial.
In some countries, access to the national programme is suboptimal because of long travel times and waits. Some prevention trials have a staff member to help the participant enroll in the government programmes or provide transportation for seroconverters to government clinics. Providing such individual attention only to trial participants also creates disparities between neighbors who face similar problems with transportation or waiting. Prevention trials instead can designate funds to make government HIV programmes more accessible within the area where trial participants are recruited. For example, an amount of money equivalent to the cost of drugs could be used to increase staff at national ART clinics or improve transportation.
A few resource-poor countries have well-functioning national AIDS programmes that provide broad access to ART. Although the reasons for the prevention trial to provide funds for ART in these countries are not as compelling, researchers and staff should still make in-kind contributions, such as providing some teaching or clinical care at a local hospital or donating computers and laboratory equipment.
Funding for ART requires financial as well as medical planning in the host country. Explicit earmarking of funds can help ensure they are used as intended. Transmitting funds through a trusted organization that will remain in the host country after the prevention trial is completed, such as a medical school, a well-functioning non-governmental organization, or an international relief agency can help ensure accountability.
Who should be responsible for providing ART? Researchers are the public faces of a prevention trial, who are typically targeted when criticism or opposition arises. To date, discussions on providing ART to seroconverters in prevention trials have focused on the responsibilities of researchers. Other stakeholders who have the opportunity and means to provide ART also have important responsibilities.
Governments in resource-poor countries ultimately have a long-term responsibility for providing ART . Governments may, however, lack the resources or will to so do. Prevention researchers can help governments establish infrastructure by helping to write grants to fund ART (including sites that participants from the prevention trial can attend), training host-country healthcare workers, and helping scale up ART.
Research sponsors have more resources than individual researchers to fund ART for seroconverters. The National Institutes of Health, however, does not allow its research funds to be used to purchase ART . It is logically inconsistent to expect researchers to make arrangements for ART for participants who seroconvert during the trial if sponsors do not make funds available. United States government agencies such as the National Institutes of Health and the Centers for Disease Control and Prevention that sponsor prevention trials should try to influence the allocation of funds for the US President's Emergency Plan for AIDS Relief (PEPFAR). PEPFAR will spend US$15 billion over 5 years for HIV prevention, treatment, and care in resource-poor countries , more than any other assistance programme for ART in low-income countries. In addition to designated ‘focus’ countries, which are selected on the basis of the United States’ national interests, the US government should make PEPFAR funds available in all countries that host large prevention or clinical trials sponsored by US government agencies. Such coordination among federal agencies might be a political challenge, but the magnitude of the HIV epidemic requires that bureaucratic obstacles be overcome. Such funding would take advantage of the extensive infrastructure that prevention and clinical trials build. Prevention researchers and host-country governments might, however, regard some goals of PEPFAR funding, such as abstinence-only prevention programmes, as not supported by scientific evidence or as inconsistent with the country's needs and priorities. Host-country governments holding such views will need to address ethical and practical dilemmas: whether or not to accept PEPFAR funds under these conditions, while trying to change them through negotiations with US officials or pressure from international organizations.
Large pharmaceutical companies sponsoring prevention or vaccine studies generally enjoy substantial profit margins and have programmes to assist US patients who cannot afford medications. Similar funding can be provided to resource-poor countries that host industry-sponsored HIV prevention trials, for example by contributing a negotiated amount to the host country's national HIV programme . Promises to sell drugs at the manufacturer's cost may not be enough because ART usually requires drugs from several manufacturers and because the manufacturer's cost may exceed the cost of generic drugs produced in the developing world.
Realistically, these recommendations to improve access to ART can only reduce health disparities, not eliminate them. Difficult dilemmas and trade-offs will persist. Prevention trials might cluster in areas where access to national HIV programmes is feasible. Disparities between more urban and remote areas may, however, be less problematical than disparities among neighbors, because lack of transportation and infrastructure in remote regions provides an ethical as well as a practical distinction.
Another dilemma is that funding for ART for seroconverters may not be feasible in some situations. For example, a country might not have a well-functioning national ART programme. Alternatively, small start-up companies sponsoring innovative prevention trials might lack the means to assure ART to participants who seroconvert. Therefore, requiring prevention trials to guarantee ART might close off important prevention research where effective HIV prevention is most needed. Strong evidence of the efficacy and safety of a new HIV prevention intervention might, however, stimulate new funding commitments. The host-country government and communities may thus decide to allow such trials without firm assurances of ART for seroconverters. Specific arrangements for ART access will depend on the local situation and should be negotiated among the host country government, community groups, researchers, and sponsors before the study begins. For example, a small sponsor may commit to the national HIV programme a percentage of any profits if the product is successful.
In conclusion, the goal of prevention trials is to identify more effective prevention interventions. In addition, the resources and expertise of prevention trials can be leveraged to obtain collateral benefits for both participants and others in the host country. The challenge is to set high expectations for guaranteeing ART to seroconverters in prevention trials, while also enhancing care for other HIV-infected individuals and allowing promising prevention research to proceed.
Sponsorship: This research was partly supported by National Institutes of Health grants MH062246 and U01A146749, by the Greenwall Foundation, and by the Gates Foundation.
M.B.'s firm has clients that conduct HIV prevention studies throughout the world, and he can be called upon to defend the design of these studies against legal and ethical challenges.
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